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who appointed as the responsible person on this issue ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

Mr. Saito, MR. SAITO

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

On the purpose of teleconference, how many topics were to be discussed?

fsjf0226

fsjf0226_p0, fsjf0226_p1

3 topics, 3

EXHIBIT 102 FDA Conference Call on July 31, 2002 TPNA Personnel: Wendell Cheatham, M.D. Vice President, of Medial and Scientific Affairs Michael Elisseou, Ph.D., Director, Product Development and Planning Janet Haskins, Manager, Regulatory Affairs Ingrid Hoos, Director, Regulatory Affairs John Page, M.D., Director Product Safety Alfonso Perez, M.D., Sr. Director of Clinical Development Mary Ramstack, Sr. Manager, Product Development and Planning Claire Thom, Pharm.D., Vice President, Research and Development FDA Personnel: David Orloff, M.D., Division Director Bob Misbin, M.D., Medical Review Jena Weber, Project Manager Jeri El-Hage, Toxicology Team Leader Dr. Orloff stated that the purpose of the teleconference was to discuss three topics related to additional nonclinical data recently received by the Divisica: 1. a proposal to monitor bladder toxicity in long term clinical trials 2. the Division's inclination to rescind the written request for pediatric exclusivity 3. a labeling change that would reflect possible relatedness of tumor formation to drug mechanism of action Dr. Orloff stated_that the Division is considering additional data that indicates that the bladder tumors seen in the rat carcinogenicity study maybe a mixed PPAR class effect. He further noted that when pioglitazone was approved by the Division, the significance of these findings was tempered by the data presented by Takeda relating the tumor formation to the presence of calculi. He further indicated thatHowever_,-as-the Division has recently reviewed data for similar compounds, the additional--Additional data suggests that those tumors may have beenbe- drug related. Dr. Perez inquired about the Division's definition of long term trials and stated that urine cytology was preformed in two trials that were over one year in duration. Dr. Misbin noted that the Division considers long-term as a trial longer than one-year and inquired about what type of testing was conducted in the titals mentioned by Dr. Perez. Dr. Perez noted that urine cytology was performed for any subject presenting hematuria at any time Confidential - Subject to Protective Order TAK-RAMSTM-00235775 Produced in MDL on 09/18/12 Source: https://www.indup5367.0000nts.ucsf.edu/docs/fsjf0226 during the study. If a subject had atypical urothelial cells, they were referred for kidney, ureter and/or bladder examinations. Dr. Misbin stated that the cytology performed in TPNA's phase III program, did not provide much information, and he suggested that we might possibly be able to screen for an antigen. Dr. El-Hage, then noted that the Division has received data from another company that implied that pioglitazone was a tumor promoter. When questioned about this data, Dr. El-Hage noted that renal and bladder transitional cell tumors were reported using a promoter-model. Dr. Cheatham then inquired if it would be possible to share this data with TPNA. The Division noted that it is not possible to disclose the study specifically and referred TPNA to published data. Dr. El-Hage noted that she would be willing to speak with TPNA's toxicologist once he returned to the office. Further, the Division is no longer convinced that the bladder tumor formation in the rats is a result of the presence of calculi, but timay be related to a dual PPAR agonist effect. Dr. Cheatham noted that pioglitazone is a PPAR gamma agonist. Dr. Misbin responded that the Division is starting to consider pioglitazone to be a PPAR gamma and alplia agonist. Dr.-Misbin then noted that with monitoring in a long-term trial, we would be able to lay the issue relating to bladder tumor formation to rest. He further requested that we consider a class effect labeling. He-further-Dr. Misbin requested thatrequested that we submit in 3-4 weeks the following information: Proposal for a monitoring or surveillance program for long-term clinical trials. Post-marketing data relating to urinary tract findings. Proposal for a label language change, Suggested changes to our consent forms. He also further stated that we should be prepared for the likelihood that the written request to conduct the pediatric study would be rescinded. Dr. Misbin finished the conversation by inquiring about the timing of the efficacy supplement for the three combination trials. He stated that there are safety issues regarding the 45 mg dose that he would like to consider for the next labeling change. TPNA committed to submitting that supplement as soon as possible and ended the conference call.: Confidential - Subject to Protective Order TAK-RAMSTM-00235776 Produced in MDL on 09/18/12 Source: https://www.indup'5367.00002 ts.ucsf.edu/docs/fsjf0226

basically by whom the current action plan was approved ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

CEO

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the date mentioned at the bottom?

fsjf0226

fsjf0226_p0, fsjf0226_p1

09/18/12

EXHIBIT 102 FDA Conference Call on July 31, 2002 TPNA Personnel: Wendell Cheatham, M.D. Vice President, of Medial and Scientific Affairs Michael Elisseou, Ph.D., Director, Product Development and Planning Janet Haskins, Manager, Regulatory Affairs Ingrid Hoos, Director, Regulatory Affairs John Page, M.D., Director Product Safety Alfonso Perez, M.D., Sr. Director of Clinical Development Mary Ramstack, Sr. Manager, Product Development and Planning Claire Thom, Pharm.D., Vice President, Research and Development FDA Personnel: David Orloff, M.D., Division Director Bob Misbin, M.D., Medical Review Jena Weber, Project Manager Jeri El-Hage, Toxicology Team Leader Dr. Orloff stated that the purpose of the teleconference was to discuss three topics related to additional nonclinical data recently received by the Divisica: 1. a proposal to monitor bladder toxicity in long term clinical trials 2. the Division's inclination to rescind the written request for pediatric exclusivity 3. a labeling change that would reflect possible relatedness of tumor formation to drug mechanism of action Dr. Orloff stated_that the Division is considering additional data that indicates that the bladder tumors seen in the rat carcinogenicity study maybe a mixed PPAR class effect. He further noted that when pioglitazone was approved by the Division, the significance of these findings was tempered by the data presented by Takeda relating the tumor formation to the presence of calculi. He further indicated thatHowever_,-as-the Division has recently reviewed data for similar compounds, the additional--Additional data suggests that those tumors may have beenbe- drug related. Dr. Perez inquired about the Division's definition of long term trials and stated that urine cytology was preformed in two trials that were over one year in duration. Dr. Misbin noted that the Division considers long-term as a trial longer than one-year and inquired about what type of testing was conducted in the titals mentioned by Dr. Perez. Dr. Perez noted that urine cytology was performed for any subject presenting hematuria at any time Confidential - Subject to Protective Order TAK-RAMSTM-00235775 Produced in MDL on 09/18/12 Source: https://www.indup5367.0000nts.ucsf.edu/docs/fsjf0226 during the study. If a subject had atypical urothelial cells, they were referred for kidney, ureter and/or bladder examinations. Dr. Misbin stated that the cytology performed in TPNA's phase III program, did not provide much information, and he suggested that we might possibly be able to screen for an antigen. Dr. El-Hage, then noted that the Division has received data from another company that implied that pioglitazone was a tumor promoter. When questioned about this data, Dr. El-Hage noted that renal and bladder transitional cell tumors were reported using a promoter-model. Dr. Cheatham then inquired if it would be possible to share this data with TPNA. The Division noted that it is not possible to disclose the study specifically and referred TPNA to published data. Dr. El-Hage noted that she would be willing to speak with TPNA's toxicologist once he returned to the office. Further, the Division is no longer convinced that the bladder tumor formation in the rats is a result of the presence of calculi, but timay be related to a dual PPAR agonist effect. Dr. Cheatham noted that pioglitazone is a PPAR gamma agonist. Dr. Misbin responded that the Division is starting to consider pioglitazone to be a PPAR gamma and alplia agonist. Dr.-Misbin then noted that with monitoring in a long-term trial, we would be able to lay the issue relating to bladder tumor formation to rest. He further requested that we consider a class effect labeling. He-further-Dr. Misbin requested thatrequested that we submit in 3-4 weeks the following information: Proposal for a monitoring or surveillance program for long-term clinical trials. Post-marketing data relating to urinary tract findings. Proposal for a label language change, Suggested changes to our consent forms. He also further stated that we should be prepared for the likelihood that the written request to conduct the pediatric study would be rescinded. Dr. Misbin finished the conversation by inquiring about the timing of the efficacy supplement for the three combination trials. He stated that there are safety issues regarding the 45 mg dose that he would like to consider for the next labeling change. TPNA committed to submitting that supplement as soon as possible and ended the conference call.: Confidential - Subject to Protective Order TAK-RAMSTM-00235776 Produced in MDL on 09/18/12 Source: https://www.indup'5367.00002 ts.ucsf.edu/docs/fsjf0226

in which month and date it was reported to CEO ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

AUGUST 6, August 6

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What are shown on the x-axis?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

FULL MONTHS POST LAUNCH, Full Months Post Launch

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what has to be reported to CEO on August 20 (japan time) ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

AN OUTLINE OF THE FDA RESPONSE, an outline of the FDA response

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the percentage of Avandamet scripts from Actos mentioned?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

36%, 36

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what is the name of the policy on Actos issue ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

Takeda basic policy, TAKEDA BASIC POLICY

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is on the horizonal axis of the graph?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

Full Months Post Launch

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

who is the chief leader ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

MR. K SAITO, Mr.K Saito

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the percentage of Nondiabetic patients with prior MI?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

18.8, 18.8%

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

who is the responsible person for TPNA ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

Dr. C Thom

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

what is the name of the organization ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

Actos issue organization, ACTOS ISSUE ORGANIZATION

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

who is the responsible person of TCI ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

MR. K SAITO

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the Handwritten sentence on the top?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

Row-Contract (as of 7/19/99)

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

What is the date mentioned?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

JULY 19, 1999, July 19, 1999

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

who is the first contact person of EuR&D ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

DR. P COLLETT, Dr. P Collett

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

With whom is the discussion being held?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

JIM HARPER, Jim Harper

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

who is the responsible person for EuR&D ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

DR. D ECKLAND, Dr. D Eckland

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the date of randomisation?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

05/11/01, 05-11-01

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

who is the first contact person of TPNA ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

MS. M RAMSTACK, MS. J HASKINS, Ms. M Ramstack ,Ms. J Haskins

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the patient number?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

014

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

What is the Centre number?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

49013

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

who is the first contact person of TCI ?

ymjf0226

ymjf0226_p0, ymjf0226_p1, ymjf0226_p2, ymjf0226_p3, ymjf0226_p4

MR. M MIYAZAKI, Mr. M Miyazaki

Saito 8/12/02 Takeda Basic Policy on Actos Issue Reported to CEO on August 6 Basically the current action plan was approved by CEO Mr. Saito was appointed as the responsible person on this issue An outline of the FDA response has to be reported to CEO on August 20 (Japan time) for approval before submission. August 12 - 13, 2002 1 Confidential - Subject to Protective Order TAK-THOMCL-00019735 Produced in MDL on 09/14/12 Source: https://www.induspo452-00001s.ucsf.edu/docs/ymjf0226 Actos Issue Organization Chief leader : Mr. K Saito Responsible persons - TPNA : Dr. C Thom - EuR&D : Dr. D Eckland - TCI : Mr. K Saito First contact persons - TPNA : Ms. M Ramstack, Ms. J Haskins - EuR&D : Dr. P Collett - TCI : Mr. M Miyazaki August 12 - 13, 2002 2 Confidential - Subject to Protective Order TAK-THOMCL-00019736 Produced in MDL on 09/14/12 Source: Basic Strategy for FDA Response(1) 1. Label change - To make best efforts to keep the current wording for carcinogenicity There is the last option to accept the label change if the FDA requests the same label change for Avandia as well. August 12-13,2002 - 3 Confidential - Subject to Protective Order TAK-THOMCL-00019737 Produced in MDL on 09/14/12 Source: https://www.induso45200003s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(2) 2. Bladder toxicity monitoring - To find a good rationale for not conducting monitoring - To investigate appropriate monitoring methods There is an option to accept the FDA suggestion if this satisfies FDA and allows us to keep the current label wording August 12 - 13, 2002 4 Confidential - Subject to Protective Order TAK-THOMCL-00019738 Produced in MDL on 09/14/12 Source: https://www.indupo452-00004s.ucsf.edu/docs/ymjf0226 Basic Strategy for FDA Response(3) 3. Pediatric exclusivity - To convince the FDA to conduct 508 study There is a option to agree to postpone the 508 study until the FDA concerns are resolved. August 12 - 13, 2002 5 Confidential - Subject to Protective Order TAK-THOMCL-00019739 Produced in MDL on 09/14/12

What is the Reference mentioned here?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

135037-HRT-11, 135037-hrt-11

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

What is the heading of the table?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

what is the total number of drug claims under the title of "summary of litigation risk in the ous territories"?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

5

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what are secondary endpoints ?

fzjf0226

fzjf0226_p0, fzjf0226_p1, fzjf0226_p2, fzjf0226_p3, fzjf0226_p4, fzjf0226_p5, fzjf0226_p6, fzjf0226_p7, fzjf0226_p8, fzjf0226_p9, fzjf0226_p10, fzjf0226_p11, fzjf0226_p12, fzjf0226_p13, fzjf0226_p14, fzjf0226_p15

cardiovascular mortality, CARDIOVASCULAR MORTALITY

PLA-TAK-00053920 PLA-TAK-00053921 Source: :ttps://www.indupt340-00002ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Grow the customer base who differentiate and prefer ACTOS versus Avandia because of the lipid profile by Q3 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Demonstrate significant GLAI Q4'02-Q2'03 Publication lipid differences versus Abstracts Avandia Update slide series Symposia Speaker Training Demonstrate Possible IIT (US) TBD Abstracts improvement in Publication postprandial lipidemia 9/18/2013 Company Confidential 3 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053922 Source: https://www.indupt340-00003ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053923 Source: https://www.indupt340-00004ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Create perception of ACTOS reducing risk of cardiovascular complications starting in 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Demonstrate GLAE Q2'02-Q1'02 Included in symposia improvement in Update slide series SBP/DBP Demonstrate GLAC reduction in C- GLAI Q4'02-Q2'03 Reactive Protein Demonstrate effects GLAI Q4'02-Q2'03 on PAI-1 Demonstrate TL-OPI-516 Q3'03? Publication to be planned prevention of Abstracts to be submitted Secondary MI after Symposia first MI Prevention of PROactive Q3'05 Takeda to submit for Cardiovascular EC-444 label change outcomes Publication to be planned Symposia Focus 9/18/2013 Company Confidential 5 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053924 Source: https://www.indup5340-00005ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Create perception of ACTOS reducing risk of cardiovascular complications starting in 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Show effects in LDL GLAI -Q4'02-Q2'03 Update slides particle size Incorporate into articles on diabetes dyslipidemia Effects on plaque TL-OPI-516 Q3'03? Symposia topic biology/endothelium US IIT - Fronseca TBD Publication Abstract 9/18/2013 Company Confidential 6 Copyright C 2000 Eli Lilly and Company PLA-TAK-00053925 Source: https://www.indup6340-00006ts.ucsf.edu/docs/fzjf0226 PROactive Objective: Demonstrate that pioglitazone reduces total mortality and macrovascular morbidity in high-risk patients with type 2 diabetes mellitus Number of patients: 5,000 Countries: Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Sweden, Switzerland, UK FPV: June 2001 LPV: Q2 2005 Primary Endpoints: All-cause mortality, non-fatal MI, acute coronary syndrome, cardiac intervention, stroke, major leg amputation, bypass surgery, or revascularisation in the leg Secondary Endpoints: Cardiovascular mortality 9/18/2013 Company Confidential 7 Copyright 2000 Eli Lilly and Company PLA-TAK-00053926 Source: https://www.indupe340-00007ts.ucsf.edu/docs/fzjf0226 Clinical Data to Support CV Risk Reduction PROactive 2005 EC 409 EC 410 TL-OPI-503 2004 GLAI EC 404 GLAG 2003 GLAL Evident 2002 2001 9/18/2013 Company Confidential 8 Copyright 2000 Eli Lilly and Company PLA-TAK-00053927 Source: https://www.indup340-00008ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Ensure access and reimbursement of ACTOS in maximize markets Strategic Clinical Study Target Date Action Plan Objective Database Locked Expand European EC 404 Q2'02 Takeda to submit for Label to include EC 405/GLAG label expansion monotherapy Submit abstract in 2003 ADA/EASD/IDF Expand the European PNFP-341 - SU Q2'02 Takeda to submit for label to include 45 mg, PNFP-342 - Met label change Utilize 45 mg EC 409 / GLAP Q3'04-Q3'02 (1 Year) Production forecasts to combination in US EC 410 / GLAQ Q3'04-Q3'02 (1 Year) be modified Expand European PNFP-343 Q2'02 Takeda to submit for Label to include Insulin comb. trial for Q4'04 Q2'04 label change Combination with efficacy and Guidelines/algorithm Insulin European safety-not- developed on yet funded- decreases in suggested insulin? Establish safety in TL-OPI-504 (II-III) Q1'02 Takeda to submit for Class I, II and III CHF TL-OP-520 (I) Q1'03- Q2'03 label modification in Europe Update slide series 9/18/2013 Company Confidential 9 Copyright 2000 Eli Lilly and Company PLA-TAK-00053928 Source: https://www.indupt340-00009ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053929 Source: https://www.indupe340-00070ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Strategic Clinical Study Target Date Action Plan Objective Database Locked Reduction/Removal of TL-OPI-506 Q2'04 Discussions need to the liver monitoring continue with the FDA to requirements establish clear safety milestones Demonstrate lack of TL-OPI-509 ? Publication(s) to be Drug-Drug (Cyclosporine B) planned Interactions TL-OPI-510 Q2'01 Abstracts to be submitted (Theophylline) on each study TL-OPI-511 Q2'01 (Atorvastatin) Adolescent data/use TL-OPI-507 TBD 9/18/2013 Company Confidential 11 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053930 PLA-TAK-00053931 Source: https://www.indup5340-0002ts.ucsf.edu/docs/fzjf0226 Possible Suggested Topics for IITs Blood Pressure effects Onset of Action Metformin VS Actos Mechanism of Action Post-Prandial lipids Weight Management Beta-cell Protection (preclinical studies to support theory) 9/18/2013 Company Confidential 13 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053932 Source: https://www.indup6340-00013ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053933 Source: https://www.indupt340-00094ts.ucsf.edu/docs/fzjf0226 Clinical Experience Programs Program Description Affiliates Investigator Initiated A trial/study initiated by Recommended for all Trials (IITs) investigator(s) not Maximize Affiliates Or study (IIS) affiliated with Lilly Observational Studies A study based on US "Evident" collection of data from patient charts Physician Experience Provide free products Mexico, Canada, Programs (PEPs) for specified time Australia frames to physicians for them to gain experience Post Marketing A study based on Spain Surveillance (PMS) collection of AE data from patient charts 9/18/2013 Company Confidential 15 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053934 Source: https://www.indup340-00095ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053935 Source: https://www.indup6340-00076ts.ucsf.edu/docs/fzjf0226

what is the title of this page?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

objectives and methodology, OBJECTIVES AND METHODOLOGY

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

What is the number of patients ?

fzjf0226

fzjf0226_p0, fzjf0226_p1, fzjf0226_p2, fzjf0226_p3, fzjf0226_p4, fzjf0226_p5, fzjf0226_p6, fzjf0226_p7, fzjf0226_p8, fzjf0226_p9, fzjf0226_p10, fzjf0226_p11, fzjf0226_p12, fzjf0226_p13, fzjf0226_p14, fzjf0226_p15

5,000

PLA-TAK-00053920 PLA-TAK-00053921 Source: :ttps://www.indupt340-00002ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Grow the customer base who differentiate and prefer ACTOS versus Avandia because of the lipid profile by Q3 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Demonstrate significant GLAI Q4'02-Q2'03 Publication lipid differences versus Abstracts Avandia Update slide series Symposia Speaker Training Demonstrate Possible IIT (US) TBD Abstracts improvement in Publication postprandial lipidemia 9/18/2013 Company Confidential 3 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053922 Source: https://www.indupt340-00003ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053923 Source: https://www.indupt340-00004ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Create perception of ACTOS reducing risk of cardiovascular complications starting in 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Demonstrate GLAE Q2'02-Q1'02 Included in symposia improvement in Update slide series SBP/DBP Demonstrate GLAC reduction in C- GLAI Q4'02-Q2'03 Reactive Protein Demonstrate effects GLAI Q4'02-Q2'03 on PAI-1 Demonstrate TL-OPI-516 Q3'03? Publication to be planned prevention of Abstracts to be submitted Secondary MI after Symposia first MI Prevention of PROactive Q3'05 Takeda to submit for Cardiovascular EC-444 label change outcomes Publication to be planned Symposia Focus 9/18/2013 Company Confidential 5 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053924 Source: https://www.indup5340-00005ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Create perception of ACTOS reducing risk of cardiovascular complications starting in 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Show effects in LDL GLAI -Q4'02-Q2'03 Update slides particle size Incorporate into articles on diabetes dyslipidemia Effects on plaque TL-OPI-516 Q3'03? Symposia topic biology/endothelium US IIT - Fronseca TBD Publication Abstract 9/18/2013 Company Confidential 6 Copyright C 2000 Eli Lilly and Company PLA-TAK-00053925 Source: https://www.indup6340-00006ts.ucsf.edu/docs/fzjf0226 PROactive Objective: Demonstrate that pioglitazone reduces total mortality and macrovascular morbidity in high-risk patients with type 2 diabetes mellitus Number of patients: 5,000 Countries: Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Sweden, Switzerland, UK FPV: June 2001 LPV: Q2 2005 Primary Endpoints: All-cause mortality, non-fatal MI, acute coronary syndrome, cardiac intervention, stroke, major leg amputation, bypass surgery, or revascularisation in the leg Secondary Endpoints: Cardiovascular mortality 9/18/2013 Company Confidential 7 Copyright 2000 Eli Lilly and Company PLA-TAK-00053926 Source: https://www.indupe340-00007ts.ucsf.edu/docs/fzjf0226 Clinical Data to Support CV Risk Reduction PROactive 2005 EC 409 EC 410 TL-OPI-503 2004 GLAI EC 404 GLAG 2003 GLAL Evident 2002 2001 9/18/2013 Company Confidential 8 Copyright 2000 Eli Lilly and Company PLA-TAK-00053927 Source: https://www.indup340-00008ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Ensure access and reimbursement of ACTOS in maximize markets Strategic Clinical Study Target Date Action Plan Objective Database Locked Expand European EC 404 Q2'02 Takeda to submit for Label to include EC 405/GLAG label expansion monotherapy Submit abstract in 2003 ADA/EASD/IDF Expand the European PNFP-341 - SU Q2'02 Takeda to submit for label to include 45 mg, PNFP-342 - Met label change Utilize 45 mg EC 409 / GLAP Q3'04-Q3'02 (1 Year) Production forecasts to combination in US EC 410 / GLAQ Q3'04-Q3'02 (1 Year) be modified Expand European PNFP-343 Q2'02 Takeda to submit for Label to include Insulin comb. trial for Q4'04 Q2'04 label change Combination with efficacy and Guidelines/algorithm Insulin European safety-not- developed on yet funded- decreases in suggested insulin? Establish safety in TL-OPI-504 (II-III) Q1'02 Takeda to submit for Class I, II and III CHF TL-OP-520 (I) Q1'03- Q2'03 label modification in Europe Update slide series 9/18/2013 Company Confidential 9 Copyright 2000 Eli Lilly and Company PLA-TAK-00053928 Source: https://www.indupt340-00009ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053929 Source: https://www.indupe340-00070ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Strategic Clinical Study Target Date Action Plan Objective Database Locked Reduction/Removal of TL-OPI-506 Q2'04 Discussions need to the liver monitoring continue with the FDA to requirements establish clear safety milestones Demonstrate lack of TL-OPI-509 ? Publication(s) to be Drug-Drug (Cyclosporine B) planned Interactions TL-OPI-510 Q2'01 Abstracts to be submitted (Theophylline) on each study TL-OPI-511 Q2'01 (Atorvastatin) Adolescent data/use TL-OPI-507 TBD 9/18/2013 Company Confidential 11 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053930 PLA-TAK-00053931 Source: https://www.indup5340-0002ts.ucsf.edu/docs/fzjf0226 Possible Suggested Topics for IITs Blood Pressure effects Onset of Action Metformin VS Actos Mechanism of Action Post-Prandial lipids Weight Management Beta-cell Protection (preclinical studies to support theory) 9/18/2013 Company Confidential 13 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053932 Source: https://www.indup6340-00013ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053933 Source: https://www.indupt340-00094ts.ucsf.edu/docs/fzjf0226 Clinical Experience Programs Program Description Affiliates Investigator Initiated A trial/study initiated by Recommended for all Trials (IITs) investigator(s) not Maximize Affiliates Or study (IIS) affiliated with Lilly Observational Studies A study based on US "Evident" collection of data from patient charts Physician Experience Provide free products Mexico, Canada, Programs (PEPs) for specified time Australia frames to physicians for them to gain experience Post Marketing A study based on Spain Surveillance (PMS) collection of AE data from patient charts 9/18/2013 Company Confidential 15 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053934 Source: https://www.indup340-00095ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053935 Source: https://www.indup6340-00076ts.ucsf.edu/docs/fzjf0226

What is "FPV" ?

fzjf0226

fzjf0226_p0, fzjf0226_p1, fzjf0226_p2, fzjf0226_p3, fzjf0226_p4, fzjf0226_p5, fzjf0226_p6, fzjf0226_p7, fzjf0226_p8, fzjf0226_p9, fzjf0226_p10, fzjf0226_p11, fzjf0226_p12, fzjf0226_p13, fzjf0226_p14, fzjf0226_p15

JUNE 2001, June 2001

PLA-TAK-00053920 PLA-TAK-00053921 Source: :ttps://www.indupt340-00002ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Grow the customer base who differentiate and prefer ACTOS versus Avandia because of the lipid profile by Q3 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Demonstrate significant GLAI Q4'02-Q2'03 Publication lipid differences versus Abstracts Avandia Update slide series Symposia Speaker Training Demonstrate Possible IIT (US) TBD Abstracts improvement in Publication postprandial lipidemia 9/18/2013 Company Confidential 3 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053922 Source: https://www.indupt340-00003ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053923 Source: https://www.indupt340-00004ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Create perception of ACTOS reducing risk of cardiovascular complications starting in 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Demonstrate GLAE Q2'02-Q1'02 Included in symposia improvement in Update slide series SBP/DBP Demonstrate GLAC reduction in C- GLAI Q4'02-Q2'03 Reactive Protein Demonstrate effects GLAI Q4'02-Q2'03 on PAI-1 Demonstrate TL-OPI-516 Q3'03? Publication to be planned prevention of Abstracts to be submitted Secondary MI after Symposia first MI Prevention of PROactive Q3'05 Takeda to submit for Cardiovascular EC-444 label change outcomes Publication to be planned Symposia Focus 9/18/2013 Company Confidential 5 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053924 Source: https://www.indup5340-00005ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Create perception of ACTOS reducing risk of cardiovascular complications starting in 2003 Strategic Clinical Study Target Date Action Plan Objective Database Locked Show effects in LDL GLAI -Q4'02-Q2'03 Update slides particle size Incorporate into articles on diabetes dyslipidemia Effects on plaque TL-OPI-516 Q3'03? Symposia topic biology/endothelium US IIT - Fronseca TBD Publication Abstract 9/18/2013 Company Confidential 6 Copyright C 2000 Eli Lilly and Company PLA-TAK-00053925 Source: https://www.indup6340-00006ts.ucsf.edu/docs/fzjf0226 PROactive Objective: Demonstrate that pioglitazone reduces total mortality and macrovascular morbidity in high-risk patients with type 2 diabetes mellitus Number of patients: 5,000 Countries: Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Sweden, Switzerland, UK FPV: June 2001 LPV: Q2 2005 Primary Endpoints: All-cause mortality, non-fatal MI, acute coronary syndrome, cardiac intervention, stroke, major leg amputation, bypass surgery, or revascularisation in the leg Secondary Endpoints: Cardiovascular mortality 9/18/2013 Company Confidential 7 Copyright 2000 Eli Lilly and Company PLA-TAK-00053926 Source: https://www.indupe340-00007ts.ucsf.edu/docs/fzjf0226 Clinical Data to Support CV Risk Reduction PROactive 2005 EC 409 EC 410 TL-OPI-503 2004 GLAI EC 404 GLAG 2003 GLAL Evident 2002 2001 9/18/2013 Company Confidential 8 Copyright 2000 Eli Lilly and Company PLA-TAK-00053927 Source: https://www.indup340-00008ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Marketing Objective : Ensure access and reimbursement of ACTOS in maximize markets Strategic Clinical Study Target Date Action Plan Objective Database Locked Expand European EC 404 Q2'02 Takeda to submit for Label to include EC 405/GLAG label expansion monotherapy Submit abstract in 2003 ADA/EASD/IDF Expand the European PNFP-341 - SU Q2'02 Takeda to submit for label to include 45 mg, PNFP-342 - Met label change Utilize 45 mg EC 409 / GLAP Q3'04-Q3'02 (1 Year) Production forecasts to combination in US EC 410 / GLAQ Q3'04-Q3'02 (1 Year) be modified Expand European PNFP-343 Q2'02 Takeda to submit for Label to include Insulin comb. trial for Q4'04 Q2'04 label change Combination with efficacy and Guidelines/algorithm Insulin European safety-not- developed on yet funded- decreases in suggested insulin? Establish safety in TL-OPI-504 (II-III) Q1'02 Takeda to submit for Class I, II and III CHF TL-OP-520 (I) Q1'03- Q2'03 label modification in Europe Update slide series 9/18/2013 Company Confidential 9 Copyright 2000 Eli Lilly and Company PLA-TAK-00053928 Source: https://www.indupt340-00009ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053929 Source: https://www.indupe340-00070ts.ucsf.edu/docs/fzjf0226 Clinical Plan supporting Marketing Objectives Strategic Clinical Study Target Date Action Plan Objective Database Locked Reduction/Removal of TL-OPI-506 Q2'04 Discussions need to the liver monitoring continue with the FDA to requirements establish clear safety milestones Demonstrate lack of TL-OPI-509 ? Publication(s) to be Drug-Drug (Cyclosporine B) planned Interactions TL-OPI-510 Q2'01 Abstracts to be submitted (Theophylline) on each study TL-OPI-511 Q2'01 (Atorvastatin) Adolescent data/use TL-OPI-507 TBD 9/18/2013 Company Confidential 11 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053930 PLA-TAK-00053931 Source: https://www.indup5340-0002ts.ucsf.edu/docs/fzjf0226 Possible Suggested Topics for IITs Blood Pressure effects Onset of Action Metformin VS Actos Mechanism of Action Post-Prandial lipids Weight Management Beta-cell Protection (preclinical studies to support theory) 9/18/2013 Company Confidential 13 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053932 Source: https://www.indup6340-00013ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053933 Source: https://www.indupt340-00094ts.ucsf.edu/docs/fzjf0226 Clinical Experience Programs Program Description Affiliates Investigator Initiated A trial/study initiated by Recommended for all Trials (IITs) investigator(s) not Maximize Affiliates Or study (IIS) affiliated with Lilly Observational Studies A study based on US "Evident" collection of data from patient charts Physician Experience Provide free products Mexico, Canada, Programs (PEPs) for specified time Australia frames to physicians for them to gain experience Post Marketing A study based on Spain Surveillance (PMS) collection of AE data from patient charts 9/18/2013 Company Confidential 15 Copyright © 2000 Eli Lilly and Company PLA-TAK-00053934 Source: https://www.indup340-00095ts.ucsf.edu/docs/fzjf0226 PLA-TAK-00053935 Source: https://www.indup6340-00076ts.ucsf.edu/docs/fzjf0226

What is the ACTOS 15 mg of Monotherapy?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

0.9(-0.5/3.4) N=79, 0.9(-0.5/3.4) n=79

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

What is the trial duration mentioned?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

16 TO 26 WEEKS, 16 to 26 weeks

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

what is the name of the form ?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

URGENT DATA ENQUIRY, URGENT DATA ENQUIRY FORM, urgent data enquiry form

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

what is the centre number ?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

49013

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

What is the ACTOS 45 mg of Combination Therapy of Insulin?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

4.1 (1.4/6.8) N=338, 4.1 (1.4/6.8) N=338

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

What is the date mentioned?

mnjf0226

mnjf0226_p0, mnjf0226_p1, mnjf0226_p2

August 12-13, 2002

TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 FDA Response Outline LABEL CHANGE CLINICAL PEDIATRIC INDICATION Current label adequately reflects General epidemiology of bladder We believe that there is no information that we have cancer increased risk for bladder cancer Not genotoxic Incidence associated with Actos Two year studies, one sex one Latency We would like to proceed with the species Risk factors Actos 508 study No data to correlate those Observations with pio Propose delay until resolved findings to man Post-marketing surveillance No new data OCT020 Summire resists Critique presumed promoter model Findings to be expected Microcrystals known to increase appendix: tumors in those models MONITORING Any findings found require Expert opinion confirmation with a 2 year Restate that there are no findings - which suggest a need to monitor Coher methodsy carcinogenicity study Unvalidated We have already presented in the Possible Question definition of dual agonist NDA the standard of care (-001, - Evidence in literature that pio 011, -031), and no tumors were suppresses urothellal cells as well found as other cell types Talked to experts, evaluated Reinforce Cohen hypothesis existing methods Reiterate that current label is Latency adequate Markers not approved We don't believe we should monitor 70s: cancer We will watch current clinical trials carefully Redding TAK-THOMCL-00017302 Confidential - Subject to Protective Order Produced in MOL on 09/14/12 EXHIBIT 27 cone sue TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 Action Item List/Document Timelines Item Person Responsible Create table summarizing medium term toxicology studies Nonoyama Historical data on incidence of bladder hyperplasia in Toxicology mouse Exposure Toxicology Mouse versus rat Male rat versus female rat Get literature on transient nature of stones in rat Michael Elisseou will fosits A 71 R.S. ask Sam Cohen Add troglitazone to PPAR activation table Dr. Odaka In carcinogenecity studies, did rosiglitazone exposure lead Through FOI, Ray Chart to PPAR alpha activation Run NN622 through liver homogenetic/GCMS/Identify TCI will conduct metabolites/SAR assay Literature to support role of urinary pH and microcrystals Michael Elisseou will in promoter model ask Sam Cohen tukishing Summary of US/EU bladder cancer for NDA/MAA Glyn Belcher Add renal colic to clinical AE search Bob Ahlbrandt will send to John Search PDR for label wording based on results from tumor Janet Haskins model study and for class tox label wording Send rion-serious bladder cancer AE to John Page Glyn Belcher Source: is Confidential - Subject to Protective Order TAK-THOMCL-00017304 Produced In MDL on 09/14/12

what is the date issued mentioned in the form ?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

22-04-04

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

what is the patient number ?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

014

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

What is the Item that shows Person Responsible Bob Ahlbrandt will send to John?

mnjf0226

mnjf0226_p0, mnjf0226_p1, mnjf0226_p2

Add renal colic to clinical AE search

TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 FDA Response Outline LABEL CHANGE CLINICAL PEDIATRIC INDICATION Current label adequately reflects General epidemiology of bladder We believe that there is no information that we have cancer increased risk for bladder cancer Not genotoxic Incidence associated with Actos Two year studies, one sex one Latency We would like to proceed with the species Risk factors Actos 508 study No data to correlate those Observations with pio Propose delay until resolved findings to man Post-marketing surveillance No new data OCT020 Summire resists Critique presumed promoter model Findings to be expected Microcrystals known to increase appendix: tumors in those models MONITORING Any findings found require Expert opinion confirmation with a 2 year Restate that there are no findings - which suggest a need to monitor Coher methodsy carcinogenicity study Unvalidated We have already presented in the Possible Question definition of dual agonist NDA the standard of care (-001, - Evidence in literature that pio 011, -031), and no tumors were suppresses urothellal cells as well found as other cell types Talked to experts, evaluated Reinforce Cohen hypothesis existing methods Reiterate that current label is Latency adequate Markers not approved We don't believe we should monitor 70s: cancer We will watch current clinical trials carefully Redding TAK-THOMCL-00017302 Confidential - Subject to Protective Order Produced in MOL on 09/14/12 EXHIBIT 27 cone sue TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 Action Item List/Document Timelines Item Person Responsible Create table summarizing medium term toxicology studies Nonoyama Historical data on incidence of bladder hyperplasia in Toxicology mouse Exposure Toxicology Mouse versus rat Male rat versus female rat Get literature on transient nature of stones in rat Michael Elisseou will fosits A 71 R.S. ask Sam Cohen Add troglitazone to PPAR activation table Dr. Odaka In carcinogenecity studies, did rosiglitazone exposure lead Through FOI, Ray Chart to PPAR alpha activation Run NN622 through liver homogenetic/GCMS/Identify TCI will conduct metabolites/SAR assay Literature to support role of urinary pH and microcrystals Michael Elisseou will in promoter model ask Sam Cohen tukishing Summary of US/EU bladder cancer for NDA/MAA Glyn Belcher Add renal colic to clinical AE search Bob Ahlbrandt will send to John Search PDR for label wording based on results from tumor Janet Haskins model study and for class tox label wording Send rion-serious bladder cancer AE to John Page Glyn Belcher Source: is Confidential - Subject to Protective Order TAK-THOMCL-00017304 Produced In MDL on 09/14/12

What is written just below the date?

mnjf0226

mnjf0226_p0, mnjf0226_p1, mnjf0226_p2

Action Item List/Document Timelines

TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 FDA Response Outline LABEL CHANGE CLINICAL PEDIATRIC INDICATION Current label adequately reflects General epidemiology of bladder We believe that there is no information that we have cancer increased risk for bladder cancer Not genotoxic Incidence associated with Actos Two year studies, one sex one Latency We would like to proceed with the species Risk factors Actos 508 study No data to correlate those Observations with pio Propose delay until resolved findings to man Post-marketing surveillance No new data OCT020 Summire resists Critique presumed promoter model Findings to be expected Microcrystals known to increase appendix: tumors in those models MONITORING Any findings found require Expert opinion confirmation with a 2 year Restate that there are no findings - which suggest a need to monitor Coher methodsy carcinogenicity study Unvalidated We have already presented in the Possible Question definition of dual agonist NDA the standard of care (-001, - Evidence in literature that pio 011, -031), and no tumors were suppresses urothellal cells as well found as other cell types Talked to experts, evaluated Reinforce Cohen hypothesis existing methods Reiterate that current label is Latency adequate Markers not approved We don't believe we should monitor 70s: cancer We will watch current clinical trials carefully Redding TAK-THOMCL-00017302 Confidential - Subject to Protective Order Produced in MOL on 09/14/12 EXHIBIT 27 cone sue TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 Action Item List/Document Timelines Item Person Responsible Create table summarizing medium term toxicology studies Nonoyama Historical data on incidence of bladder hyperplasia in Toxicology mouse Exposure Toxicology Mouse versus rat Male rat versus female rat Get literature on transient nature of stones in rat Michael Elisseou will fosits A 71 R.S. ask Sam Cohen Add troglitazone to PPAR activation table Dr. Odaka In carcinogenecity studies, did rosiglitazone exposure lead Through FOI, Ray Chart to PPAR alpha activation Run NN622 through liver homogenetic/GCMS/Identify TCI will conduct metabolites/SAR assay Literature to support role of urinary pH and microcrystals Michael Elisseou will in promoter model ask Sam Cohen tukishing Summary of US/EU bladder cancer for NDA/MAA Glyn Belcher Add renal colic to clinical AE search Bob Ahlbrandt will send to John Search PDR for label wording based on results from tumor Janet Haskins model study and for class tox label wording Send rion-serious bladder cancer AE to John Page Glyn Belcher Source: is Confidential - Subject to Protective Order TAK-THOMCL-00017304 Produced In MDL on 09/14/12

What is the EXHIBIT number mentioned?

gpjf0226

gpjf0226_p0, gpjf0226_p1, gpjf0226_p2, gpjf0226_p3, gpjf0226_p4, gpjf0226_p5, gpjf0226_p6

R-12

EXHIBIT B-12 Takeda Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: E-mail Management and Retention Name/Title Signature Date Originator Amold D'Angelo, Associate General Counsel Signature on File 4/21/06 Approver Nancy Loeb, General Counsel Signature on File 4/21/06 Approver Jeanine Jiganti, VP. Chief Compliance Officer Signature on File 4/21/06 Approver Lee Voight, VP. Information Technology Signature on File 4/27/06 Approver Claire Thom, SVP, QA and Compliance Signature on File 4/25/06 Approver John Yates, President, TGRD Signature on File 4/24/06 Approver Mark Booth, President, TPNA Signature on File 4/21/06 1,0 Purpose The purpose of this Operating Procedure is to describe the requirements for personnel of Takeda Pharmaceuticals North America, Inc., Takeda Global Research and Development Center, Inc, and their U.S. subsidiaries (collectively Takeda) to fulfill our legal, financial, regulatory, and organizational obligations as they relate to E-Mail Management and Retention. 2.0 Scope 2.1 This BOP is applicable to all functional areas and all Takeda employees. 2.2 This BOP is applicable to all Takeda corporate e-mail messages. 2.3 This BOP is not applicable to electronic records that are required to be maintained under records requirements set by the Food and Drug Administration. Electronic records required to be maintained under any FDA regulation shall be maintained in alternate systems provided by Takeda, and shall not be stored or maintained in the e-mail system in any folder other than a "Reference" folder. 2.4 This BOP does not apply to e-mail, e-mail messages, e-mail records, documents, materials information, or things that are hosted on any system that is not the Takeda e-mail system. 3.0 Responsibility 3.1 Takeda employees are responsible for management and retention of corporate e-mail records and the proper disposition of e-mail non-records, 3.2 Takeda functional managers are responsible for facilitating adherence to this Operating Procedure for all current employees and terminating employees. 3.3 The responsible party(ies) cited may delegate activities, but retains the responsibility for the outcome. Takeda Pharmaceuticais North America, Inc. and Affiliates Page 1 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000083 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 4.0 Definitions 4.1 Active E-mail Folder. shall mean the Inbox, Sent Items, Deleted Items, other default folders and any folders that you have created in the Takeda E-mail System. 4.2 Company or Takeda: shall mean Takeda Pharmaceuticals North America, Inc., Takeda Global Research and Development Center, Inc., and their subsidiaries. 4,3 Draft E-mail: shall mean any e-mail that is in the process of being composed, edited or modified by the author and that has not been sent by the author to any person. A "draft" usually resides in the "Drafts" folder within the Takeda E-mail System. 4.4 Electronic Communications: shall mean and include the use of information systems in the communicating or posting of information or material by way of electronic mail, bulletin boards, World Wide Web (internet), or other such electronic tools. 4.5 E-mail Folder List: shall mean the list of folders in the Takeda E-mail System that allows users to store e-mail messages in a logical file/folder structure. 4.6 Electronic Mail (E-mail) and E-mail Messages: shall mean communications that are transmitted electronically by the Takeda E-mail System and shall include all components of the E-Mail message, such as routing or header information, metadata and any attachments. 4.7 E-mail Copies: shall include any e-mail that is a subsequent duplicate of an original e-mail. 4.8 E-mail Records: refers to any e-mail message that has record value. An E-mail Record has record value where it has been created or received by Takeda Employees and contains information that has on-going business, legal, operational, or compliance value, or that the Company is legally required to retain as evidence of its business for a specific period of time. Takeda has made reasonable efforts to define all such materials that have record value in its Record Retention Schedules. Takeda Employees shall evaluate whether E-Mail has record value based on either the content of the e-mail or any attachment thereto, or both. Takeda shall support Takeda Employees with training and instruction on the Record Retention Schedules. 4.9 Legal Hold: is an advisory issued by Takeda to inform Takeda employees, and contractors to retain Legal Hold Materials described therein until the Legal Hold is terminated, 4.10 Legal Hold Materials: shall include those documents, materials, information, and things, including e-mails, electronic documents, materials, information and things that are retained pursuant to a Legal Hold. Legal Hold Materials includes e-mail records, non-record e-mails, and Draft E-mail. 4,11 Non-record E-mail: shall include e-mail communications of a transitory or administrative nature or that do not contain information with on-going business, legal, operational, or compliance value, and that the Company does not intend to keep and is not legally required to retain as evidence of its business for a specific period of time, Non-record E-mail includes documents, materials, information, and things stored in Exchange as invitations, acceptance/declination of invitations, calendared items, tasks and reminders. 4.12 Takeda E-mail System: shall include all Takeda computer hardware and software, including workstations and connected networks, required to create, receive and maintain electronic mail. The Takeda E-Mail System does not include services such as Yahoo, Hotmail, Intralinks, and other services hosted by non-Takeda business and entities. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 2 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000084 Source: https://www.indu23703c00002s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 4.13 Takeda Employee or Employee: includes Takeda Employees and contractors. A contractor is a leased worker such as a contractor or consultant that is assigned to perform services for Takeda by a temporary staffing agency, in the position of a full or part time equivalent Employee, and who are assigned E-mail accounts in the Takeda E-mail system. Contractor does not include, by way of example, contractors or consultants such as auditors from an outside accounting firm. 4.14 Wireless Handheld Devices: shall include all handheld wireless devices that are used to send and receive messages with the Takeda E-Mail System. 5.0 Policies and Procedures 5.1 Overview: 5.1.1 E-mail records are assets of the Company that must be properly maintained and managed. Every employee shares responsibility for the proper management of Company E-mail Records. 5.1.2 Non-record E-Mails need to be discarded in the ordinary course of business, following their period of retention. Failure to dispose of Non-record E-mail increases the costs and complexity of electronic storage, and makes accessing and retrieving information less efficient. 5.2 The policies applicable to the E-mails Management Structure are described below: Prior to the implementation date of this Operating Procedure, storage folders will be available in your E-mail Folder List. These folders shall not be deleted, and are named as follows: 5.2.1 An "E-mail Records" folder will be available for the retention of e-mail that is a Company E-mail Record. E-mail Records may NOT be retained in any other folder, except as defined in Section 5.3. 5.2.2 The E-mail Records folder should NOT be used for any reason other than the storage of E-Mail Records. The use of subfolders for further classification within this folder is allowed. 5.2.3 A "Legal Hold" folder will be available for the storage of e-mail that is required to be preserved for the purpose of actual or anticipated audits, investigations or litigation. Legal hold e-mails may NOT be preserved in any other location. Subfolders for specific litigation cases will be provided by the Law Department and IT for further classification within this folder. 5.2.4 A 'Transition" folder will be available for the storage of all e-mails that exist in each employee e-mail mailbox at the time of implementation of this Operating Procedure, Subfolders identified as "Inbox," "Sent Items," and "Deleted Items" will be provided to organize transition materials. The use of additional subfolders for further classification within this folder is not allowed. 5.2.5 A "Reference" folder will be available to store Non-Record e-mails for personal reference related to Company business. The use of subfolders for further classification within this folder is allowed. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 3 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000085 Source: https://www.indup2373500003s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5.3 The procedures for Retaining E-mail Records are described below: 5.3.1 It is each employee's responsibility to move any e-mail message meeting the definition of an E-Mail Record from their Active E-mail Folders to their E-mail Records folders. E-mail Records must be moved to the E-mail Records folders within 90 days of their creation or receipt. 5.3.2 The E-mail Records folders provided by Takeda are the acceptable locations for the retention of E-mail Records. E-mail Records should not be retained in any other location than in the E-mail Records folders, unless (a) the E-mail Records are subject to a Legal Hold, in which case the e-mail must also be maintained in the Legal Hold folder; or (b) the e-mail is required to be maintained under record requirements of the FDA or other regulatory agency and Takeda has established by BOP, SOP or established business practice, an alternate tool, location, or system for the retention of E-mail records. In the latter case, E-mail Records shall be retained according to the BOP, SOP or established business practice. 5.3.3 The following rules will help you determine which E-mail Record messages need to be retained in the E-mail Records folder: An Employee is required to retain an E-mail Record if the Employee generated or forwarded the E-mail Record or was an addressee of the E-mail Record (excluding carbon copies or blind carbon copies). An Employee is required to retain an E-mail Record if the Employee is required to take some action based on an E-mail Record, and the Employee is the addressee, or appears as a CC or bcc. An Employee is required to retain an E-mail Record if the Employee was sent the E-mail Record from a non-company source (whether or not the Employee is required to take some action based on the E- mail). The E-mail Record shall be retained regardless of whether the Employee receiving the e-mail received il as an addressee, CC, or bcc. 5.3.4 In all cases, E-mail Records that are subject to a Legal Hold must be stored in the E-mail Records folder; (or elsewhere pursuant to 5.3.2 for regulated records) and a copy of the original message should be stored in the Legal Hold folder where it will be preserved. 5.4 The procedures for retaining Legal Hold Materials are described below: 5.4.1 From time to time the Company may instruct you to preserve materials relating to audits, investigations, and/or litigation. IN SUCH CIRCUMSTANCES, ANY AND ALL LEGAL HOLD MATERIALS MUST BE PRESERVED AND NOT MODIFIED, DELETED, CONCEALED, OR OTHERWISE CHANGED IN ANY WAY THAT WOULD ALTER THEIR MEANING OR MAKE THEM INACCESSIBLE. 5.4.2 Employees who become aware of a potential legal requirement to preserve documents, materials, information or things (including electronic documents, materials, information and, things). even though they have not received any official notice to do so, should contact the Law Department. In this situation, do not discard any e-mail about which you have questions until being advised by the Law Department that it is proper to do so. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 4 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000086 Source: https://www.indup2373500004s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5.4.3 Both Record and Non-record E-mails that are subject to a Legal Hold that are contained in your Inbox, Sent Items and Deleted Iterns or that exist in the Draft mailbox folders shall be moved to the "Legal Hold" folder. Such e-mails need to be moved within 90 days of receipt or creation. 5.4.4 Draft e-mails that exist as of the time a Legal Hold comes into effect must be preserved. Draft e-mails must be preserved by moving the draft to the "Legal Hold" folder without change; e.g., additional drafting, alteration, modification, or deletion, of the e-mail's contents. 5.4.5 The following rules will help you determine which Legal Hold Materials need to be retained in the Legal Hold folder: An Employee is required to retain Legal Hold Material if the Employee generated or forwarded the E-mail or was an addressee of the E-mail (excluding carbon copies or blind carbon copies). An Employee is required to retain any Legal Hold Material if the Employee is required to take some action based on an E-mail and the Employee is the addressee, or appears as a carbon copy or blind carbon copy. An Employee is required to retain any Legal Hold Material if the Employee was sent the E-mail from a non-company source (whether or not the Employee is required to take some action based on the E- mail). The E-mail shall be retained regardless of whether the Employee receiving the e-mail received it as an addressee, carbon copy or blind carbon copy. 5.5 The procedures for the maintenance and storage of E-mail non-records are described below: 5.5.1 Non-Record E-mails must only be kept for as long as necessary to conduct business. 5.5.2 Move all reference Non-Record e-mails to the "Reference" folder. Non-Record e- mails needed for reference for more than 90 days are to be moved to the "Reference", folder until they are no longer needed. Once Non-Record e-mails in the "Reference" folder are no longer needed they should be deleted, unless specific e-mails in your "Reference" folder become subject to a Legal Hold, at which point they must be transferred to the "Legal Hold" folder as addressed above. 5.6 The procedures governing the Transition of E-mail is described below. 5.6.1 When this Operating Procedure becomes effective, all e-mail that exists in an Employee's e-mail account, either within the Inbox Folder, other non-default folders, Sent Items Folder or Deleted Items Folder must be moved to the "Transition" folder and its subfolders, Employees shall review all e-mails and determine whether they qualify as E-mail Records or are subject to a Legal Hold. Any e-mails qualifying as an as E-mail Records or subject to a Legal Hold shall be moved to the E-mail Record or Legal Hold folder, respectively. E-mails may be moved to the Reference folder if needed for personal reference for Takeda business. E-mail messages in the Transition folder that are no longer needed should be deleted. UNDER NO CIRCUMSTANCES MAY ANY E-MAIL MESSAGE BE MOVED FROM YOUR TRANSITION FOLDER TO ANY LOCATION OTHER THAN THE Takeda Pharmaceuticals North America, Inc. and Affiliates Page 5 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000087 Source: https://www.indup2373-00005s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention E-MAIL RECORDS FOLDER, THE LEGAL HOLD FOLDER, OR THE REFERENCE FOLDER. 5.7 The procedures for the Automated Disposition of E-mail Non-records are described below: 5.7.1 Following implementation of this Operating Procedure, any e-mail message which is not moved to the "E-mail Records" folder, "Legal Hold" folder, or "Reference" folder, and which remains within either the "Inbox," "Sent Items," or "Deleted Items" folder of the Active E-mail Folders will be deleted by the system every 90 days (quarterly), and will no longer be available. 5.7,2 Employees must decide within 90 days of receipt or creation whether or not each e-mail message is an E-mail Record or is subject to a Legal Hold that should be retained or preserved. Failure to take the appropriate retention or preservation action within this 90 day period is a violation of this Operating Procedure. 5.7.3 Employees that are unable to access their e-mail account for more than 90-days, or that are otherwise unable to classify e-mail messages in accordance with this Operating Procedure, shall contact their supervisor to make arrangements for the management of their e-mail account. 5.7.4 Employees will receive electronic notification in advance advising of the dates for which e-mails received or created, and that have not been transferred to an E- mail Record, Legal Hold or Reference folder, will be deleted by the system. 5.8 The procedures for the Disposition of E-mail Records and Non-records are described below: 5.8.1 Unless this Operating Procedure authorizes an exception, as described in Section (5.3.2) e-mail shall be retained in electronic form. Generally, printing and filing hardcopies of e-mail messages is not an acceptable form of e-mail retention as it makes the access, management, and retention of E-mail Records and Legal Hold Materials more difficult. 5.8.2 Employees may not move or store any e-mail message, whether Record or Non- Record, outside of the Takeda E-mail system. Examples of such activities prohibited under this Operating Procedure include, but are not limited to: Exporting e-mail from the Company e-mail system to a .pst" or other similar file types; Storing copies of e-mail messages on a Company laptop computer (other than through the automatic synchronization process) to allow access to e-mails when not connected to the Company computer network; Moving e-mail to, or storing it on, any type of portable tape, disk, diskette or storage device, including Personal Digital Assistants, Compact Disks, or USB Drives for the purpose of retention or preservation. Moving e-mail to, or storing it on, any device not owned or provided by Takeda. This would include, for example, the forwarding of Company e-mails to personal e-mail accounts. 5.8.3 Your compliance with these procedures may be periodically audited. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 6 of 7 Confidential n Subject to Protective Order TAK-RIM3056-00000088 Source: Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5,9 Restrictions for Wireless Handheld Devices: Wireless handheld devices that allow the management of E-Mail in the Takeda E-mail System, such as a Blackberry, cannot be used to move e-mail files into the e-mail file folder management structure because of limitations with the technology. Therefore, employees using wireless devices to connect to their Takeda E-Mail shall not delete E-mail records from their wireless handheld device that must be retained or preserved pursuant to this Operating Procedure. Employees shall appropriately classify e-mail that must be retained or preserved in accordance with this Operating Procedure by connecting to the Takeda E-Mail system from their Takeda office computer, laptop or workstation to manage their retainable e-mail. 5.10 Restrictions on Use of Disaster Recovery Back-up Tapes: Following implementation of this Operating Procedure, disaster recovery backup tapes and disks that are used for business continuity or disaster recovery purposes shall not be used for any other purpose, and shall not to be used to satisfy retention requirements for Company E- mail Records or Legal Hold Materials. 5.11 Implementation: 5.11.1 The implementation of this Operating Procedure will be announced by an e-mail communication to all Takeda Employees. 5.11.2 Prior to implementation of this Operating Procedure, Employees shall receive pre-implementation instruction and education to facilitate the transition to this new methodology. 6.0 References 6.1 Corp-P-001 Electronic Records and Electronic Signatures 6.2 Corp-P-003 Corporate Records Management and Retention 6.3 Corp-S-010 Creating, Maintaining, and Revising Corporate Records Retention Schedules 6.4 Corp-S-011 Maintaining, Storing, Retrieving, Destroying and Preserving Corporate Records 6,5 Corp-S-012 Legal Holds 7.0 Attachments 7.1 N/A Takeda Pharmaceuticals North America, Inc. and Affiliates Page 7 of 7 Confidential - Subject to Protective Order TAK-RIM3056-00000089 Source: https://www.indup2373-00007ts.ucsf.edu/docs/gpjf0226

What is the BOP Number?

gpjf0226

gpjf0226_p0, gpjf0226_p1, gpjf0226_p2, gpjf0226_p3, gpjf0226_p4, gpjf0226_p5, gpjf0226_p6

CORP-B-019

EXHIBIT B-12 Takeda Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: E-mail Management and Retention Name/Title Signature Date Originator Amold D'Angelo, Associate General Counsel Signature on File 4/21/06 Approver Nancy Loeb, General Counsel Signature on File 4/21/06 Approver Jeanine Jiganti, VP. Chief Compliance Officer Signature on File 4/21/06 Approver Lee Voight, VP. Information Technology Signature on File 4/27/06 Approver Claire Thom, SVP, QA and Compliance Signature on File 4/25/06 Approver John Yates, President, TGRD Signature on File 4/24/06 Approver Mark Booth, President, TPNA Signature on File 4/21/06 1,0 Purpose The purpose of this Operating Procedure is to describe the requirements for personnel of Takeda Pharmaceuticals North America, Inc., Takeda Global Research and Development Center, Inc, and their U.S. subsidiaries (collectively Takeda) to fulfill our legal, financial, regulatory, and organizational obligations as they relate to E-Mail Management and Retention. 2.0 Scope 2.1 This BOP is applicable to all functional areas and all Takeda employees. 2.2 This BOP is applicable to all Takeda corporate e-mail messages. 2.3 This BOP is not applicable to electronic records that are required to be maintained under records requirements set by the Food and Drug Administration. Electronic records required to be maintained under any FDA regulation shall be maintained in alternate systems provided by Takeda, and shall not be stored or maintained in the e-mail system in any folder other than a "Reference" folder. 2.4 This BOP does not apply to e-mail, e-mail messages, e-mail records, documents, materials information, or things that are hosted on any system that is not the Takeda e-mail system. 3.0 Responsibility 3.1 Takeda employees are responsible for management and retention of corporate e-mail records and the proper disposition of e-mail non-records, 3.2 Takeda functional managers are responsible for facilitating adherence to this Operating Procedure for all current employees and terminating employees. 3.3 The responsible party(ies) cited may delegate activities, but retains the responsibility for the outcome. Takeda Pharmaceuticais North America, Inc. and Affiliates Page 1 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000083 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 4.0 Definitions 4.1 Active E-mail Folder. shall mean the Inbox, Sent Items, Deleted Items, other default folders and any folders that you have created in the Takeda E-mail System. 4.2 Company or Takeda: shall mean Takeda Pharmaceuticals North America, Inc., Takeda Global Research and Development Center, Inc., and their subsidiaries. 4,3 Draft E-mail: shall mean any e-mail that is in the process of being composed, edited or modified by the author and that has not been sent by the author to any person. A "draft" usually resides in the "Drafts" folder within the Takeda E-mail System. 4.4 Electronic Communications: shall mean and include the use of information systems in the communicating or posting of information or material by way of electronic mail, bulletin boards, World Wide Web (internet), or other such electronic tools. 4.5 E-mail Folder List: shall mean the list of folders in the Takeda E-mail System that allows users to store e-mail messages in a logical file/folder structure. 4.6 Electronic Mail (E-mail) and E-mail Messages: shall mean communications that are transmitted electronically by the Takeda E-mail System and shall include all components of the E-Mail message, such as routing or header information, metadata and any attachments. 4.7 E-mail Copies: shall include any e-mail that is a subsequent duplicate of an original e-mail. 4.8 E-mail Records: refers to any e-mail message that has record value. An E-mail Record has record value where it has been created or received by Takeda Employees and contains information that has on-going business, legal, operational, or compliance value, or that the Company is legally required to retain as evidence of its business for a specific period of time. Takeda has made reasonable efforts to define all such materials that have record value in its Record Retention Schedules. Takeda Employees shall evaluate whether E-Mail has record value based on either the content of the e-mail or any attachment thereto, or both. Takeda shall support Takeda Employees with training and instruction on the Record Retention Schedules. 4.9 Legal Hold: is an advisory issued by Takeda to inform Takeda employees, and contractors to retain Legal Hold Materials described therein until the Legal Hold is terminated, 4.10 Legal Hold Materials: shall include those documents, materials, information, and things, including e-mails, electronic documents, materials, information and things that are retained pursuant to a Legal Hold. Legal Hold Materials includes e-mail records, non-record e-mails, and Draft E-mail. 4,11 Non-record E-mail: shall include e-mail communications of a transitory or administrative nature or that do not contain information with on-going business, legal, operational, or compliance value, and that the Company does not intend to keep and is not legally required to retain as evidence of its business for a specific period of time, Non-record E-mail includes documents, materials, information, and things stored in Exchange as invitations, acceptance/declination of invitations, calendared items, tasks and reminders. 4.12 Takeda E-mail System: shall include all Takeda computer hardware and software, including workstations and connected networks, required to create, receive and maintain electronic mail. The Takeda E-Mail System does not include services such as Yahoo, Hotmail, Intralinks, and other services hosted by non-Takeda business and entities. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 2 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000084 Source: https://www.indu23703c00002s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 4.13 Takeda Employee or Employee: includes Takeda Employees and contractors. A contractor is a leased worker such as a contractor or consultant that is assigned to perform services for Takeda by a temporary staffing agency, in the position of a full or part time equivalent Employee, and who are assigned E-mail accounts in the Takeda E-mail system. Contractor does not include, by way of example, contractors or consultants such as auditors from an outside accounting firm. 4.14 Wireless Handheld Devices: shall include all handheld wireless devices that are used to send and receive messages with the Takeda E-Mail System. 5.0 Policies and Procedures 5.1 Overview: 5.1.1 E-mail records are assets of the Company that must be properly maintained and managed. Every employee shares responsibility for the proper management of Company E-mail Records. 5.1.2 Non-record E-Mails need to be discarded in the ordinary course of business, following their period of retention. Failure to dispose of Non-record E-mail increases the costs and complexity of electronic storage, and makes accessing and retrieving information less efficient. 5.2 The policies applicable to the E-mails Management Structure are described below: Prior to the implementation date of this Operating Procedure, storage folders will be available in your E-mail Folder List. These folders shall not be deleted, and are named as follows: 5.2.1 An "E-mail Records" folder will be available for the retention of e-mail that is a Company E-mail Record. E-mail Records may NOT be retained in any other folder, except as defined in Section 5.3. 5.2.2 The E-mail Records folder should NOT be used for any reason other than the storage of E-Mail Records. The use of subfolders for further classification within this folder is allowed. 5.2.3 A "Legal Hold" folder will be available for the storage of e-mail that is required to be preserved for the purpose of actual or anticipated audits, investigations or litigation. Legal hold e-mails may NOT be preserved in any other location. Subfolders for specific litigation cases will be provided by the Law Department and IT for further classification within this folder. 5.2.4 A 'Transition" folder will be available for the storage of all e-mails that exist in each employee e-mail mailbox at the time of implementation of this Operating Procedure, Subfolders identified as "Inbox," "Sent Items," and "Deleted Items" will be provided to organize transition materials. The use of additional subfolders for further classification within this folder is not allowed. 5.2.5 A "Reference" folder will be available to store Non-Record e-mails for personal reference related to Company business. The use of subfolders for further classification within this folder is allowed. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 3 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000085 Source: https://www.indup2373500003s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5.3 The procedures for Retaining E-mail Records are described below: 5.3.1 It is each employee's responsibility to move any e-mail message meeting the definition of an E-Mail Record from their Active E-mail Folders to their E-mail Records folders. E-mail Records must be moved to the E-mail Records folders within 90 days of their creation or receipt. 5.3.2 The E-mail Records folders provided by Takeda are the acceptable locations for the retention of E-mail Records. E-mail Records should not be retained in any other location than in the E-mail Records folders, unless (a) the E-mail Records are subject to a Legal Hold, in which case the e-mail must also be maintained in the Legal Hold folder; or (b) the e-mail is required to be maintained under record requirements of the FDA or other regulatory agency and Takeda has established by BOP, SOP or established business practice, an alternate tool, location, or system for the retention of E-mail records. In the latter case, E-mail Records shall be retained according to the BOP, SOP or established business practice. 5.3.3 The following rules will help you determine which E-mail Record messages need to be retained in the E-mail Records folder: An Employee is required to retain an E-mail Record if the Employee generated or forwarded the E-mail Record or was an addressee of the E-mail Record (excluding carbon copies or blind carbon copies). An Employee is required to retain an E-mail Record if the Employee is required to take some action based on an E-mail Record, and the Employee is the addressee, or appears as a CC or bcc. An Employee is required to retain an E-mail Record if the Employee was sent the E-mail Record from a non-company source (whether or not the Employee is required to take some action based on the E- mail). The E-mail Record shall be retained regardless of whether the Employee receiving the e-mail received il as an addressee, CC, or bcc. 5.3.4 In all cases, E-mail Records that are subject to a Legal Hold must be stored in the E-mail Records folder; (or elsewhere pursuant to 5.3.2 for regulated records) and a copy of the original message should be stored in the Legal Hold folder where it will be preserved. 5.4 The procedures for retaining Legal Hold Materials are described below: 5.4.1 From time to time the Company may instruct you to preserve materials relating to audits, investigations, and/or litigation. IN SUCH CIRCUMSTANCES, ANY AND ALL LEGAL HOLD MATERIALS MUST BE PRESERVED AND NOT MODIFIED, DELETED, CONCEALED, OR OTHERWISE CHANGED IN ANY WAY THAT WOULD ALTER THEIR MEANING OR MAKE THEM INACCESSIBLE. 5.4.2 Employees who become aware of a potential legal requirement to preserve documents, materials, information or things (including electronic documents, materials, information and, things). even though they have not received any official notice to do so, should contact the Law Department. In this situation, do not discard any e-mail about which you have questions until being advised by the Law Department that it is proper to do so. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 4 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000086 Source: https://www.indup2373500004s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5.4.3 Both Record and Non-record E-mails that are subject to a Legal Hold that are contained in your Inbox, Sent Items and Deleted Iterns or that exist in the Draft mailbox folders shall be moved to the "Legal Hold" folder. Such e-mails need to be moved within 90 days of receipt or creation. 5.4.4 Draft e-mails that exist as of the time a Legal Hold comes into effect must be preserved. Draft e-mails must be preserved by moving the draft to the "Legal Hold" folder without change; e.g., additional drafting, alteration, modification, or deletion, of the e-mail's contents. 5.4.5 The following rules will help you determine which Legal Hold Materials need to be retained in the Legal Hold folder: An Employee is required to retain Legal Hold Material if the Employee generated or forwarded the E-mail or was an addressee of the E-mail (excluding carbon copies or blind carbon copies). An Employee is required to retain any Legal Hold Material if the Employee is required to take some action based on an E-mail and the Employee is the addressee, or appears as a carbon copy or blind carbon copy. An Employee is required to retain any Legal Hold Material if the Employee was sent the E-mail from a non-company source (whether or not the Employee is required to take some action based on the E- mail). The E-mail shall be retained regardless of whether the Employee receiving the e-mail received it as an addressee, carbon copy or blind carbon copy. 5.5 The procedures for the maintenance and storage of E-mail non-records are described below: 5.5.1 Non-Record E-mails must only be kept for as long as necessary to conduct business. 5.5.2 Move all reference Non-Record e-mails to the "Reference" folder. Non-Record e- mails needed for reference for more than 90 days are to be moved to the "Reference", folder until they are no longer needed. Once Non-Record e-mails in the "Reference" folder are no longer needed they should be deleted, unless specific e-mails in your "Reference" folder become subject to a Legal Hold, at which point they must be transferred to the "Legal Hold" folder as addressed above. 5.6 The procedures governing the Transition of E-mail is described below. 5.6.1 When this Operating Procedure becomes effective, all e-mail that exists in an Employee's e-mail account, either within the Inbox Folder, other non-default folders, Sent Items Folder or Deleted Items Folder must be moved to the "Transition" folder and its subfolders, Employees shall review all e-mails and determine whether they qualify as E-mail Records or are subject to a Legal Hold. Any e-mails qualifying as an as E-mail Records or subject to a Legal Hold shall be moved to the E-mail Record or Legal Hold folder, respectively. E-mails may be moved to the Reference folder if needed for personal reference for Takeda business. E-mail messages in the Transition folder that are no longer needed should be deleted. UNDER NO CIRCUMSTANCES MAY ANY E-MAIL MESSAGE BE MOVED FROM YOUR TRANSITION FOLDER TO ANY LOCATION OTHER THAN THE Takeda Pharmaceuticals North America, Inc. and Affiliates Page 5 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000087 Source: https://www.indup2373-00005s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention E-MAIL RECORDS FOLDER, THE LEGAL HOLD FOLDER, OR THE REFERENCE FOLDER. 5.7 The procedures for the Automated Disposition of E-mail Non-records are described below: 5.7.1 Following implementation of this Operating Procedure, any e-mail message which is not moved to the "E-mail Records" folder, "Legal Hold" folder, or "Reference" folder, and which remains within either the "Inbox," "Sent Items," or "Deleted Items" folder of the Active E-mail Folders will be deleted by the system every 90 days (quarterly), and will no longer be available. 5.7,2 Employees must decide within 90 days of receipt or creation whether or not each e-mail message is an E-mail Record or is subject to a Legal Hold that should be retained or preserved. Failure to take the appropriate retention or preservation action within this 90 day period is a violation of this Operating Procedure. 5.7.3 Employees that are unable to access their e-mail account for more than 90-days, or that are otherwise unable to classify e-mail messages in accordance with this Operating Procedure, shall contact their supervisor to make arrangements for the management of their e-mail account. 5.7.4 Employees will receive electronic notification in advance advising of the dates for which e-mails received or created, and that have not been transferred to an E- mail Record, Legal Hold or Reference folder, will be deleted by the system. 5.8 The procedures for the Disposition of E-mail Records and Non-records are described below: 5.8.1 Unless this Operating Procedure authorizes an exception, as described in Section (5.3.2) e-mail shall be retained in electronic form. Generally, printing and filing hardcopies of e-mail messages is not an acceptable form of e-mail retention as it makes the access, management, and retention of E-mail Records and Legal Hold Materials more difficult. 5.8.2 Employees may not move or store any e-mail message, whether Record or Non- Record, outside of the Takeda E-mail system. Examples of such activities prohibited under this Operating Procedure include, but are not limited to: Exporting e-mail from the Company e-mail system to a .pst" or other similar file types; Storing copies of e-mail messages on a Company laptop computer (other than through the automatic synchronization process) to allow access to e-mails when not connected to the Company computer network; Moving e-mail to, or storing it on, any type of portable tape, disk, diskette or storage device, including Personal Digital Assistants, Compact Disks, or USB Drives for the purpose of retention or preservation. Moving e-mail to, or storing it on, any device not owned or provided by Takeda. This would include, for example, the forwarding of Company e-mails to personal e-mail accounts. 5.8.3 Your compliance with these procedures may be periodically audited. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 6 of 7 Confidential n Subject to Protective Order TAK-RIM3056-00000088 Source: Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5,9 Restrictions for Wireless Handheld Devices: Wireless handheld devices that allow the management of E-Mail in the Takeda E-mail System, such as a Blackberry, cannot be used to move e-mail files into the e-mail file folder management structure because of limitations with the technology. Therefore, employees using wireless devices to connect to their Takeda E-Mail shall not delete E-mail records from their wireless handheld device that must be retained or preserved pursuant to this Operating Procedure. Employees shall appropriately classify e-mail that must be retained or preserved in accordance with this Operating Procedure by connecting to the Takeda E-Mail system from their Takeda office computer, laptop or workstation to manage their retainable e-mail. 5.10 Restrictions on Use of Disaster Recovery Back-up Tapes: Following implementation of this Operating Procedure, disaster recovery backup tapes and disks that are used for business continuity or disaster recovery purposes shall not be used for any other purpose, and shall not to be used to satisfy retention requirements for Company E- mail Records or Legal Hold Materials. 5.11 Implementation: 5.11.1 The implementation of this Operating Procedure will be announced by an e-mail communication to all Takeda Employees. 5.11.2 Prior to implementation of this Operating Procedure, Employees shall receive pre-implementation instruction and education to facilitate the transition to this new methodology. 6.0 References 6.1 Corp-P-001 Electronic Records and Electronic Signatures 6.2 Corp-P-003 Corporate Records Management and Retention 6.3 Corp-S-010 Creating, Maintaining, and Revising Corporate Records Retention Schedules 6.4 Corp-S-011 Maintaining, Storing, Retrieving, Destroying and Preserving Corporate Records 6,5 Corp-S-012 Legal Holds 7.0 Attachments 7.1 N/A Takeda Pharmaceuticals North America, Inc. and Affiliates Page 7 of 7 Confidential - Subject to Protective Order TAK-RIM3056-00000089 Source: https://www.indup2373-00007ts.ucsf.edu/docs/gpjf0226

What is the Effective Date?

gpjf0226

gpjf0226_p0, gpjf0226_p1, gpjf0226_p2, gpjf0226_p3, gpjf0226_p4, gpjf0226_p5, gpjf0226_p6

05/01/2006

EXHIBIT B-12 Takeda Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: E-mail Management and Retention Name/Title Signature Date Originator Amold D'Angelo, Associate General Counsel Signature on File 4/21/06 Approver Nancy Loeb, General Counsel Signature on File 4/21/06 Approver Jeanine Jiganti, VP. Chief Compliance Officer Signature on File 4/21/06 Approver Lee Voight, VP. Information Technology Signature on File 4/27/06 Approver Claire Thom, SVP, QA and Compliance Signature on File 4/25/06 Approver John Yates, President, TGRD Signature on File 4/24/06 Approver Mark Booth, President, TPNA Signature on File 4/21/06 1,0 Purpose The purpose of this Operating Procedure is to describe the requirements for personnel of Takeda Pharmaceuticals North America, Inc., Takeda Global Research and Development Center, Inc, and their U.S. subsidiaries (collectively Takeda) to fulfill our legal, financial, regulatory, and organizational obligations as they relate to E-Mail Management and Retention. 2.0 Scope 2.1 This BOP is applicable to all functional areas and all Takeda employees. 2.2 This BOP is applicable to all Takeda corporate e-mail messages. 2.3 This BOP is not applicable to electronic records that are required to be maintained under records requirements set by the Food and Drug Administration. Electronic records required to be maintained under any FDA regulation shall be maintained in alternate systems provided by Takeda, and shall not be stored or maintained in the e-mail system in any folder other than a "Reference" folder. 2.4 This BOP does not apply to e-mail, e-mail messages, e-mail records, documents, materials information, or things that are hosted on any system that is not the Takeda e-mail system. 3.0 Responsibility 3.1 Takeda employees are responsible for management and retention of corporate e-mail records and the proper disposition of e-mail non-records, 3.2 Takeda functional managers are responsible for facilitating adherence to this Operating Procedure for all current employees and terminating employees. 3.3 The responsible party(ies) cited may delegate activities, but retains the responsibility for the outcome. Takeda Pharmaceuticais North America, Inc. and Affiliates Page 1 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000083 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 4.0 Definitions 4.1 Active E-mail Folder. shall mean the Inbox, Sent Items, Deleted Items, other default folders and any folders that you have created in the Takeda E-mail System. 4.2 Company or Takeda: shall mean Takeda Pharmaceuticals North America, Inc., Takeda Global Research and Development Center, Inc., and their subsidiaries. 4,3 Draft E-mail: shall mean any e-mail that is in the process of being composed, edited or modified by the author and that has not been sent by the author to any person. A "draft" usually resides in the "Drafts" folder within the Takeda E-mail System. 4.4 Electronic Communications: shall mean and include the use of information systems in the communicating or posting of information or material by way of electronic mail, bulletin boards, World Wide Web (internet), or other such electronic tools. 4.5 E-mail Folder List: shall mean the list of folders in the Takeda E-mail System that allows users to store e-mail messages in a logical file/folder structure. 4.6 Electronic Mail (E-mail) and E-mail Messages: shall mean communications that are transmitted electronically by the Takeda E-mail System and shall include all components of the E-Mail message, such as routing or header information, metadata and any attachments. 4.7 E-mail Copies: shall include any e-mail that is a subsequent duplicate of an original e-mail. 4.8 E-mail Records: refers to any e-mail message that has record value. An E-mail Record has record value where it has been created or received by Takeda Employees and contains information that has on-going business, legal, operational, or compliance value, or that the Company is legally required to retain as evidence of its business for a specific period of time. Takeda has made reasonable efforts to define all such materials that have record value in its Record Retention Schedules. Takeda Employees shall evaluate whether E-Mail has record value based on either the content of the e-mail or any attachment thereto, or both. Takeda shall support Takeda Employees with training and instruction on the Record Retention Schedules. 4.9 Legal Hold: is an advisory issued by Takeda to inform Takeda employees, and contractors to retain Legal Hold Materials described therein until the Legal Hold is terminated, 4.10 Legal Hold Materials: shall include those documents, materials, information, and things, including e-mails, electronic documents, materials, information and things that are retained pursuant to a Legal Hold. Legal Hold Materials includes e-mail records, non-record e-mails, and Draft E-mail. 4,11 Non-record E-mail: shall include e-mail communications of a transitory or administrative nature or that do not contain information with on-going business, legal, operational, or compliance value, and that the Company does not intend to keep and is not legally required to retain as evidence of its business for a specific period of time, Non-record E-mail includes documents, materials, information, and things stored in Exchange as invitations, acceptance/declination of invitations, calendared items, tasks and reminders. 4.12 Takeda E-mail System: shall include all Takeda computer hardware and software, including workstations and connected networks, required to create, receive and maintain electronic mail. The Takeda E-Mail System does not include services such as Yahoo, Hotmail, Intralinks, and other services hosted by non-Takeda business and entities. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 2 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000084 Source: https://www.indu23703c00002s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 4.13 Takeda Employee or Employee: includes Takeda Employees and contractors. A contractor is a leased worker such as a contractor or consultant that is assigned to perform services for Takeda by a temporary staffing agency, in the position of a full or part time equivalent Employee, and who are assigned E-mail accounts in the Takeda E-mail system. Contractor does not include, by way of example, contractors or consultants such as auditors from an outside accounting firm. 4.14 Wireless Handheld Devices: shall include all handheld wireless devices that are used to send and receive messages with the Takeda E-Mail System. 5.0 Policies and Procedures 5.1 Overview: 5.1.1 E-mail records are assets of the Company that must be properly maintained and managed. Every employee shares responsibility for the proper management of Company E-mail Records. 5.1.2 Non-record E-Mails need to be discarded in the ordinary course of business, following their period of retention. Failure to dispose of Non-record E-mail increases the costs and complexity of electronic storage, and makes accessing and retrieving information less efficient. 5.2 The policies applicable to the E-mails Management Structure are described below: Prior to the implementation date of this Operating Procedure, storage folders will be available in your E-mail Folder List. These folders shall not be deleted, and are named as follows: 5.2.1 An "E-mail Records" folder will be available for the retention of e-mail that is a Company E-mail Record. E-mail Records may NOT be retained in any other folder, except as defined in Section 5.3. 5.2.2 The E-mail Records folder should NOT be used for any reason other than the storage of E-Mail Records. The use of subfolders for further classification within this folder is allowed. 5.2.3 A "Legal Hold" folder will be available for the storage of e-mail that is required to be preserved for the purpose of actual or anticipated audits, investigations or litigation. Legal hold e-mails may NOT be preserved in any other location. Subfolders for specific litigation cases will be provided by the Law Department and IT for further classification within this folder. 5.2.4 A 'Transition" folder will be available for the storage of all e-mails that exist in each employee e-mail mailbox at the time of implementation of this Operating Procedure, Subfolders identified as "Inbox," "Sent Items," and "Deleted Items" will be provided to organize transition materials. The use of additional subfolders for further classification within this folder is not allowed. 5.2.5 A "Reference" folder will be available to store Non-Record e-mails for personal reference related to Company business. The use of subfolders for further classification within this folder is allowed. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 3 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000085 Source: https://www.indup2373500003s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5.3 The procedures for Retaining E-mail Records are described below: 5.3.1 It is each employee's responsibility to move any e-mail message meeting the definition of an E-Mail Record from their Active E-mail Folders to their E-mail Records folders. E-mail Records must be moved to the E-mail Records folders within 90 days of their creation or receipt. 5.3.2 The E-mail Records folders provided by Takeda are the acceptable locations for the retention of E-mail Records. E-mail Records should not be retained in any other location than in the E-mail Records folders, unless (a) the E-mail Records are subject to a Legal Hold, in which case the e-mail must also be maintained in the Legal Hold folder; or (b) the e-mail is required to be maintained under record requirements of the FDA or other regulatory agency and Takeda has established by BOP, SOP or established business practice, an alternate tool, location, or system for the retention of E-mail records. In the latter case, E-mail Records shall be retained according to the BOP, SOP or established business practice. 5.3.3 The following rules will help you determine which E-mail Record messages need to be retained in the E-mail Records folder: An Employee is required to retain an E-mail Record if the Employee generated or forwarded the E-mail Record or was an addressee of the E-mail Record (excluding carbon copies or blind carbon copies). An Employee is required to retain an E-mail Record if the Employee is required to take some action based on an E-mail Record, and the Employee is the addressee, or appears as a CC or bcc. An Employee is required to retain an E-mail Record if the Employee was sent the E-mail Record from a non-company source (whether or not the Employee is required to take some action based on the E- mail). The E-mail Record shall be retained regardless of whether the Employee receiving the e-mail received il as an addressee, CC, or bcc. 5.3.4 In all cases, E-mail Records that are subject to a Legal Hold must be stored in the E-mail Records folder; (or elsewhere pursuant to 5.3.2 for regulated records) and a copy of the original message should be stored in the Legal Hold folder where it will be preserved. 5.4 The procedures for retaining Legal Hold Materials are described below: 5.4.1 From time to time the Company may instruct you to preserve materials relating to audits, investigations, and/or litigation. IN SUCH CIRCUMSTANCES, ANY AND ALL LEGAL HOLD MATERIALS MUST BE PRESERVED AND NOT MODIFIED, DELETED, CONCEALED, OR OTHERWISE CHANGED IN ANY WAY THAT WOULD ALTER THEIR MEANING OR MAKE THEM INACCESSIBLE. 5.4.2 Employees who become aware of a potential legal requirement to preserve documents, materials, information or things (including electronic documents, materials, information and, things). even though they have not received any official notice to do so, should contact the Law Department. In this situation, do not discard any e-mail about which you have questions until being advised by the Law Department that it is proper to do so. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 4 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000086 Source: https://www.indup2373500004s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5.4.3 Both Record and Non-record E-mails that are subject to a Legal Hold that are contained in your Inbox, Sent Items and Deleted Iterns or that exist in the Draft mailbox folders shall be moved to the "Legal Hold" folder. Such e-mails need to be moved within 90 days of receipt or creation. 5.4.4 Draft e-mails that exist as of the time a Legal Hold comes into effect must be preserved. Draft e-mails must be preserved by moving the draft to the "Legal Hold" folder without change; e.g., additional drafting, alteration, modification, or deletion, of the e-mail's contents. 5.4.5 The following rules will help you determine which Legal Hold Materials need to be retained in the Legal Hold folder: An Employee is required to retain Legal Hold Material if the Employee generated or forwarded the E-mail or was an addressee of the E-mail (excluding carbon copies or blind carbon copies). An Employee is required to retain any Legal Hold Material if the Employee is required to take some action based on an E-mail and the Employee is the addressee, or appears as a carbon copy or blind carbon copy. An Employee is required to retain any Legal Hold Material if the Employee was sent the E-mail from a non-company source (whether or not the Employee is required to take some action based on the E- mail). The E-mail shall be retained regardless of whether the Employee receiving the e-mail received it as an addressee, carbon copy or blind carbon copy. 5.5 The procedures for the maintenance and storage of E-mail non-records are described below: 5.5.1 Non-Record E-mails must only be kept for as long as necessary to conduct business. 5.5.2 Move all reference Non-Record e-mails to the "Reference" folder. Non-Record e- mails needed for reference for more than 90 days are to be moved to the "Reference", folder until they are no longer needed. Once Non-Record e-mails in the "Reference" folder are no longer needed they should be deleted, unless specific e-mails in your "Reference" folder become subject to a Legal Hold, at which point they must be transferred to the "Legal Hold" folder as addressed above. 5.6 The procedures governing the Transition of E-mail is described below. 5.6.1 When this Operating Procedure becomes effective, all e-mail that exists in an Employee's e-mail account, either within the Inbox Folder, other non-default folders, Sent Items Folder or Deleted Items Folder must be moved to the "Transition" folder and its subfolders, Employees shall review all e-mails and determine whether they qualify as E-mail Records or are subject to a Legal Hold. Any e-mails qualifying as an as E-mail Records or subject to a Legal Hold shall be moved to the E-mail Record or Legal Hold folder, respectively. E-mails may be moved to the Reference folder if needed for personal reference for Takeda business. E-mail messages in the Transition folder that are no longer needed should be deleted. UNDER NO CIRCUMSTANCES MAY ANY E-MAIL MESSAGE BE MOVED FROM YOUR TRANSITION FOLDER TO ANY LOCATION OTHER THAN THE Takeda Pharmaceuticals North America, Inc. and Affiliates Page 5 of 7 Confidential - Subject to Protective Order TAK-RIM30b6-00000087 Source: https://www.indup2373-00005s.ucsf.edu/docs/gpjf0226 Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention E-MAIL RECORDS FOLDER, THE LEGAL HOLD FOLDER, OR THE REFERENCE FOLDER. 5.7 The procedures for the Automated Disposition of E-mail Non-records are described below: 5.7.1 Following implementation of this Operating Procedure, any e-mail message which is not moved to the "E-mail Records" folder, "Legal Hold" folder, or "Reference" folder, and which remains within either the "Inbox," "Sent Items," or "Deleted Items" folder of the Active E-mail Folders will be deleted by the system every 90 days (quarterly), and will no longer be available. 5.7,2 Employees must decide within 90 days of receipt or creation whether or not each e-mail message is an E-mail Record or is subject to a Legal Hold that should be retained or preserved. Failure to take the appropriate retention or preservation action within this 90 day period is a violation of this Operating Procedure. 5.7.3 Employees that are unable to access their e-mail account for more than 90-days, or that are otherwise unable to classify e-mail messages in accordance with this Operating Procedure, shall contact their supervisor to make arrangements for the management of their e-mail account. 5.7.4 Employees will receive electronic notification in advance advising of the dates for which e-mails received or created, and that have not been transferred to an E- mail Record, Legal Hold or Reference folder, will be deleted by the system. 5.8 The procedures for the Disposition of E-mail Records and Non-records are described below: 5.8.1 Unless this Operating Procedure authorizes an exception, as described in Section (5.3.2) e-mail shall be retained in electronic form. Generally, printing and filing hardcopies of e-mail messages is not an acceptable form of e-mail retention as it makes the access, management, and retention of E-mail Records and Legal Hold Materials more difficult. 5.8.2 Employees may not move or store any e-mail message, whether Record or Non- Record, outside of the Takeda E-mail system. Examples of such activities prohibited under this Operating Procedure include, but are not limited to: Exporting e-mail from the Company e-mail system to a .pst" or other similar file types; Storing copies of e-mail messages on a Company laptop computer (other than through the automatic synchronization process) to allow access to e-mails when not connected to the Company computer network; Moving e-mail to, or storing it on, any type of portable tape, disk, diskette or storage device, including Personal Digital Assistants, Compact Disks, or USB Drives for the purpose of retention or preservation. Moving e-mail to, or storing it on, any device not owned or provided by Takeda. This would include, for example, the forwarding of Company e-mails to personal e-mail accounts. 5.8.3 Your compliance with these procedures may be periodically audited. Takeda Pharmaceuticals North America, Inc. and Affiliates Page 6 of 7 Confidential n Subject to Protective Order TAK-RIM3056-00000088 Source: Function: Corporate Effective Date: 05/01/2006 BOP Number: CORP-B-019 Supersedes: NA BOP Name: Email Management and Retention 5,9 Restrictions for Wireless Handheld Devices: Wireless handheld devices that allow the management of E-Mail in the Takeda E-mail System, such as a Blackberry, cannot be used to move e-mail files into the e-mail file folder management structure because of limitations with the technology. Therefore, employees using wireless devices to connect to their Takeda E-Mail shall not delete E-mail records from their wireless handheld device that must be retained or preserved pursuant to this Operating Procedure. Employees shall appropriately classify e-mail that must be retained or preserved in accordance with this Operating Procedure by connecting to the Takeda E-Mail system from their Takeda office computer, laptop or workstation to manage their retainable e-mail. 5.10 Restrictions on Use of Disaster Recovery Back-up Tapes: Following implementation of this Operating Procedure, disaster recovery backup tapes and disks that are used for business continuity or disaster recovery purposes shall not be used for any other purpose, and shall not to be used to satisfy retention requirements for Company E- mail Records or Legal Hold Materials. 5.11 Implementation: 5.11.1 The implementation of this Operating Procedure will be announced by an e-mail communication to all Takeda Employees. 5.11.2 Prior to implementation of this Operating Procedure, Employees shall receive pre-implementation instruction and education to facilitate the transition to this new methodology. 6.0 References 6.1 Corp-P-001 Electronic Records and Electronic Signatures 6.2 Corp-P-003 Corporate Records Management and Retention 6.3 Corp-S-010 Creating, Maintaining, and Revising Corporate Records Retention Schedules 6.4 Corp-S-011 Maintaining, Storing, Retrieving, Destroying and Preserving Corporate Records 6,5 Corp-S-012 Legal Holds 7.0 Attachments 7.1 N/A Takeda Pharmaceuticals North America, Inc. and Affiliates Page 7 of 7 Confidential - Subject to Protective Order TAK-RIM3056-00000089 Source: https://www.indup2373-00007ts.ucsf.edu/docs/gpjf0226

What is the date mentioned?

mnjf0226

mnjf0226_p0, mnjf0226_p1, mnjf0226_p2

August 12-13, 2002

TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 FDA Response Outline LABEL CHANGE CLINICAL PEDIATRIC INDICATION Current label adequately reflects General epidemiology of bladder We believe that there is no information that we have cancer increased risk for bladder cancer Not genotoxic Incidence associated with Actos Two year studies, one sex one Latency We would like to proceed with the species Risk factors Actos 508 study No data to correlate those Observations with pio Propose delay until resolved findings to man Post-marketing surveillance No new data OCT020 Summire resists Critique presumed promoter model Findings to be expected Microcrystals known to increase appendix: tumors in those models MONITORING Any findings found require Expert opinion confirmation with a 2 year Restate that there are no findings - which suggest a need to monitor Coher methodsy carcinogenicity study Unvalidated We have already presented in the Possible Question definition of dual agonist NDA the standard of care (-001, - Evidence in literature that pio 011, -031), and no tumors were suppresses urothellal cells as well found as other cell types Talked to experts, evaluated Reinforce Cohen hypothesis existing methods Reiterate that current label is Latency adequate Markers not approved We don't believe we should monitor 70s: cancer We will watch current clinical trials carefully Redding TAK-THOMCL-00017302 Confidential - Subject to Protective Order Produced in MOL on 09/14/12 EXHIBIT 27 cone sue TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 Action Item List/Document Timelines Item Person Responsible Create table summarizing medium term toxicology studies Nonoyama Historical data on incidence of bladder hyperplasia in Toxicology mouse Exposure Toxicology Mouse versus rat Male rat versus female rat Get literature on transient nature of stones in rat Michael Elisseou will fosits A 71 R.S. ask Sam Cohen Add troglitazone to PPAR activation table Dr. Odaka In carcinogenecity studies, did rosiglitazone exposure lead Through FOI, Ray Chart to PPAR alpha activation Run NN622 through liver homogenetic/GCMS/Identify TCI will conduct metabolites/SAR assay Literature to support role of urinary pH and microcrystals Michael Elisseou will in promoter model ask Sam Cohen tukishing Summary of US/EU bladder cancer for NDA/MAA Glyn Belcher Add renal colic to clinical AE search Bob Ahlbrandt will send to John Search PDR for label wording based on results from tumor Janet Haskins model study and for class tox label wording Send rion-serious bladder cancer AE to John Page Glyn Belcher Source: is Confidential - Subject to Protective Order TAK-THOMCL-00017304 Produced In MDL on 09/14/12

What is the heading of the handwritten words in Pediatric Indication?

mnjf0226

mnjf0226_p0, mnjf0226_p1, mnjf0226_p2

appendix, Appendix

TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 FDA Response Outline LABEL CHANGE CLINICAL PEDIATRIC INDICATION Current label adequately reflects General epidemiology of bladder We believe that there is no information that we have cancer increased risk for bladder cancer Not genotoxic Incidence associated with Actos Two year studies, one sex one Latency We would like to proceed with the species Risk factors Actos 508 study No data to correlate those Observations with pio Propose delay until resolved findings to man Post-marketing surveillance No new data OCT020 Summire resists Critique presumed promoter model Findings to be expected Microcrystals known to increase appendix: tumors in those models MONITORING Any findings found require Expert opinion confirmation with a 2 year Restate that there are no findings - which suggest a need to monitor Coher methodsy carcinogenicity study Unvalidated We have already presented in the Possible Question definition of dual agonist NDA the standard of care (-001, - Evidence in literature that pio 011, -031), and no tumors were suppresses urothellal cells as well found as other cell types Talked to experts, evaluated Reinforce Cohen hypothesis existing methods Reiterate that current label is Latency adequate Markers not approved We don't believe we should monitor 70s: cancer We will watch current clinical trials carefully Redding TAK-THOMCL-00017302 Confidential - Subject to Protective Order Produced in MOL on 09/14/12 EXHIBIT 27 cone sue TPNA/TEUR&D/TCI ACTOS RESPONSE MEETING August 12-13, 2002 Action Item List/Document Timelines Item Person Responsible Create table summarizing medium term toxicology studies Nonoyama Historical data on incidence of bladder hyperplasia in Toxicology mouse Exposure Toxicology Mouse versus rat Male rat versus female rat Get literature on transient nature of stones in rat Michael Elisseou will fosits A 71 R.S. ask Sam Cohen Add troglitazone to PPAR activation table Dr. Odaka In carcinogenecity studies, did rosiglitazone exposure lead Through FOI, Ray Chart to PPAR alpha activation Run NN622 through liver homogenetic/GCMS/Identify TCI will conduct metabolites/SAR assay Literature to support role of urinary pH and microcrystals Michael Elisseou will in promoter model ask Sam Cohen tukishing Summary of US/EU bladder cancer for NDA/MAA Glyn Belcher Add renal colic to clinical AE search Bob Ahlbrandt will send to John Search PDR for label wording based on results from tumor Janet Haskins model study and for class tox label wording Send rion-serious bladder cancer AE to John Page Glyn Belcher Source: is Confidential - Subject to Protective Order TAK-THOMCL-00017304 Produced In MDL on 09/14/12

what is the patient number?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

014

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

Which Procedures No is being decribed here?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

Procedures No. 19

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

how many targeted primary care physicians are included in these meetings ?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

350

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

in which month and year eight regional market research consultants meetings were held ?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

October and November 2001, october and november 2001

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

In which Article, Persons In Charge of Retention is described?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

Article 2

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

what is diagnosis?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

benign tumor of the urinary bladder

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

what are the challenges of ACTOS positive data?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

small numbers in the studies, non-randomized, company-sponsored.

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

In U.S. clinical trials, how many patients have received ACTOS?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

over 4700 patients, OVER 4700

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

What does alternate terms include?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

core therapy; cornerstone therapy; first-line.

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

which is an effective and liver-safe agent accepted by the participants ?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

ACTOS

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

what is an effective and trusted agent ?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

Metformin, metformin

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

Which medicine is used for treating type 2 diabetes in over 5900 patients?

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hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

ACTOS

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

what are the most commonly mentioned reasons not to prescribe TZD's ?

rnjf0226

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1) Cost, 2) Edema/weight gain, and 3) Reimbursement.

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

in one ACTOS treatment group how much amount of initial dose is given to the patients daily ?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

7.5 mg once daily, 7.5 mg

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

in a 24 week placebo controlled study how many patients with type 2 diabetes were randomized ?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

260 patients, 260

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

What is the retention time period of monthly reports?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

30 years

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

in the second ACTOS treatment group,how much amount of initial dose patients should receive daily ?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

15 mg, 15 mg once daily

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

What does Attachment 1 describes?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

List of Retention Periods of Time, Retention Locations

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

What is the retention time period of contracts?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

Permanently

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

where participants seemed more cautious more resistant to the entire message?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

In Boston, in Boston

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

What is the fullform of ARA?

kqbn0226

kqbn0226_p13, kqbn0226_p14, kqbn0226_p15

Alliance for Risk Assessment

NAS (2014) & IRIS Process "Finding: IRIS-specific guidelines for consistent, coherent, and transparent assessment and communication of uncertainty remain incompletely developed. The inconsistent treatment of uncertainties remains a source of confusion and causes difficulty in characterizing and communicating uncertainty. Recommendation: Uncertainty analysis should be conducted systematically and coherently in IRIS assessments. To that end, EPA should develop IRIS-specific guidelines to frame uncertainty analysis and uncertainty communication. Moreover, uncertainty analysis should become an integral component of the IRIS process." [emphasis added] 12 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) ARA TCE Workgroup formed in the Fall of 2012 Open invitation: over 300 scientists from multiple international organizations, including government, industry, academia and NGOs, on 6 conference calls and one webinar. Trichloroethylene (TCE) Risk Assessment Guidance for Contaminated Sites (April 2013) Webcast: Practical Guidance for Contaminated Sites:TCE Risk Assessment Case Study (November 4, 2013) 13 Source: ttps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) Guidance for Contaminated Sites:Trichloroethylene Case Study. Gadagbui, et al., SOT, 53rd Annual Meeting & ToxExpo,23-27 March 2014, Phoenix,AZ. Development of a Non-cancer Hazard Range for Effective Risk Assessment and Risk Management of Contaminated Sites:A Case Study with TCE and Other Chemicals, Beyond Science & Decisions: Problem Formulation to Dose- Response Assessment,Workshop VIII, 21-22 May 2014, Austin, TX. 14 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226

where were responses more strongly positive than in other cities?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

In Philadelphia, in philadelphia (home of glaxosmithkline)

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

Who is the President of The Fertilizer Institute?

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Chris Jahn

To: Greenwalt, Sarah[greenwalt.sarah@epa.gov]; Dravis, Samantha[dravis.samantha@epa.gov] Brown, Byron[brown.byron@epa.gov];Wagner, Kenneth[wagner.kenneth@epa.gov] From: Hupp, Sydney Sent: Thur 3/30/2017 5:11:34 PM Subject: FW: FINAL Meeting Agenda and Materials Pruitt Meeting Materials.pd FYI. Sydney Hupp Office of the Administrator- Scheduling 202.816.1659 From: Mary Jo Tomalewski [mailto:mjtomalewski@croplifeamerica.org] Sent: Thursday, March 30, 2017 11:22 AM To: Hupp, Sydney <hupp.sydney@epa.gov> Cc: Jay Vroom <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000061-00001 MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobile Ex. 6 Personal Privacy Fax (202)466-5832 Email mjtomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000061-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00011 The Fertilizer Institute Nourish, Replenish, Grow BIOGRAPHY OF CHRISTOPHER JAHN President The Fertilizer Institute and the Nutrients for Life Foundation Christopher L. Jahn is president of The Fertilizer Institute (TFI), the fertilizer industry's national trade association. As TFI president, Jahn works to represent, promote and protect a sound fertilizer industry through legislative and regulatory activities and to promote a favorable public image of the fertilizer industry and agriculture. Jahn also serves as president of the Nutrients for Life Foundation (NFL). Jahn comes to TFI having served as president of the National Association of Chemical Distributors (NACD) since 2006. Prior to leading NACD, Jahn served as president of the Contract Services Association (CSA). Before joining CSA, Jahn had an active role in the United States Senate working for nearly 10 years for U.S. Senator Craig Thomas (R-Wyo.) in a variety of roles, including legislative assistant, legislative director and Chief of Staff. After graduating from Columbia University with a B.A. in Political Science, Jahn co-founded a book distribution business. He also earned an MBA from the University of Maryland. A native of Wyoming, Chris and his wife, Ex. 6 - Personal Privacy Ex. Personal Privacy Capitol View 202.962.0490 425 Third Street, S.W., Suite 950 202.962.0577 fax Washington, DC 20024 www.tfi.org Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00012 National Farmers Union Roger Johnson President Roger Johnson is president of the National Farmers Union (NFU), a grassroots organization that represents more than 200,000 family farmers, ranchers, fisherman and rural communities across the Unites States. Johnson was elected to lead the family farm organization at NFU's 107th anniversary convention in 2009. He has since expanded the education department by providing more programs for beginning, college-aged and women farmers, increased the number of Farmers Union state divisions, and developed a strategic plan for the organization. Johnson has also overseen a number of important policy initiatives important to family farmers including: passage of the 2014 Farm Bill; maintaining a strong Renewable Fuel Standard and Country-of-Origir Labeling, promoting policies that allow farmers to address the growing threat of climate change; and renewing the nation's focus on eliminating an overwhelming trade deficit that results in lost jobs and prosperity for rural America. Prior to leading National Farmers Union, Johnson, a third-generation family farmer from Turtle Lake, N.D., served as North Dakota Agriculture Commissioner, a position he was first elected to in 1996. While Agriculture Commissioner, Johnson served on the State Industrial Commission, the North Dakota Trade Office Advisory Board, and the State Board of Agricultural Research and Education, among many other boards and commissions. From 2007-2008, Johnson served as president of the National Association of State Departments of Agriculture (NASDA). He is a past president of the Midwestern Association of State Departments of Agriculture (MASDA), past president of the Food Export Association of the Midwest and a former chairman of the Interstate Pest Control Compact. Johnson graduated from North Dakota State University with a degree in agricultural economics. Johnson and his wife Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00013 AMERICAN SEED TRADE ASSOCIATION asta first-the - seed R Andrew W. "Andy" LaVigne President & CEO Andrew W. LaVigne is currently the President and CEO of the Ame rican Seed Trade Association. He joined ASTA in February, 2006. Andy has had a 30-year career i n government relations, industry representation, public affairs advocacy, and management. His C ore areas of expertise include agriculture, food policy and international trade. Prior to joining ASTA, Andy was Executive Vice President/CEC of Florida Citrus Mutual, representing citrus growers on issues affecting their business. Prejaiming tFdorida Citrus Mutual, Andy spent four years as Florida Fertilizer and Agrichemical Association's (FFAA) President and Executive Director. FFAA is a non-profit, agricultural trade organization representing companies that specialize in crop protection and plant nutrition products. Before his position at FFAA, Andy spent eight years in Washingt on, D.C. working in the U.S. Congress and the U.S. Department of Agriculture. He served as Legislative Director for Congressman Charles Canady, Agriculture Committee staffer for Congressman Tom Lewis , and on the staff of USDA Secretary Ed Madigan. Andy is a native of Florida with a BA degree in Political Scien ce, with a minor in economics, from the University of Florida. 1701 Duke Street Suite 275 Alexandria, VA 22314 Phone: (703)837-8140 Fax: (703)837-9365 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00014 Biotechnology Innovation Organization Dana O'Brien Executive Vice President, Food & Agriculture Dana O'Brien is Executive Vice President for Food and Agriculture and is responsible for the development of public policy and strategic advocacy, public affairo, and legal strategies that advance industry and stakeholder objectives in the United States. Prior to becoming EVP, Dana served bs BIO Food and Agriculture's chief legislative advocate as Senior Director of Federal Government Relations aince March 2011. Before BIO, Dana worked in Congress for the late Representative lke Skelton (D-MO) managing his legislative team and concentrating on a variety of agricultural, energy, and trade matters. A native of Sedalia, Missouri, and a graduate of Missouri University with a bachelor's degree in psychology, Dana joined the Skelton team immediately out of college and served there for nearly 14 years Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00015 UNITED FRESH is PRODUCE ASSOCIATION Tom Stenzel President and CEO United Fresh Produce Association 1901 Pennsylvania Avenue NW, Suite 1100 Washington, DC 20006 202/303-3400 tstenzel@unitedfresh.org Tom Stenzel is President and CEO of the United Fresh Produce Association, a position he has held since 1993. United Fresh is the pre-eminent trade association for the produce industry in shaping legislative and regulatory policies; providing scientific and technical leadership in food safety and nutrition; and developing educational programs for its members. Founded in 1904, United Fresh represents the interests of companies from small family businesses to the largest international corporations throughout the global fresh produce supply chain. United Fresh is widely known for its work in government affairs, agricultural policy, food safety and nutrition, working to promote political and environmental change to help the next generation of children double their consumption of fresh produce. The United Fresh Start Foundation is committed to increasing children's access to fresh fruits and vegetables, and is a founding partner of the Let's Move Salad Bars to Schools campaign. The campaign has donated salad bars to more than 6,000 schools across the country. Tom is a frequent speaker on industry issues and has been recognized often by the produce industry throughout his career. He was honored as the 2002 Produce Man of the Year by The Packer newspaper, and is the past Chairman of the International Federation for Produce Standards, a global body representing national produce associations around the world. He is a member of the U.S. Chamber of Commerce Committee of 100 leading association executives, the Advisory Board of the International Food Protection Training Institute, and the Key Industry Associations Committee of the American Society of Association Executives, from which he achieved the Certified Association Executive (CAE) designation in 1990. He has served in many government and industry leadership positions, including the first U.S. Department of Agriculture Fruit and Vegetable Industry Advisory Committee, President George W. Bush's Transition Advisory Team for Agriculture, and as an advisor on the U.S. Agricultural Policy Advisory Committee for Trade. Tom was the founding President of the International Food Information Council (IFIC) in 1986, and was previously director of public affairs for the National Soft Drink Association. Tom is a 1977 graduate of the University of Richmond. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00016 as of January 17, 2017 Jay Vroom has served as President and CEO of the trade association known as CropLife America (CLA) since 1989. CLA is the leading U.S. trade group for the crop protection industry in the U.S. Vroom is a founding member of the CropLife Foundation, serving as chairman since its inception in 2001, and now serves as the Foundation's Vice-Chair, since 2015. His sits of the Board of Directors for the Agricultural Retailers Association, Asmark, National Wheat Foundation, the National Association of Manufacturers Council of Manufacturing Associations, and the Soil Health Institute. He is also a member of the Farm Foundation Roundtable Steering Committee, and the North American Climate Smart Ag Alliance Steering Committee. Vroom was a member of the youth organization, Future Farmers of America, and served as an elected state officer in Illinois. Today, he is a member of the FFA Foundation's Individual Giving Council and Board of Trustees. Vroom co-chairs the Coalition for the Advancement of Precision Agriculture and the CEO Council. He is a member of the Friends of the National Arboretum (FONA) FONA Council. He graduated with honors from the College of Agriculture, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign. Vroom was raised on a grain and livestock farm in north-central Illinois and continues to own the farming operation. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00017 Elizabeth Ward Betsy Ward was appointed President & CEO of the USA Rice Federation in 2007. From 2003- 2005, Ward was the Vice President of International and Domestic Promotion at USA Rice where she was in charge of developing and implementing domestic and international promotion, and food aid programs. From 2005-2007, Ward served as the chief executive for the Hardwood Federation, a trade association representing over 15,000 hardwood producers across the United States. From 1995 to 2003, she ran the Wood Products International Group at the American Forest & Paper Association, directing the wood trade policy and global forestry agenda for the industry. In 2011, Ward was elected Chairman of the U.S. Agricultural Export Development Council (USAEDC) which represents the interests of more than 80 commodity organizations who grow and process a wide variety of U.S. agricultural products. She currently serves as Past Chair. Since 2011, Ward has also served on the Board of Directors of the Sustainable Fisheries Partnership, an independent non-governmental organization (NGO) working to ensure healthy marine and aquatic tecosystems; secure seafood supplies; and a thriving, responsible seafood economy. Ward served for six years as a cleared advisor on the Industry Trade Advisory Committee for forest and paper products (ITAC-7) and was appointed forest products representative to USDA's Agricultural Policy Advisory Committee (APAC) in 2001. Ward holds a Bachelor's degree in History and Political Science from the University of New Hampshire and a Master's degree in International Security Affairs from the School of International Affairs at Columbia University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00018 To: Brown, Byron[brown.byron@epa.gov]; Jackson, Ryan[jackson.ryan@epa.gov] From: Rebeckah Adcock Sent: Thur 3/30/2017 4:10:52 PM Subject: FW: FINAL CEO Council Meeting Agenda and Materials Pruitt Meeting Materials.pdf ATT00001.htm FYI - final materials for today's meeting. Reb From: "Mary Jo Tomalewski" <mjtomalewski@croplifeamerica.org> To: "Hupp, Sydney" <hupp.sydney@epa.gov> Cc: "Jay Vroom" <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00001 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobilé Ex. 6 Personal Privacy Fax (202) 466-5832 Email mitomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00002

What is the exhibit number?

rljf0226

rljf0226_p0, rljf0226_p1, rljf0226_p2

39

0 6 MAY 2004 A15778-001 page 007 A15778 event description: part 1 PROACTIVE Centre number Patient initials Patient number 4 g o A 3 0 1 4 Reason for alert report: Complete pages 001 and 002 for all events, complete additional pages as indicated (tick all that apply) Serious Episode of chest Coronary Carebrovercular Amputation / Other a adverse pain discomfort revascularisation event reváscularisation of the leg see note 2 event paga 003 complete pago aso page 004 complete page 004 Medical event (diagnosis) benign turna of the unhay bladder Serlousness Data of onset (tick all that apply) day month year Completer death MO NO 04 Fatal report R CRF Life-threatening Relationship to study medication (lick only one) 29 Required or prolonged hospitalisation Definite 30 se Persistent or significant disability or incapacity Probable " Congenital anomaly Possible is Important medical event Unlikely / unrelated a Does not meet definition of serious adverse event Study Medication day month year 45 mg 00 mg 15 mg Date first Current dose Medication ongolng yes started 0 5 A A 0 1 at event onset 20 at onset of event? day month year no Date first Date started stopped is " not yet started Details (Please write in English) (include relevant medical history, course of the event, diagnostic evaluations and management) ISDICO - 10/2/04 V Rospublication because of an turner of the unbay bladder 16/2/04 & suggery abiology: sonigo tumor A: on Daga 000 2 Revised 30-DEC-01 Contre Ìi I EXHIBIT 39 Canny send Confidential - Subject to Protective Order TAK-INDNDA-00456038 Produced in MDL on 09/12/12 Source: https://wwww.indup0026-0000nts.ucsf.edu/docs/rljf0226 49 931 20136759 04/05/2004 11:05 43-931-20136759 DIABETESAMBULANZ 22/04/2084 12:03 S. 01/03 NCRL + 9004993120136283 NO.938 0002 PROactive Urgent Data Enquiry Form Cantre number Patient number Patient Initiais Date of rendomisation 49013 014 05-11-01 Reference Date Issued Date resolved 135035-hr/hrt/net-10 22-04-04 14 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bia ITEM 01: Reason for Alert Report; Serieus adverse event As the patient was hospitalised for this event, this qualifies as a SAE: Other hospitalisation should only be ticked for admission la hospital for a procedure or treatment for an event which is not new or has not worsened aftei randomisation. We have theretore ticked box 01 and box 10, Please confirm that we may remove the ticks from Dox 06 and box 14. Repty; Okay 15 Alert Report Bookiet A15778 (page 001) ".--04, Benign tumor of the urinary bla ITEM 21: Details: summary of relevant medical details Please provide a brief description of the events/sympterns which lead to the patient baing hospitalised Reply; the patient had a nacrofemoduria 16 Alen Report Bocklet A15778 (page 008) -04, Benign tumor of the umary bia ITEM 50: Datails: new / medical detaite The date of resolution has been reported as 16-04-04 nowever we note that this is 2 months after the date of discharge. Please provide details of any treatment given to the patient after discharge. Reply: Sorry that 5000 a mictake ! Date of resolution is of course 16/02/04 , the date of the suggy Signature: Bed Date: 04/5/04 Please write your reply in the space previded and ensure that the reply is signed as this sheel will become part of the patient's necord form. Once completed, please fax the form back to the Study Coordinating Centre (++44115 956 77 22) end retain the original in the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456052 Produced in MDL on 09/12/12 Source: https://www.indup0026-00002 ts.ucsf.edu/docs/rljf0226 04/05/2084 11:05 49-931-20136759 22/04/2004 DIABETESAMBLLLANZ 12:03 NCPL + 9084993120136283 s. 02/03 2803 PROactive Urgent Data Enquiry Form Centra number Patient number Pattent initiais Date of randomisation 49013 014 05-11-01 Reference Date issued Date resolved 135037-hrt-11 22-04-04 17 Alert Report Booklet A15778 (page 001) Benign tumor of the urinary bla ITEM 07: Medical event (diagnosis) For all serioue epísodes of Bladder cancer, Takeda Drug Safety require additional information and would appreci- ate It as you could complete the attached questionnaire and return is to us with this enquiry form signed and dated as soon as possible. Reply: It was no cancer , it was a benign turnor (see the diagnosis of the about report) Signature: C Beds Date: 4/5/04 Please write your reply in the space provided and ensure that the raply is signed as this sheet will become part of the patient's record form. Once completed, please fax the form back to the Study Coordinating Centre (++ 44 115 956 77 22) and retain the original In the patient's Case Report Form. Confidential - Subject to Protective Order TAK-INDNDA-00456053 Produced in MDL on 09/12/12 Source: https://www.indup0u26-00003 ts.ucsf.edu/docs/rljf0226

Roger Johnson is associated with which union?

ffcn0226

ffcn0226_p0, ffcn0226_p1, ffcn0226_p2, ffcn0226_p3, ffcn0226_p4, ffcn0226_p5, ffcn0226_p6, ffcn0226_p7, ffcn0226_p8, ffcn0226_p9, ffcn0226_p10, ffcn0226_p11, ffcn0226_p12, ffcn0226_p13, ffcn0226_p14, ffcn0226_p15, ffcn0226_p16, ffcn0226_p17, ffcn0226_p18, ffcn0226_p19, ffcn0226_p20, ffcn0226_p21, ffcn0226_p22, ffcn0226_p23

National Farmers Union

To: Greenwalt, Sarah[greenwalt.sarah@epa.gov]; Dravis, Samantha[dravis.samantha@epa.gov] Brown, Byron[brown.byron@epa.gov];Wagner, Kenneth[wagner.kenneth@epa.gov] From: Hupp, Sydney Sent: Thur 3/30/2017 5:11:34 PM Subject: FW: FINAL Meeting Agenda and Materials Pruitt Meeting Materials.pd FYI. Sydney Hupp Office of the Administrator- Scheduling 202.816.1659 From: Mary Jo Tomalewski [mailto:mjtomalewski@croplifeamerica.org] Sent: Thursday, March 30, 2017 11:22 AM To: Hupp, Sydney <hupp.sydney@epa.gov> Cc: Jay Vroom <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000061-00001 MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobile Ex. 6 Personal Privacy Fax (202)466-5832 Email mjtomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000061-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00011 The Fertilizer Institute Nourish, Replenish, Grow BIOGRAPHY OF CHRISTOPHER JAHN President The Fertilizer Institute and the Nutrients for Life Foundation Christopher L. Jahn is president of The Fertilizer Institute (TFI), the fertilizer industry's national trade association. As TFI president, Jahn works to represent, promote and protect a sound fertilizer industry through legislative and regulatory activities and to promote a favorable public image of the fertilizer industry and agriculture. Jahn also serves as president of the Nutrients for Life Foundation (NFL). Jahn comes to TFI having served as president of the National Association of Chemical Distributors (NACD) since 2006. Prior to leading NACD, Jahn served as president of the Contract Services Association (CSA). Before joining CSA, Jahn had an active role in the United States Senate working for nearly 10 years for U.S. Senator Craig Thomas (R-Wyo.) in a variety of roles, including legislative assistant, legislative director and Chief of Staff. After graduating from Columbia University with a B.A. in Political Science, Jahn co-founded a book distribution business. He also earned an MBA from the University of Maryland. A native of Wyoming, Chris and his wife, Ex. 6 - Personal Privacy Ex. Personal Privacy Capitol View 202.962.0490 425 Third Street, S.W., Suite 950 202.962.0577 fax Washington, DC 20024 www.tfi.org Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00012 National Farmers Union Roger Johnson President Roger Johnson is president of the National Farmers Union (NFU), a grassroots organization that represents more than 200,000 family farmers, ranchers, fisherman and rural communities across the Unites States. Johnson was elected to lead the family farm organization at NFU's 107th anniversary convention in 2009. He has since expanded the education department by providing more programs for beginning, college-aged and women farmers, increased the number of Farmers Union state divisions, and developed a strategic plan for the organization. Johnson has also overseen a number of important policy initiatives important to family farmers including: passage of the 2014 Farm Bill; maintaining a strong Renewable Fuel Standard and Country-of-Origir Labeling, promoting policies that allow farmers to address the growing threat of climate change; and renewing the nation's focus on eliminating an overwhelming trade deficit that results in lost jobs and prosperity for rural America. Prior to leading National Farmers Union, Johnson, a third-generation family farmer from Turtle Lake, N.D., served as North Dakota Agriculture Commissioner, a position he was first elected to in 1996. While Agriculture Commissioner, Johnson served on the State Industrial Commission, the North Dakota Trade Office Advisory Board, and the State Board of Agricultural Research and Education, among many other boards and commissions. From 2007-2008, Johnson served as president of the National Association of State Departments of Agriculture (NASDA). He is a past president of the Midwestern Association of State Departments of Agriculture (MASDA), past president of the Food Export Association of the Midwest and a former chairman of the Interstate Pest Control Compact. Johnson graduated from North Dakota State University with a degree in agricultural economics. Johnson and his wife Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00013 AMERICAN SEED TRADE ASSOCIATION asta first-the - seed R Andrew W. "Andy" LaVigne President & CEO Andrew W. LaVigne is currently the President and CEO of the Ame rican Seed Trade Association. He joined ASTA in February, 2006. Andy has had a 30-year career i n government relations, industry representation, public affairs advocacy, and management. His C ore areas of expertise include agriculture, food policy and international trade. Prior to joining ASTA, Andy was Executive Vice President/CEC of Florida Citrus Mutual, representing citrus growers on issues affecting their business. Prejaiming tFdorida Citrus Mutual, Andy spent four years as Florida Fertilizer and Agrichemical Association's (FFAA) President and Executive Director. FFAA is a non-profit, agricultural trade organization representing companies that specialize in crop protection and plant nutrition products. Before his position at FFAA, Andy spent eight years in Washingt on, D.C. working in the U.S. Congress and the U.S. Department of Agriculture. He served as Legislative Director for Congressman Charles Canady, Agriculture Committee staffer for Congressman Tom Lewis , and on the staff of USDA Secretary Ed Madigan. Andy is a native of Florida with a BA degree in Political Scien ce, with a minor in economics, from the University of Florida. 1701 Duke Street Suite 275 Alexandria, VA 22314 Phone: (703)837-8140 Fax: (703)837-9365 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00014 Biotechnology Innovation Organization Dana O'Brien Executive Vice President, Food & Agriculture Dana O'Brien is Executive Vice President for Food and Agriculture and is responsible for the development of public policy and strategic advocacy, public affairo, and legal strategies that advance industry and stakeholder objectives in the United States. Prior to becoming EVP, Dana served bs BIO Food and Agriculture's chief legislative advocate as Senior Director of Federal Government Relations aince March 2011. Before BIO, Dana worked in Congress for the late Representative lke Skelton (D-MO) managing his legislative team and concentrating on a variety of agricultural, energy, and trade matters. A native of Sedalia, Missouri, and a graduate of Missouri University with a bachelor's degree in psychology, Dana joined the Skelton team immediately out of college and served there for nearly 14 years Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00015 UNITED FRESH is PRODUCE ASSOCIATION Tom Stenzel President and CEO United Fresh Produce Association 1901 Pennsylvania Avenue NW, Suite 1100 Washington, DC 20006 202/303-3400 tstenzel@unitedfresh.org Tom Stenzel is President and CEO of the United Fresh Produce Association, a position he has held since 1993. United Fresh is the pre-eminent trade association for the produce industry in shaping legislative and regulatory policies; providing scientific and technical leadership in food safety and nutrition; and developing educational programs for its members. Founded in 1904, United Fresh represents the interests of companies from small family businesses to the largest international corporations throughout the global fresh produce supply chain. United Fresh is widely known for its work in government affairs, agricultural policy, food safety and nutrition, working to promote political and environmental change to help the next generation of children double their consumption of fresh produce. The United Fresh Start Foundation is committed to increasing children's access to fresh fruits and vegetables, and is a founding partner of the Let's Move Salad Bars to Schools campaign. The campaign has donated salad bars to more than 6,000 schools across the country. Tom is a frequent speaker on industry issues and has been recognized often by the produce industry throughout his career. He was honored as the 2002 Produce Man of the Year by The Packer newspaper, and is the past Chairman of the International Federation for Produce Standards, a global body representing national produce associations around the world. He is a member of the U.S. Chamber of Commerce Committee of 100 leading association executives, the Advisory Board of the International Food Protection Training Institute, and the Key Industry Associations Committee of the American Society of Association Executives, from which he achieved the Certified Association Executive (CAE) designation in 1990. He has served in many government and industry leadership positions, including the first U.S. Department of Agriculture Fruit and Vegetable Industry Advisory Committee, President George W. Bush's Transition Advisory Team for Agriculture, and as an advisor on the U.S. Agricultural Policy Advisory Committee for Trade. Tom was the founding President of the International Food Information Council (IFIC) in 1986, and was previously director of public affairs for the National Soft Drink Association. Tom is a 1977 graduate of the University of Richmond. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00016 as of January 17, 2017 Jay Vroom has served as President and CEO of the trade association known as CropLife America (CLA) since 1989. CLA is the leading U.S. trade group for the crop protection industry in the U.S. Vroom is a founding member of the CropLife Foundation, serving as chairman since its inception in 2001, and now serves as the Foundation's Vice-Chair, since 2015. His sits of the Board of Directors for the Agricultural Retailers Association, Asmark, National Wheat Foundation, the National Association of Manufacturers Council of Manufacturing Associations, and the Soil Health Institute. He is also a member of the Farm Foundation Roundtable Steering Committee, and the North American Climate Smart Ag Alliance Steering Committee. Vroom was a member of the youth organization, Future Farmers of America, and served as an elected state officer in Illinois. Today, he is a member of the FFA Foundation's Individual Giving Council and Board of Trustees. Vroom co-chairs the Coalition for the Advancement of Precision Agriculture and the CEO Council. He is a member of the Friends of the National Arboretum (FONA) FONA Council. He graduated with honors from the College of Agriculture, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign. Vroom was raised on a grain and livestock farm in north-central Illinois and continues to own the farming operation. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00017 Elizabeth Ward Betsy Ward was appointed President & CEO of the USA Rice Federation in 2007. From 2003- 2005, Ward was the Vice President of International and Domestic Promotion at USA Rice where she was in charge of developing and implementing domestic and international promotion, and food aid programs. From 2005-2007, Ward served as the chief executive for the Hardwood Federation, a trade association representing over 15,000 hardwood producers across the United States. From 1995 to 2003, she ran the Wood Products International Group at the American Forest & Paper Association, directing the wood trade policy and global forestry agenda for the industry. In 2011, Ward was elected Chairman of the U.S. Agricultural Export Development Council (USAEDC) which represents the interests of more than 80 commodity organizations who grow and process a wide variety of U.S. agricultural products. She currently serves as Past Chair. Since 2011, Ward has also served on the Board of Directors of the Sustainable Fisheries Partnership, an independent non-governmental organization (NGO) working to ensure healthy marine and aquatic tecosystems; secure seafood supplies; and a thriving, responsible seafood economy. Ward served for six years as a cleared advisor on the Industry Trade Advisory Committee for forest and paper products (ITAC-7) and was appointed forest products representative to USDA's Agricultural Policy Advisory Committee (APAC) in 2001. Ward holds a Bachelor's degree in History and Political Science from the University of New Hampshire and a Master's degree in International Security Affairs from the School of International Affairs at Columbia University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00018 To: Brown, Byron[brown.byron@epa.gov]; Jackson, Ryan[jackson.ryan@epa.gov] From: Rebeckah Adcock Sent: Thur 3/30/2017 4:10:52 PM Subject: FW: FINAL CEO Council Meeting Agenda and Materials Pruitt Meeting Materials.pdf ATT00001.htm FYI - final materials for today's meeting. Reb From: "Mary Jo Tomalewski" <mjtomalewski@croplifeamerica.org> To: "Hupp, Sydney" <hupp.sydney@epa.gov> Cc: "Jay Vroom" <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00001 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobilé Ex. 6 Personal Privacy Fax (202) 466-5832 Email mitomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00002

What is accepted as an effective glucose control agent?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

ACTOS

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

what are reasons not to prescribe TZDs ?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

1) Cost, 2) Edema/Weight gain, and 3) Reimbursement., 1)cost,2)edema/weight gain, and 3) reimbursement

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

what is the subheading under the title of "specific findings"?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

A. Reaction to IR Information, reaction to IR information, Reaction to IR Information

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

What is the date mentioned?

rnjf0226

rnjf0226_p0, rnjf0226_p1, rnjf0226_p2, rnjf0226_p3, rnjf0226_p4, rnjf0226_p5, rnjf0226_p6, rnjf0226_p7, rnjf0226_p8, rnjf0226_p9, rnjf0226_p10, rnjf0226_p11

December, 2001

ral Report 12-13-01.doc DALY 61 ACTOS® (pioglitazone HCI) Market Research Consultants Meetings "Assessing TZD Effects Beyond Glycemic Control" CTK-ACTLAP - Final Report - This report contains three levels of detail- Level 1: One-page Top-Line Summary on page 2 Level 2: Text boxes at each Heading or Sub-heading Level 3: Full details appear under each Sub-heading Prepared For: Takeda Pharmaceuticals America, Inc. Prepared By: C. Beck, LLC Date: December, 2001 Confidential - Subject to Protective Order TAK-DALYRI-00058796 Produced in MDL on 09/17/12 Source: https://www.induptisacoooonts.ucsf.edu/docs/rnjf0226 Table of Contents I. Top-Line Summary 2 II. Objectives and Methodology 3 A. Objectives 3 B. Methodology 3 III. Summary of Pre/Post Survey Results 5 IV. Special Examinations 5 A. Examination of Responses: Differences between Sites 6 B. Examination of Responses: High Potentials vs. Splitters 6 V. Specific Findings 8 A. Reaction to IR Information 8 B. Reaction to Information on Dyslipidemia and CVD 9 C. Reaction to Data Regarding TZD Performance in Practice 9 D. Reaction to ACTOS Foundation Therapy Strategy 10 1 Confidential - Subject to Protective Order TAK-DALYRI-00058797 Produced in MDL on 09/17/12 Top-Line Summary Eight Regional Market Research Consultants Meetings were held in October and November 2001. Each location featured the same program: 1) A 3-hour plenary session featuring speakers and Q&A; and 2) 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. These meetings included 350 targeted primary care physicians- 181 High Potentials and 169 TZD Splitters. The presentations strengthened already-positive perceptions of TZDs. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. Most believe intuitively that TZDs preserve beta cell function. If convinced by clinical data that TZDs do, in fact, preserve beta cells, many participants would feel compelled to use TZDs as 1st-line therapy. There is broad and substantial recognition of the relationship of diabetic dyslipidemia and cardiovascular disease. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Most believe that TZDs have the best potential for a positive cardiovascular profile. Participants accept ACTOS as an effective and liver-safe agent. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes, including lipid effects. While participants accept the head-to-head lipid studies as validly- conducted research (with some reservations), most are reluctant to attach a great deal of clinical value to the data. Head-to-head data from clinical studies (TZDs vs. other OADs, AND ACTOS vs. Avandia) is needed to significantly alter prescribing habits. Splitters and High Potentiais responded similarly with regard to most of the observed core issues, although Splitters are clearly more likely than High Potentials to use TZDs as first-line therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, assuming the accumulation of clinical outcomes data. Metformin is an effective and trusted agent. Doctors caution against fighting against it - instead, promote combo use with metformin. The most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. 2 Confidential - Subject to Protective Order TAK-DALYRI-00058798 Produced in MDL on 09/17/12 de Objectives and Methodology A. Objectives The primary objectives of these market research meetings were to 1) Present new data regarding Type 2 diabetes in the context of insulin resistance, dyslipidemia, CVD, and TZD therapy; 2) Quantitatively measure participant response to the data presented, including distinctions between High Potentials and Splitters; and 3) Gather qualitative feedback on the current product message. Takeda will use the data gathered to develop future promotional programming. B. Methodology Eight on-site half-day market research consultants meetings were conducted over a six-week-period in October and November 2001. A total of 350 targeted physicians participated -- 181 High Potentials and 169 Splitters. The eight market research meetings occurred between October 12 and November 17, 2001. 350 target physicians attended - 181 High TZD Potentials and 169 TZD Splitters. At each location, participants arrived on Friday evening. The plenary session and breakout groups occurred on Saturday morning. Each site featured a unique three-speaker panel. The three speakers each presented one of three topics: 1) The Insulin Resistance Syndrome: Understanding and Treating Core Defects; 2) The Relationship Between Dyslipidemia and CVD in Patients with Type 2 Diabetes; and 3) TZD Performance in Daily Practice: A Review of Comparative Studies. Each of the three presentations included a core set of slides provided by Takeda/Lilly. Beyond these core slides, each speaker added slides at will. The plenary session at each site included an electronic pre-survey, the three expert presentations, Q & A, and an electronic post-survey. 3 Confidential - Subject to Protective Order TAK-DALYRI-00058799 Produced in MDL on 09/17/12 Source: https://www.indup89c00004t.ucsf.edu/docs/rnjf0226 The plenary session was followed by 90-minute breakout discussion sessions in which High Potential TZD users were separated from TZD Splitters. An average of 11.3 physicians were in each breakout group. Takeda/Lilly paid all participant travel and living expenses and a cash honorarium. Dates, locations and speakers are detailed in the following table. Date City Hotel IR CVD Comp. Studies 10/12-13 Chicago, IL Chicago O'Hare Marriott Rajeev Jain Mark Stolar Stanley Schwartz Great Lakes: IL, IN, KY, 8535 West Higgins Road MI Chicago, IL 60631 Phone: 773-693-4444 10/19-20 San Francisco, CA San Francisco Airport Marriott David Robert Henry Mark Stolar West: AZ, CA, ID, MT, 1800 Old Bayshore Highway Robertson NV, NM, OR, UT, WA, Burlingame, CA 94010 WY, Hi, AK Phone: 650-692-9100 10/19-20 Denver, CO Renaissance Denver Hotel Paulos Jaime Davidson Howard Brand Midwest: CO, IA, KS, 3801 Quebec Street Berhanu MN, NE, ND, OK, SD, Denver, CO 80207 WI Phone: 303-399-7500 10/26-27 Washington DC Crystal City Marriott Silvio Inzucchi Enrique John Buse Mid-Atlantic South: DE, 1999 Jefferson Davis Highway Caballero DC; MD, NC; TN, VA, Arlington, VA 22202 WV Phone: 703-413-5500 11/2-3 Boston, MA Boston Marriott Long Wharf Silvio Inzucchi Enrique Samuel Engel Northeast: CT, ME, MA, 296 State Street Caballero NH, NY, RI, VT Boston, MA 02109 Phone: 617-227-0800 11/9-10 Dallas, TX Hotel Adolphus Sean Ellison Thomas Blevins Leann Olansky Southwest: AR, LA, MS, 1321 Commerce Street MO, TX Dallas, TX 75202 Phone: 214-742-8200 11/9-10 Philadelphia, PA Philadelphia Marrioft Silvio inzucchi Joel Zonszein Samuel Engel Mid-Atlantic North: NJ, 1201 Market Street OH, PA Philadelphia, PA 19107 Phone: 215-625-2900 11/16-17 Miami, FL JW Marriott Miami William Croom Om Ganda Ronald Goldberg Southeast: AL, FL, GA, 1111 Brickell Avenue SC, PR Miami, FL 33131 Phone: 305-374-1224 4 Confidential - Subject to Protective Order TAK-DALYRI-00058800 Produced in MDL on 09/17/12 Summary of Pre/Post Survey Results A nine-slide data-intensive summary of the pre/post survey results is presented in a separate document accompanying this report. Pre/post survey responses align well with responses in the breakout groups. Key points from the pre/post summary are presented below. The speaker presentations strengthened already-positive perceptions of TZDs. Although participants accept the lipid distinctions between ACTOS and Avandia, they are not wholly convinced that those differences result in a more positive patient outcome. Head-to-head data from clinical studies is needed to significantly alter prescribing habits. Although weight gain is a common objection to using more TZDs, it is ranked as least important in impact on the decision to prescribe an OAD. TZDs are currently perceived to be better than other OADs on most concepts related to IR and vascular health. Exceptions include ability to reduce blood glucose and blood pressure. Perception of TZD safety is mixed, with High Potentials feeling less positive than Splitters. The speaker presentations strengthened current beliefs, particularly with regard to reducing FFAs, reducing blood pressure, and improving lipids. ACTOS is currently perceived to be better than or equal to Avandia on all key attributes. The presentations strengthened the perceptions of superiority over Avandia with regard to all attributes except glycemic control. As reducing atherosclerosis is most closely linked to positive CV outcomes, ACTOS should benefit significantly from an atherosclerosis indication. In the absence of an atherosclerosis indication, lipid benefits continue to hold potential for ACTOS to differentiate from Avandia. As would be expected, Splitters are more likely than High Potentials to agree that TZDs should be used as initial therapy either alone or in combination. IV. Special Examinations 5 Confidential - Subject to Protective Order TAK-DALYRI-00058801 Produced in MDL on 09/17/12 Source: https://www.indupsgoooo6ts.ucsf.edu/docs/rnjf0226 Examination of Responses: Differences between Sites Participants at all sites expressed a good to high level of satisfaction with the data presented in the plenary sessions. A search to identify substantively different responses unique to a particular location revealed two incidences - Boston and Philadelphia. In Boston, two unique and important issues were raised by more participants, and with a higher level of intensity, than in other cities. First, participants in Boston seemed generally more cautious, more resistant to the entire message than doctors in other cities. Second, there was evidence of a great deal of interference from Avandia reps - more than in any other city. Participants mentioned "different" lipid data, ACTOS side-effect concerns, skepticism toward ACTOS studies, concern about ACTOS "propaganda", light fluffy LDL. Reasons for these differences are unclear. In Philadelphia (home of GlaxoSmithKline), responses were more strongly positive than in other cities. All four breakout groups seemed pleased by the entire experience, and were quite favorably disposed to ACTOS by the end of the day. Few-objections were raised. This must have been a very positive setting with a smooth and meaningful set of presentations and Q & A. B. Examination of Responses: High Potentials vs. Splitters Breakout discussions revealed that High Potential groups gave generally similar responses to TZD Splitters with regard to most key concepts, including the acceptance of insulin resistance as an important phenomenon, the relationship of IR to CVD, and the lipid distinctions between ACTOS and Avandia. However, Splitters report being clearly more likely to use TZDs as first- line therapy compared to their High Potential counterparts. Reasons for this distinction are unclear. In searching for potential differences between breakout group responses of High Potentials vs. Splitters, it is actually the similarity of responses that stands out. While one might have expected to find stark distinctions, we instead find, with one exception, the same basic mix of responses regardless of group identity. 6 Confidential - Subject to Protective Order TAK-DALYRI-00058802 Produced in MDL on 09/17/12 Source: https://www.indupts0ooo7ts.ucsf.edu/docs/rnjf0226 Splitters and High Potentials seem quite similar with regard to most of the observed core issues: - Acceptance of IR as the core defect in T2D - Agreement that TZDs probably preserve beta cell function - Acceptance of NCEP IR identification system - IR is correlated to CVD - Acceptance of lipid data ACTOS vs. Avandia - Limitations to Rxing TZDs; cost, edema/weight gain, formularies Splitters are clearly more likely than High Potentials to use TZDs for first-line therapy (6 of 8 sites). It seems that - -75-80% of Splitters report using TZDs first-line (mono or combo), vs. only about half of the High Potentials. The reason for this distinction is unclear. The discussions did not reveal any distinctions in the areas that might be expected to offer insight - importance of IR, belief in beta cell preservation, preference for metformin, side effect fears, formulary restrictions, etc. 7 Confidential - Subject to Protective Order TAK-DALYRI-00058803 Produced in MDL on 09/17/12 Specific Findings A. Reaction to IR Information Participants accept ACTOS as an effective glucose control agent, and as a drug free of liver toxicity. If convinced by compelling clinical data that TZDs preserve beta cell function, many participants would feel compelled to use TZDs as first line therapy. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Ederna/weight gain, and 3) Reimbursement. Participants overwhelmingly accept ACTOS as an effective glucose control agent. Participants overwhelmingly accept ACTOS as a drug free of liver toxicity. Participants in all groups agree that insulin resistance is the primary or foundational defect in Type 2 diabetes. They are learning to identify IR primarily via family history, lipids and waist size. Few are using the NCEP ATPIII Guidelines as a strict model to identify the insulin resistant patient, and few use any office-based system beyond simple random observation of the markers listed above. Beta cell preservation is a very important consideration in the treatment of patients with T2D. If convinced by clinical data that TZDs do, in fact, preserve beta cell function, many (perhaps most) participants would feel compelled to use TZDs as first line therapy. Most believe intuitively that TZDs preserve beta cells. Across all groups, the most commonly mentioned reasons NOT to prescribe TZDs are 1) Cost, 2) Edema/weight gain, and 3) Reimbursement. In Dallas and Miami, Steve Crow asked his High Potential groups "If a doctor accepts IR as the core defect, and agrees that TZDs directly address IR, what would preclude the use of TZDs as primary mono/combo therapy?" Responses included, in no particular order: 8 Confidential - Subject to Protective Order TAK-DALYRI-00058804 Produced in MDL on 09/17/12 Source: https://www.indup1s700009ts.ucsf.edu/docs/rnjf0226 - Residual fear of liver toxicity - Cost issues, especially for self-pay patients - Managed care formulary restrictions, reimbursement - The position of the patient in the disease process (Very high HBA1c would needa.faster-acting.agent) - TZDs are newer, and older drugs like metformin are more comfortable - Weight gain and/or edema - Hassle of liver function testing - Insulin works, and it's cheap - Restrictions in fatty liver patients B. Reaction to Information on Dyslipidemia and CVD Participants realize the relationship of diabetic dyslipidemia and CVD. Most already believe that TZDs probably have the best cardiovascular profile. Doctors are waiting for clinical data to prove TZD cardiovascular benefit. There is broad and substantial recognition of the relationship between diabetic dyslipidemia and cardiovascular disease. Based on VA-HIT data, they believe that correcting diabetic dyslipidemia can reduce CVD. Most believe that TZDs have the best potential for a positive cardiovascular profile based on mechanism of action. Metformin has some suggestion of CVD benefit; sulfonylureas have none. There is a real desire for clinical data that demonstrates a cardiovascular benefit with TZD therapy. In lieu of clinical outcomes data, participants offer numerous possible surrogate markers that would suggest CVD benefit: - PPAR-alpha activation - C-reactive Protein - Apo-Protein B - PAI-1 - Homocysteine - CAT-based calcification - LDL particle size - Animal data C. Reaction to Data Regarding TZD Performance in Practice 9 Confidential - Subject to Protective Order TAK-DALYRI-00058805 Produced in MDL on 09/17/12 There is generally broad acceptance of the lipid distinctions between ACTOS and Avandia. Participants are seeking clinical endpoint data comparing ACTOS to Avandia. There is broad general acceptance of the lipid distinctions between ACTOS and Avandia, although some groups thought the presentation might have been slanted toward ACTOS-positive data. Overall, there were few challenges to the data as presented. Challenges included: small numbers in the studies, non-randomized, company- sponsored. While participants accept the head-to-head lipid studies as validly conducted research (with the caveats mentioned above), they are reluctant to attach a great deal of clinical value to the data. Most are not willing to base their decision of ACTOS or Avandia on these data. In certain cities a slide was presented showing differences in PPAR-alpha activation by ACTOS and Avandia. This data provided an important "hook" for participants that helped them accept the lipid effect differences. Multiple groups noted that standard territory reps may not be trusted to present and discuss detailed information on PPAR activation. There is a real desire for clinical endpoint data that compares CVD endpoints of ACTOS vs. Avandia. In lieu of those clinical endpoint data, surrogates would include those listed in the previous section. D. Reaction to ACTOS Foundation Therapy Strategy All groups believe ACTOS can eventually capture the position of "Foundation Therapy". Participants caution against promoting against metformin. Instead, promote combination therapy. All groups believe that ACTOS can be shown to be valid foundation therapy, with clinical outcomes data. Alternative terms include: core therapy; cornerstone therapy; first-line. Several impediments to broad first-line use were mentioned: edema, cost, reimbursement, potential liver toxicity. Several groups noted the need for patient education efforts, although specific programs were not defined. 10 Confidential - Subject to Protective Order TAK-DALYRI-00058806 Produced in MDL on 09/17/12 Many groups mentioned the importance of the strategic interaction-wit metformin. The message is clear and consistent: metformin is an effective and trusted agent - do not try to denigrate it in the marketplace. Instead, promote combination use with metformin (after all, roughly 80% of T2D patients require at least two drugs to gain adequate glycemic control). [As an aside, many of the speakers currently appearing in the STS series of promotional meetings agree with this sentiment] 11 Confidential - Subject to Protective Order TAK-DALYRI-00058807 Produced in MDL on 09/17/12 Source:

What is the name of the Article 6?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

Self Inspection

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

When was the second revision?

xpjf0226

xpjf0226_p0, xpjf0226_p1, xpjf0226_p2

2011 April 26

Translation of TAKJ-TPC-00000431 Research. Div. Procedures Regarding Document Control Procedures No. 19 Article 1 (Purpose) These procedures make stipulations about the retention and disposal of documents that the Pharmaceutical Research Division (hereinafter referred to as "this Division") handles and other handling details, based on the Policy on Document Control (Policy #8) (hereinafter referred to as "the Policy"). Article 2 (Persons In Charge of Retention) The Persons In Charge of Retention in Article 3 of the Policy within this Division shall be as it is below for work subdivision units. Existing Location of Work Subdivision Unit Person In Charge of Retention Pharmacentical Research Division (Shonan Region) Senior Manager of Research Work Article 3 (Retention) For the retention format of documents this Division retains, we shall retain them in the format of the document (for electromagnetic records, after printing). However, whenever necessary in work duties, they can be retained in electromagnetic records. Further, if having received a request stipulated in Article 12 Section 1 of the Policy, the Person In Charge of Retention shall immediately take necessary measures. 2 For documents this Division retains, we shall have it made at each control unit in accordance with the format of Attachment 1, and shall stipulate the retention time period and retention location by specific type of such document. Further, regardless of the retention time period that has been stipulated, when it is recognized to be necessary in work duties, based on the determination of the Person Responsible for Retention (the Head of the Pharmaceutical Research Division), for a portion of the retained documents, the retention can be continued by stipulating an extended period of time. Article 4 (Disposal Record Ledger) The Person Responsible of each control unit, for retained documents it keeps, shall create a Disposal Record Ledger in accordance with the form of Attachment 2. 2 When the members affiliated in this Division dispose of documents for which the retention period has elapsed. they shall carry it out obtaining the approval of the Person Responsible of each control unit, and when disposed of, shall enter it that into the Disposal Record Ledger. 3 The Person Responsible of each control unit shall properly control the Disposal Record Ledger, and the Persons In Charge of Retention shall inspect them after having periodically gathered each Disposal Record Ledger within this Division, and when necessary shall report those results to the Person Responsible for Retention. Article 5 (Items to Confirm At the Time of Retained Document Disposal) 1 EXHIBIT 5762823 v2 P-16 3/02823 V/2 Confidential . Crihicat to Orlar Each of the Persons In Charge of Retention, when disposing of retained documents they have, shall carry out an inspection of whether or not there are duplications for the same documents, and for these documents also shall dispose of them. Article 6 (Self Inspection) The Person Responsible of each control unit or the Persons In Charge of Retention shall plan on reviews as appropriate with reference to Attachment 1 which pertains to retained documents they keep, and thereby, shall plan on appropriate revisions for retention locations and retention time periods from the viewpoint of making work duties efficient, etc. Further, when the Person Responsible of each control unit has carried out such reviews, they shall report those details to the Persons In Charge of Retention. Enacted: 2006 May 31 Implemented: 2006 May 31 Revised: 2006 October 20 Implemented: 2006 May 31 Revised: 2011 April 26 Implemented: 2011 April 26 2 5762823 V2 3/02823 VL Confidential - Subhant to Dentantive Order Attachment 1 List of Retention Periods of Time, Retention Locations Retention Classification Type of Document Retention Location Remarks Time Period Experiment Notes, etc. 30 years Technical Research Reports Permanently Documents Monthly Reports 30 years Contracts Contracts Permanently Medium-Term Medium-Term Plans, Permanently Plans, Annual Plans Annual Plans Substantiating Documents 7 years Accounting Related What This Division Keeps 5 years of TACT Output Forms Other Collections of Regulations Permanently Attachment 2 Disposal Record Ledger Classification Document Name Document Creation Date Retention Time Period Disposal Date Disposal Method Person Doing Disposal Remarks 3 5762823 v2 3/02523 VL Confidential - Antiant to Contentive Arrier Source: https://www.indup2377000003S s.ucsf.edu/docs/xpjf0226

When was the rule PROPOSED?

mmcn0226

mmcn0226_p0

JAN. 19, 2017, Jan. 19, 2017

EPA'S PROPOSED CHEMICAL SAFENY ROLES, CHEMICAL INDUSTRY COMMENTS AND EPAS FINAL RULES PROPOSED RULE AMERICAN CHEMISTRY FINAL RULE, JAN. 19, 2017 COUNCIL COMMENTS JUNE 22, 2017 "Pre-prioritization" period for information gathering Get rid of pre-prioritization No pre-prionitization period Mas chemicals Get rid of default High-priority Deletes majority of references as default chemical designation to high-priority default No reference to science standards In prioritization, Reference science standards in Includes direct references to giving EPA needed discretion prioritization rule science standards and flexibility Not much emphasis on low- More emphasis on More emphasis on priority "safe" designations designations No tiered approach to Use tiered approach to Includes tiered approach to information gathering Information gathering Information gathering PISK EVALVATION Risk evaluations must include Do not include all uses or EPA may exclude uses from all uses and exposures exposures in risk evaluation risk evaluations No indication non-TSCA uses EPA may exclude Exclude non-TSCA * uses will be excluded No indication OSMA-regulated EPA may exclude uses assessed uses will be excluded Exclude DSHA-regulated uses by other agencies like OSHA May exclude "de minimus" No indication Exclude low -exposure unes exposures or uses in a closed uses will be excluded system. may exclude impurities Declined to include science standards in rule to provide Science standards defined Define science standards in rule EPA with needed discretion in rule and flexibility Expanded definition for Do not expand definition for Removed expanded definition vulnerablepopulations walnerable populations of vulnerable populations Manufacturers must submit a Allow manufacturers to make Manufacturers may submit a requesti for the whole chemical request on only a small set of requests on specific uses only and all its uses uses, EPA responsible for rest Preference: for most No for Preference will be given to hazandous requests manufacturer requests requests in order inceived Manufacturers must Manufacturers should not Manufacturers can exclude include all reasonably have to include all prior risk some prior risk assessments available information assessments in request on the chemical Source: :ttps://www.industrydocuments.ucsf.edu/docs/mmcn0226

What is the name of the FOUNDATION this PROPOSAL belongs to?

nfcn0226

nfcn0226_p0, nfcn0226_p1, nfcn0226_p2, nfcn0226_p3, nfcn0226_p4, nfcn0226_p5

TOXICOLOGY EDUCATION FOUNDATION, Toxicology Education Foundation

025 From: Ann de Peyster To: James Zappia Cc: nvsoucy@mmm.com; Ndifor. Anthony Masten Management Subject: Re: Re: Creation of Korean "Is It Safe?" Date: Thursday, July 20, 2017 8:59:32 PM Attachments: image004.ong image002.ong TEF 3M proposal7-20-17AN.pdf James, Please find attached TEF's "Is It Safe?"/Korean subtitles proposal on TEF letterhead and with the disclaimer 3M wanted inserted. Our Secretary/Treasurer has also signed this version. Included in the cc line of this email is TEF's Executive Secretary, Susie Masten, who will be expecting payment by check at the Raleigh, North Carolina PO box. Susie is also the best person to contact for any other payment questions. You did not specify yet whether 3M would be OK with sending the full donation in one check now or prefers the $5000-now-$5000-later option explained in the proposal. If you would please let us know which option 3M chooses when you return a copy of this agreement with your signature then everyone cc'ed here will know what to expect. I believe I have addressed all of the points raised in your latest email. I will simply add that I remain the primary TEF trustee contact for coordinating this effort. We are all very eager to proceed, so when I see the fully executed agreement I will send the script we want the translator to work from. I am especially eager to know who at 3M will be doing the translating, and assume that I can be in direct contact with him/her as soon as possible to work out a reasonable timeline so that everyone involved can fit this into their calendars. The ideal target date for completion in the original proposal was advanced to the end of September in this version because of unforeseen (but understandable) delays since we first contacted you. I am hoping we can finish sooner if everyone is able to make this a priority. We really appreciate all of your help moving this idea forward. Sincerely, Ann de Peyster On Wed, Jul 19, 2017 at 7:33 AM, James Zappia <jzappial@mmm.com wrote: Hi Ann, We've received approval from the legal team with the caveat that the proposal from TEF include the following language: DISCLAIMER: IN NO EVENT WILL 3M BE LIABLE TO TEF OR ANY THIRD PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL OR CONSEQUENTIAL DAMAGES FOR THE KOREAN VERSION "IS IT SAFE" VIDEO Source: :ttps://www.industrydocuments.ucsf.edu/docs/nfcn0226 026 INCLUDING, BUT NOT LIMITED TO, DAMAGES ARISING FROM LOSS OF PROFITS, BUSINESS INTERRUPTION, OR LOSS OF DATA, EVEN IF 3M IS EXPRESSLY ADVISED ABOUT THE POSSIBILITY OF SUCH DAMAGES, TO THE FULLEST EXTENT ALLOWABLE BY LAW. Could you incorporate that into the proposal and send it to me again? Some additional requests to make sure this goes into our payment system properly and minimizes any delays: Could you send the proposal on TEF letterhead with the organization's address Indicate how you would like to be paid. The options would be by check or wire transfer, as I understand our payment system. If we need a contact name for payment questions, would that be you or Anthony? I will sign as soon as I receive and then you can send us the script. Thanks for your patience and I am looking forward to actually getting this moving. Best regards, Jim 3M James Zappia 1 Director, Product Safety, Compliance, and Stewardship 3M Medical Department 3M Center, Bldg 220-8E St. Paul MN 55144 Office: 651 733 5180 Mobile: 612 735 0234 izappia1@mmm.com www.3M.com Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 027 From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Thursday, July 13, 2017 1:15 PM To: James Zappia <izappial@mmm.com> Cc: Nicole Soucy <nvsoucy@mmm.com> Subject: [EXTERNAL] Re: Creation of Korean "Is It Safe?' Thank you for this update, James. We are poised to get started should the decision be favorable. Keeping fingers crossed. Ann Virus-free. www.avast.com On Sun, Jul 9, 2017 at 4:57 PM, James Zappia <jzappial@mmun.com> wrote: Hi Ann, I wanted to get back to you to let you know that we are still very interested in the proposal. I need to have legal review before I can sign a contract with an outside agency/vendor. The proposal is with the attorneys and I expect we will have approval very soon. Thanks, Jim 3M James Zappia | Manager, Toxicology and Compliance Solutions 3M Medical Department 3M Center, Bidg 220-8E St. Paul MN 55144 Office: 651 733 5180 izappia1@mmm.com 1 www.3M.com Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 028 From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Friday, June 09, 2017 1:21 PM To: James Zappia <izappial@mmm.com> Cc: Nicole Soucy <nvsoucy@mmm.com> Subject: [EXTERNAL] Creation of Korean "Is It Safe?" Dear James, On behalf of the Toxicology Education Foundation (TEF) Board of Trustees, I am very pleased to submit for 3M's consideration the proposal attached titled "Creation of a Korean- subtitled version of the "is It Safe?" YouTube video." Former TEF trustees responsible for creating the English language version took great pains to include toxicology concepts, messages, and examples that would be relevant for a long time. The video received an Aurora Award for best educational video. We are enthusiastic about expanding its global reach to more non-English- speaking audiences. Because it is our understanding that a Korean version would be most helpful to 3M; this is what TEF is offering now. As soon as this project is underway, if 3M is interested in exploring the possibility of other language versions created with additional support, then we would welcome that discussion, possibly focasing first on Chinese if that appeals to 3M. TEF could also propose a strategy for choosing other languages based on statisties we collect on worldwide location of visitors to our website, Facebook, and YouTube channel. TEF is, as you know, a non-profit [501(c)(3)] organization that depends on charitable donations. If the terms of this request for funding are acceptable to 3M, then we would ask you to please sign and return a copy of this attachment as soon as possible, then TEF will countersign and send you a fully executed copy. TEF is prepared to initiate the steps shown in Project Scope and Responsibilities as soon as we reach an agreement. Please do not hesitate to contact me with any questions or concerns. We hope for a favorable response and look forward to working with 3M on this project. Yours sincerely, Ann de Peyster, TEF Trustee Chair, Fundraising Committee 858-699-3599 3M security scanners have not detected any malicious content in this message. Click here to report this email as spam Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 Toxicology Education Foundation Toxicology Education Foundation Proposal to 3M from the Toxicology Education Foundation (TEF) P.O. Box 98224 Raleigh, NC 27624 TITLE: Creation of Korean-subtitled version of the "Is It Safe?" YouTube video AMOUNT REQUESTED: $10,000 2017-2018 Board of Trustees PROJECT SCOPE and RESPONSIBILITIES President Michael Deurson, Ph.D., DABT 1. TEF will provide Word transcript for subtitling. University of Cincisnati 2. 3M will return an electronic document to TEF with Korean translation, Vice President Willian Farland, PhD, ATS preserving timing notes corresponding to frames of the English language Colorado State University version Secretary/Trensurer 3. TEF will import above Korean file and sync to video. Tony Ndifor, Ph.D. Johnson & 4. Graphics in the video cannot be translated into Korean so will remain in Trustees English. Nancy Bleck, Ph.D., DABT 5. An outside (non-3M) toxicologist also fluent in Korean will be engaged by American Chemistry Council TEF to also review the translation before and after sync to video. Silvia Berlanga de Moraes Barros, MSc., PI.D. 6. 3M will be encouraged to remain involved in review and approval of the University of Sac Paulo translation before TEF considers the final version ready to upload. David Cragin, Pl.D., DABT Merck 7. TEF will upload the Korean version to TEF's YouTube channel, add to the TEF website, promote by all means TEF uses to inform the global public of Ann de Peyster, ATS San Diego State University (Emeritus) the availability of all of its educational materials (e.g. TEF's Facebook, Jolin DeSesso, Pl.D., ATS Twitter, LinkedIn and donor audiences), and track viewing as a measure of Exponent expanded reach of these messages now offered in Korean. Suzanne C. Fitzpatrick, l'h.D., 8. A general timeframe for completion is offered below. To meet this DABT U.S. Food and Administration completion date, TEF will propose and track a more detailed timeline for Jay W. Gooch, Ph.D. completion to which all parties involved will have had input. & Pools Communications, LLC Mark Lafrauconi, Ph.D., DABT ToxHorizons OWNERSHIP AND USE RIGHTS: Without question or claim, TEF shall retain sole ownership of the completed product as well as all original data/information Gladys Ouédraogo, l'h.D. L'Oréal gathered for the production of such. The parties agree that the language Richaril D. Phillips, Ph.D. translation/sabtitling is being done with assistance of 3M and that 3M has the ExxonMobil (retired) right to use all, part or none of the final product as it sees fit. Nicole Soucy, Pi.D. DABT 3M TERMS OF PAYMENT: $10,000 to be paid to TEF with 3M offered the option David Steup, l'h.D., DABT Shell (retired) to hold 50% of this amount in reserve until the Korean version is uploaded to Philip Wester, BS, MLS TEF's YouTube channel and TEF's website and begins ongoing promotion and National Library of Medicine tracking reach, which will be ongoing. If 3M chooses that option, then they will be invoiced with notification when uploading is completed. In that case, the remainder ($5000) will be due within 30 days after receipt of invoice. Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 Toxicology the Education Foundation page 2 - Proposal to 3M from the Toxicology Education Foundation (TEF) Toxicology Education Foundation ESTIMATED DATE OF COMPLETION: It is TEF's intention to upload a P.O. Bex 98224, Korean version of Is It Safe? by September 30, 2017. The parties acknowledging Raleigh, NC 27624 this agreement below recognize that meeting this target date is dependent upon consensus about the timeline and cooperation of all parties involved. TEF will do everything reasonable to keep all parties involved on schedule. DISCLAIMER: IN NO EVENT WILL 3M BE LIABLE TO TEF OR ANY 2017-2018 Board of Trustees THIRD PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL OR President Michael Dourson, Ph.D., DAIT CONSEQUENTIAL DAMAGES FOR THE KOREAN VERSION "IS IT SAFE" University of VIDEO INCLUDING, BUT NOT LIMITED TO, DAMAGES ARISING FROM Vice President LOSS OF PROFITS, BUSINESS INTERRUPTION, OR LOSS OF DATA, William Farland, P&D, ATS Colorado State University EVEN IF 3M IS EXPRESSLY ADVISED ABOUT THE POSSIBILITY OF Secretary/Treasures SUCH DAMAGES, TO THE FULLEST EXTENT ALLOWABLE BY LAW. Tony Ndifor, Ph.D. Johinson & Johnson The undersigned agree to all terms of this proposal. Trustees Nancy Beck, Ph.D., DABT American Chemistry Council Silvia Berlangs de Moraes Barros, MSc., Ph.D, University of Sao Paulo For 3M: Dayid Cragin, Ph.D., DABT Merck James Zappia, Manager Ann de Peyster, Ph.D., ATS San Diego State Duiversity (Emeritis) Toxicology and Compliance Solutions, 3M Medical Department John DeSesso, Ph.D., ATS Exponent Date: Suzanne C. Fitzpatricli, Ph.D., DART U.S. Food and Drug Administration Jay W. Gnoch, Ph.D. Riffles & Podis Communications, LLC Mark Lafranconi, Ph.D., DABT For TEF: ToxHorizons Glailys Ouédrangs, Ph.D. L'Oréal Anthony Ndifor, TEF Secretary/Treasurer Richard D. Phillips, Ph.D. ExxonMobil (retired) Date: July 20th 2017 Nicale Soucy, Ph.D. DABT 3M David Steup, Ph.D., DABT Shell (retired) Philip Wexler, BS, MLS National Library of Medicine Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226

Who is the vice president of this FOUNDATION?

nfcn0226

nfcn0226_p0, nfcn0226_p1, nfcn0226_p2, nfcn0226_p3, nfcn0226_p4, nfcn0226_p5

William Farland, PhD, ATS, William Farland

025 From: Ann de Peyster To: James Zappia Cc: nvsoucy@mmm.com; Ndifor. Anthony Masten Management Subject: Re: Re: Creation of Korean "Is It Safe?" Date: Thursday, July 20, 2017 8:59:32 PM Attachments: image004.ong image002.ong TEF 3M proposal7-20-17AN.pdf James, Please find attached TEF's "Is It Safe?"/Korean subtitles proposal on TEF letterhead and with the disclaimer 3M wanted inserted. Our Secretary/Treasurer has also signed this version. Included in the cc line of this email is TEF's Executive Secretary, Susie Masten, who will be expecting payment by check at the Raleigh, North Carolina PO box. Susie is also the best person to contact for any other payment questions. You did not specify yet whether 3M would be OK with sending the full donation in one check now or prefers the $5000-now-$5000-later option explained in the proposal. If you would please let us know which option 3M chooses when you return a copy of this agreement with your signature then everyone cc'ed here will know what to expect. I believe I have addressed all of the points raised in your latest email. I will simply add that I remain the primary TEF trustee contact for coordinating this effort. We are all very eager to proceed, so when I see the fully executed agreement I will send the script we want the translator to work from. I am especially eager to know who at 3M will be doing the translating, and assume that I can be in direct contact with him/her as soon as possible to work out a reasonable timeline so that everyone involved can fit this into their calendars. The ideal target date for completion in the original proposal was advanced to the end of September in this version because of unforeseen (but understandable) delays since we first contacted you. I am hoping we can finish sooner if everyone is able to make this a priority. We really appreciate all of your help moving this idea forward. Sincerely, Ann de Peyster On Wed, Jul 19, 2017 at 7:33 AM, James Zappia <jzappial@mmm.com wrote: Hi Ann, We've received approval from the legal team with the caveat that the proposal from TEF include the following language: DISCLAIMER: IN NO EVENT WILL 3M BE LIABLE TO TEF OR ANY THIRD PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL OR CONSEQUENTIAL DAMAGES FOR THE KOREAN VERSION "IS IT SAFE" VIDEO Source: :ttps://www.industrydocuments.ucsf.edu/docs/nfcn0226 026 INCLUDING, BUT NOT LIMITED TO, DAMAGES ARISING FROM LOSS OF PROFITS, BUSINESS INTERRUPTION, OR LOSS OF DATA, EVEN IF 3M IS EXPRESSLY ADVISED ABOUT THE POSSIBILITY OF SUCH DAMAGES, TO THE FULLEST EXTENT ALLOWABLE BY LAW. Could you incorporate that into the proposal and send it to me again? Some additional requests to make sure this goes into our payment system properly and minimizes any delays: Could you send the proposal on TEF letterhead with the organization's address Indicate how you would like to be paid. The options would be by check or wire transfer, as I understand our payment system. If we need a contact name for payment questions, would that be you or Anthony? I will sign as soon as I receive and then you can send us the script. Thanks for your patience and I am looking forward to actually getting this moving. Best regards, Jim 3M James Zappia 1 Director, Product Safety, Compliance, and Stewardship 3M Medical Department 3M Center, Bldg 220-8E St. Paul MN 55144 Office: 651 733 5180 Mobile: 612 735 0234 izappia1@mmm.com www.3M.com Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 027 From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Thursday, July 13, 2017 1:15 PM To: James Zappia <izappial@mmm.com> Cc: Nicole Soucy <nvsoucy@mmm.com> Subject: [EXTERNAL] Re: Creation of Korean "Is It Safe?' Thank you for this update, James. We are poised to get started should the decision be favorable. Keeping fingers crossed. Ann Virus-free. www.avast.com On Sun, Jul 9, 2017 at 4:57 PM, James Zappia <jzappial@mmun.com> wrote: Hi Ann, I wanted to get back to you to let you know that we are still very interested in the proposal. I need to have legal review before I can sign a contract with an outside agency/vendor. The proposal is with the attorneys and I expect we will have approval very soon. Thanks, Jim 3M James Zappia | Manager, Toxicology and Compliance Solutions 3M Medical Department 3M Center, Bidg 220-8E St. Paul MN 55144 Office: 651 733 5180 izappia1@mmm.com 1 www.3M.com Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 028 From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Friday, June 09, 2017 1:21 PM To: James Zappia <izappial@mmm.com> Cc: Nicole Soucy <nvsoucy@mmm.com> Subject: [EXTERNAL] Creation of Korean "Is It Safe?" Dear James, On behalf of the Toxicology Education Foundation (TEF) Board of Trustees, I am very pleased to submit for 3M's consideration the proposal attached titled "Creation of a Korean- subtitled version of the "is It Safe?" YouTube video." Former TEF trustees responsible for creating the English language version took great pains to include toxicology concepts, messages, and examples that would be relevant for a long time. The video received an Aurora Award for best educational video. We are enthusiastic about expanding its global reach to more non-English- speaking audiences. Because it is our understanding that a Korean version would be most helpful to 3M; this is what TEF is offering now. As soon as this project is underway, if 3M is interested in exploring the possibility of other language versions created with additional support, then we would welcome that discussion, possibly focasing first on Chinese if that appeals to 3M. TEF could also propose a strategy for choosing other languages based on statisties we collect on worldwide location of visitors to our website, Facebook, and YouTube channel. TEF is, as you know, a non-profit [501(c)(3)] organization that depends on charitable donations. If the terms of this request for funding are acceptable to 3M, then we would ask you to please sign and return a copy of this attachment as soon as possible, then TEF will countersign and send you a fully executed copy. TEF is prepared to initiate the steps shown in Project Scope and Responsibilities as soon as we reach an agreement. Please do not hesitate to contact me with any questions or concerns. We hope for a favorable response and look forward to working with 3M on this project. Yours sincerely, Ann de Peyster, TEF Trustee Chair, Fundraising Committee 858-699-3599 3M security scanners have not detected any malicious content in this message. Click here to report this email as spam Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 Toxicology Education Foundation Toxicology Education Foundation Proposal to 3M from the Toxicology Education Foundation (TEF) P.O. Box 98224 Raleigh, NC 27624 TITLE: Creation of Korean-subtitled version of the "Is It Safe?" YouTube video AMOUNT REQUESTED: $10,000 2017-2018 Board of Trustees PROJECT SCOPE and RESPONSIBILITIES President Michael Deurson, Ph.D., DABT 1. TEF will provide Word transcript for subtitling. University of Cincisnati 2. 3M will return an electronic document to TEF with Korean translation, Vice President Willian Farland, PhD, ATS preserving timing notes corresponding to frames of the English language Colorado State University version Secretary/Trensurer 3. TEF will import above Korean file and sync to video. Tony Ndifor, Ph.D. Johnson & 4. Graphics in the video cannot be translated into Korean so will remain in Trustees English. Nancy Bleck, Ph.D., DABT 5. An outside (non-3M) toxicologist also fluent in Korean will be engaged by American Chemistry Council TEF to also review the translation before and after sync to video. Silvia Berlanga de Moraes Barros, MSc., PI.D. 6. 3M will be encouraged to remain involved in review and approval of the University of Sac Paulo translation before TEF considers the final version ready to upload. David Cragin, Pl.D., DABT Merck 7. TEF will upload the Korean version to TEF's YouTube channel, add to the TEF website, promote by all means TEF uses to inform the global public of Ann de Peyster, ATS San Diego State University (Emeritus) the availability of all of its educational materials (e.g. TEF's Facebook, Jolin DeSesso, Pl.D., ATS Twitter, LinkedIn and donor audiences), and track viewing as a measure of Exponent expanded reach of these messages now offered in Korean. Suzanne C. Fitzpatrick, l'h.D., 8. A general timeframe for completion is offered below. To meet this DABT U.S. Food and Administration completion date, TEF will propose and track a more detailed timeline for Jay W. Gooch, Ph.D. completion to which all parties involved will have had input. & Pools Communications, LLC Mark Lafrauconi, Ph.D., DABT ToxHorizons OWNERSHIP AND USE RIGHTS: Without question or claim, TEF shall retain sole ownership of the completed product as well as all original data/information Gladys Ouédraogo, l'h.D. L'Oréal gathered for the production of such. The parties agree that the language Richaril D. Phillips, Ph.D. translation/sabtitling is being done with assistance of 3M and that 3M has the ExxonMobil (retired) right to use all, part or none of the final product as it sees fit. Nicole Soucy, Pi.D. DABT 3M TERMS OF PAYMENT: $10,000 to be paid to TEF with 3M offered the option David Steup, l'h.D., DABT Shell (retired) to hold 50% of this amount in reserve until the Korean version is uploaded to Philip Wester, BS, MLS TEF's YouTube channel and TEF's website and begins ongoing promotion and National Library of Medicine tracking reach, which will be ongoing. If 3M chooses that option, then they will be invoiced with notification when uploading is completed. In that case, the remainder ($5000) will be due within 30 days after receipt of invoice. Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 Toxicology the Education Foundation page 2 - Proposal to 3M from the Toxicology Education Foundation (TEF) Toxicology Education Foundation ESTIMATED DATE OF COMPLETION: It is TEF's intention to upload a P.O. Bex 98224, Korean version of Is It Safe? by September 30, 2017. The parties acknowledging Raleigh, NC 27624 this agreement below recognize that meeting this target date is dependent upon consensus about the timeline and cooperation of all parties involved. TEF will do everything reasonable to keep all parties involved on schedule. DISCLAIMER: IN NO EVENT WILL 3M BE LIABLE TO TEF OR ANY 2017-2018 Board of Trustees THIRD PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL OR President Michael Dourson, Ph.D., DAIT CONSEQUENTIAL DAMAGES FOR THE KOREAN VERSION "IS IT SAFE" University of VIDEO INCLUDING, BUT NOT LIMITED TO, DAMAGES ARISING FROM Vice President LOSS OF PROFITS, BUSINESS INTERRUPTION, OR LOSS OF DATA, William Farland, P&D, ATS Colorado State University EVEN IF 3M IS EXPRESSLY ADVISED ABOUT THE POSSIBILITY OF Secretary/Treasures SUCH DAMAGES, TO THE FULLEST EXTENT ALLOWABLE BY LAW. Tony Ndifor, Ph.D. Johinson & Johnson The undersigned agree to all terms of this proposal. Trustees Nancy Beck, Ph.D., DABT American Chemistry Council Silvia Berlangs de Moraes Barros, MSc., Ph.D, University of Sao Paulo For 3M: Dayid Cragin, Ph.D., DABT Merck James Zappia, Manager Ann de Peyster, Ph.D., ATS San Diego State Duiversity (Emeritis) Toxicology and Compliance Solutions, 3M Medical Department John DeSesso, Ph.D., ATS Exponent Date: Suzanne C. Fitzpatricli, Ph.D., DART U.S. Food and Drug Administration Jay W. Gnoch, Ph.D. Riffles & Podis Communications, LLC Mark Lafranconi, Ph.D., DABT For TEF: ToxHorizons Glailys Ouédrangs, Ph.D. L'Oréal Anthony Ndifor, TEF Secretary/Treasurer Richard D. Phillips, Ph.D. ExxonMobil (retired) Date: July 20th 2017 Nicale Soucy, Ph.D. DABT 3M David Steup, Ph.D., DABT Shell (retired) Philip Wexler, BS, MLS National Library of Medicine Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226

What is the date mentioned at the bottom?

nfcn0226

nfcn0226_p0, nfcn0226_p1, nfcn0226_p2, nfcn0226_p3, nfcn0226_p4, nfcn0226_p5

July 20th 2017

025 From: Ann de Peyster To: James Zappia Cc: nvsoucy@mmm.com; Ndifor. Anthony Masten Management Subject: Re: Re: Creation of Korean "Is It Safe?" Date: Thursday, July 20, 2017 8:59:32 PM Attachments: image004.ong image002.ong TEF 3M proposal7-20-17AN.pdf James, Please find attached TEF's "Is It Safe?"/Korean subtitles proposal on TEF letterhead and with the disclaimer 3M wanted inserted. Our Secretary/Treasurer has also signed this version. Included in the cc line of this email is TEF's Executive Secretary, Susie Masten, who will be expecting payment by check at the Raleigh, North Carolina PO box. Susie is also the best person to contact for any other payment questions. You did not specify yet whether 3M would be OK with sending the full donation in one check now or prefers the $5000-now-$5000-later option explained in the proposal. If you would please let us know which option 3M chooses when you return a copy of this agreement with your signature then everyone cc'ed here will know what to expect. I believe I have addressed all of the points raised in your latest email. I will simply add that I remain the primary TEF trustee contact for coordinating this effort. We are all very eager to proceed, so when I see the fully executed agreement I will send the script we want the translator to work from. I am especially eager to know who at 3M will be doing the translating, and assume that I can be in direct contact with him/her as soon as possible to work out a reasonable timeline so that everyone involved can fit this into their calendars. The ideal target date for completion in the original proposal was advanced to the end of September in this version because of unforeseen (but understandable) delays since we first contacted you. I am hoping we can finish sooner if everyone is able to make this a priority. We really appreciate all of your help moving this idea forward. Sincerely, Ann de Peyster On Wed, Jul 19, 2017 at 7:33 AM, James Zappia <jzappial@mmm.com wrote: Hi Ann, We've received approval from the legal team with the caveat that the proposal from TEF include the following language: DISCLAIMER: IN NO EVENT WILL 3M BE LIABLE TO TEF OR ANY THIRD PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL OR CONSEQUENTIAL DAMAGES FOR THE KOREAN VERSION "IS IT SAFE" VIDEO Source: :ttps://www.industrydocuments.ucsf.edu/docs/nfcn0226 026 INCLUDING, BUT NOT LIMITED TO, DAMAGES ARISING FROM LOSS OF PROFITS, BUSINESS INTERRUPTION, OR LOSS OF DATA, EVEN IF 3M IS EXPRESSLY ADVISED ABOUT THE POSSIBILITY OF SUCH DAMAGES, TO THE FULLEST EXTENT ALLOWABLE BY LAW. Could you incorporate that into the proposal and send it to me again? Some additional requests to make sure this goes into our payment system properly and minimizes any delays: Could you send the proposal on TEF letterhead with the organization's address Indicate how you would like to be paid. The options would be by check or wire transfer, as I understand our payment system. If we need a contact name for payment questions, would that be you or Anthony? I will sign as soon as I receive and then you can send us the script. Thanks for your patience and I am looking forward to actually getting this moving. Best regards, Jim 3M James Zappia 1 Director, Product Safety, Compliance, and Stewardship 3M Medical Department 3M Center, Bldg 220-8E St. Paul MN 55144 Office: 651 733 5180 Mobile: 612 735 0234 izappia1@mmm.com www.3M.com Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 027 From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Thursday, July 13, 2017 1:15 PM To: James Zappia <izappial@mmm.com> Cc: Nicole Soucy <nvsoucy@mmm.com> Subject: [EXTERNAL] Re: Creation of Korean "Is It Safe?' Thank you for this update, James. We are poised to get started should the decision be favorable. Keeping fingers crossed. Ann Virus-free. www.avast.com On Sun, Jul 9, 2017 at 4:57 PM, James Zappia <jzappial@mmun.com> wrote: Hi Ann, I wanted to get back to you to let you know that we are still very interested in the proposal. I need to have legal review before I can sign a contract with an outside agency/vendor. The proposal is with the attorneys and I expect we will have approval very soon. Thanks, Jim 3M James Zappia | Manager, Toxicology and Compliance Solutions 3M Medical Department 3M Center, Bidg 220-8E St. Paul MN 55144 Office: 651 733 5180 izappia1@mmm.com 1 www.3M.com Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 028 From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Friday, June 09, 2017 1:21 PM To: James Zappia <izappial@mmm.com> Cc: Nicole Soucy <nvsoucy@mmm.com> Subject: [EXTERNAL] Creation of Korean "Is It Safe?" Dear James, On behalf of the Toxicology Education Foundation (TEF) Board of Trustees, I am very pleased to submit for 3M's consideration the proposal attached titled "Creation of a Korean- subtitled version of the "is It Safe?" YouTube video." Former TEF trustees responsible for creating the English language version took great pains to include toxicology concepts, messages, and examples that would be relevant for a long time. The video received an Aurora Award for best educational video. We are enthusiastic about expanding its global reach to more non-English- speaking audiences. Because it is our understanding that a Korean version would be most helpful to 3M; this is what TEF is offering now. As soon as this project is underway, if 3M is interested in exploring the possibility of other language versions created with additional support, then we would welcome that discussion, possibly focasing first on Chinese if that appeals to 3M. TEF could also propose a strategy for choosing other languages based on statisties we collect on worldwide location of visitors to our website, Facebook, and YouTube channel. TEF is, as you know, a non-profit [501(c)(3)] organization that depends on charitable donations. If the terms of this request for funding are acceptable to 3M, then we would ask you to please sign and return a copy of this attachment as soon as possible, then TEF will countersign and send you a fully executed copy. TEF is prepared to initiate the steps shown in Project Scope and Responsibilities as soon as we reach an agreement. Please do not hesitate to contact me with any questions or concerns. We hope for a favorable response and look forward to working with 3M on this project. Yours sincerely, Ann de Peyster, TEF Trustee Chair, Fundraising Committee 858-699-3599 3M security scanners have not detected any malicious content in this message. Click here to report this email as spam Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 Toxicology Education Foundation Toxicology Education Foundation Proposal to 3M from the Toxicology Education Foundation (TEF) P.O. Box 98224 Raleigh, NC 27624 TITLE: Creation of Korean-subtitled version of the "Is It Safe?" YouTube video AMOUNT REQUESTED: $10,000 2017-2018 Board of Trustees PROJECT SCOPE and RESPONSIBILITIES President Michael Deurson, Ph.D., DABT 1. TEF will provide Word transcript for subtitling. University of Cincisnati 2. 3M will return an electronic document to TEF with Korean translation, Vice President Willian Farland, PhD, ATS preserving timing notes corresponding to frames of the English language Colorado State University version Secretary/Trensurer 3. TEF will import above Korean file and sync to video. Tony Ndifor, Ph.D. Johnson & 4. Graphics in the video cannot be translated into Korean so will remain in Trustees English. Nancy Bleck, Ph.D., DABT 5. An outside (non-3M) toxicologist also fluent in Korean will be engaged by American Chemistry Council TEF to also review the translation before and after sync to video. Silvia Berlanga de Moraes Barros, MSc., PI.D. 6. 3M will be encouraged to remain involved in review and approval of the University of Sac Paulo translation before TEF considers the final version ready to upload. David Cragin, Pl.D., DABT Merck 7. TEF will upload the Korean version to TEF's YouTube channel, add to the TEF website, promote by all means TEF uses to inform the global public of Ann de Peyster, ATS San Diego State University (Emeritus) the availability of all of its educational materials (e.g. TEF's Facebook, Jolin DeSesso, Pl.D., ATS Twitter, LinkedIn and donor audiences), and track viewing as a measure of Exponent expanded reach of these messages now offered in Korean. Suzanne C. Fitzpatrick, l'h.D., 8. A general timeframe for completion is offered below. To meet this DABT U.S. Food and Administration completion date, TEF will propose and track a more detailed timeline for Jay W. Gooch, Ph.D. completion to which all parties involved will have had input. & Pools Communications, LLC Mark Lafrauconi, Ph.D., DABT ToxHorizons OWNERSHIP AND USE RIGHTS: Without question or claim, TEF shall retain sole ownership of the completed product as well as all original data/information Gladys Ouédraogo, l'h.D. L'Oréal gathered for the production of such. The parties agree that the language Richaril D. Phillips, Ph.D. translation/sabtitling is being done with assistance of 3M and that 3M has the ExxonMobil (retired) right to use all, part or none of the final product as it sees fit. Nicole Soucy, Pi.D. DABT 3M TERMS OF PAYMENT: $10,000 to be paid to TEF with 3M offered the option David Steup, l'h.D., DABT Shell (retired) to hold 50% of this amount in reserve until the Korean version is uploaded to Philip Wester, BS, MLS TEF's YouTube channel and TEF's website and begins ongoing promotion and National Library of Medicine tracking reach, which will be ongoing. If 3M chooses that option, then they will be invoiced with notification when uploading is completed. In that case, the remainder ($5000) will be due within 30 days after receipt of invoice. Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226 Toxicology the Education Foundation page 2 - Proposal to 3M from the Toxicology Education Foundation (TEF) Toxicology Education Foundation ESTIMATED DATE OF COMPLETION: It is TEF's intention to upload a P.O. Bex 98224, Korean version of Is It Safe? by September 30, 2017. The parties acknowledging Raleigh, NC 27624 this agreement below recognize that meeting this target date is dependent upon consensus about the timeline and cooperation of all parties involved. TEF will do everything reasonable to keep all parties involved on schedule. DISCLAIMER: IN NO EVENT WILL 3M BE LIABLE TO TEF OR ANY 2017-2018 Board of Trustees THIRD PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL OR President Michael Dourson, Ph.D., DAIT CONSEQUENTIAL DAMAGES FOR THE KOREAN VERSION "IS IT SAFE" University of VIDEO INCLUDING, BUT NOT LIMITED TO, DAMAGES ARISING FROM Vice President LOSS OF PROFITS, BUSINESS INTERRUPTION, OR LOSS OF DATA, William Farland, P&D, ATS Colorado State University EVEN IF 3M IS EXPRESSLY ADVISED ABOUT THE POSSIBILITY OF Secretary/Treasures SUCH DAMAGES, TO THE FULLEST EXTENT ALLOWABLE BY LAW. Tony Ndifor, Ph.D. Johinson & Johnson The undersigned agree to all terms of this proposal. Trustees Nancy Beck, Ph.D., DABT American Chemistry Council Silvia Berlangs de Moraes Barros, MSc., Ph.D, University of Sao Paulo For 3M: Dayid Cragin, Ph.D., DABT Merck James Zappia, Manager Ann de Peyster, Ph.D., ATS San Diego State Duiversity (Emeritis) Toxicology and Compliance Solutions, 3M Medical Department John DeSesso, Ph.D., ATS Exponent Date: Suzanne C. Fitzpatricli, Ph.D., DART U.S. Food and Drug Administration Jay W. Gnoch, Ph.D. Riffles & Podis Communications, LLC Mark Lafranconi, Ph.D., DABT For TEF: ToxHorizons Glailys Ouédrangs, Ph.D. L'Oréal Anthony Ndifor, TEF Secretary/Treasurer Richard D. Phillips, Ph.D. ExxonMobil (retired) Date: July 20th 2017 Nicale Soucy, Ph.D. DABT 3M David Steup, Ph.D., DABT Shell (retired) Philip Wexler, BS, MLS National Library of Medicine Source: https://www.industrydocuments.ucsf.edu/docs/nfcn0226

Whose biography is this?

ffcn0226

ffcn0226_p0, ffcn0226_p1, ffcn0226_p2, ffcn0226_p3, ffcn0226_p4, ffcn0226_p5, ffcn0226_p6, ffcn0226_p7, ffcn0226_p8, ffcn0226_p9, ffcn0226_p10, ffcn0226_p11, ffcn0226_p12, ffcn0226_p13, ffcn0226_p14, ffcn0226_p15, ffcn0226_p16, ffcn0226_p17, ffcn0226_p18, ffcn0226_p19, ffcn0226_p20, ffcn0226_p21, ffcn0226_p22, ffcn0226_p23, ffcn0226_p24, ffcn0226_p25, ffcn0226_p26, ffcn0226_p27, ffcn0226_p28, ffcn0226_p29, ffcn0226_p30, ffcn0226_p31, ffcn0226_p32

Christopher Jahn, CHRISTOPHER JAHN

To: Greenwalt, Sarah[greenwalt.sarah@epa.gov]; Dravis, Samantha[dravis.samantha@epa.gov] Brown, Byron[brown.byron@epa.gov];Wagner, Kenneth[wagner.kenneth@epa.gov] From: Hupp, Sydney Sent: Thur 3/30/2017 5:11:34 PM Subject: FW: FINAL Meeting Agenda and Materials Pruitt Meeting Materials.pd FYI. Sydney Hupp Office of the Administrator- Scheduling 202.816.1659 From: Mary Jo Tomalewski [mailto:mjtomalewski@croplifeamerica.org] Sent: Thursday, March 30, 2017 11:22 AM To: Hupp, Sydney <hupp.sydney@epa.gov> Cc: Jay Vroom <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000061-00001 MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobile Ex. 6 Personal Privacy Fax (202)466-5832 Email mjtomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000061-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00011 The Fertilizer Institute Nourish, Replenish, Grow BIOGRAPHY OF CHRISTOPHER JAHN President The Fertilizer Institute and the Nutrients for Life Foundation Christopher L. Jahn is president of The Fertilizer Institute (TFI), the fertilizer industry's national trade association. As TFI president, Jahn works to represent, promote and protect a sound fertilizer industry through legislative and regulatory activities and to promote a favorable public image of the fertilizer industry and agriculture. Jahn also serves as president of the Nutrients for Life Foundation (NFL). Jahn comes to TFI having served as president of the National Association of Chemical Distributors (NACD) since 2006. Prior to leading NACD, Jahn served as president of the Contract Services Association (CSA). Before joining CSA, Jahn had an active role in the United States Senate working for nearly 10 years for U.S. Senator Craig Thomas (R-Wyo.) in a variety of roles, including legislative assistant, legislative director and Chief of Staff. After graduating from Columbia University with a B.A. in Political Science, Jahn co-founded a book distribution business. He also earned an MBA from the University of Maryland. A native of Wyoming, Chris and his wife, Ex. 6 - Personal Privacy Ex. Personal Privacy Capitol View 202.962.0490 425 Third Street, S.W., Suite 950 202.962.0577 fax Washington, DC 20024 www.tfi.org Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00012 National Farmers Union Roger Johnson President Roger Johnson is president of the National Farmers Union (NFU), a grassroots organization that represents more than 200,000 family farmers, ranchers, fisherman and rural communities across the Unites States. Johnson was elected to lead the family farm organization at NFU's 107th anniversary convention in 2009. He has since expanded the education department by providing more programs for beginning, college-aged and women farmers, increased the number of Farmers Union state divisions, and developed a strategic plan for the organization. Johnson has also overseen a number of important policy initiatives important to family farmers including: passage of the 2014 Farm Bill; maintaining a strong Renewable Fuel Standard and Country-of-Origir Labeling, promoting policies that allow farmers to address the growing threat of climate change; and renewing the nation's focus on eliminating an overwhelming trade deficit that results in lost jobs and prosperity for rural America. Prior to leading National Farmers Union, Johnson, a third-generation family farmer from Turtle Lake, N.D., served as North Dakota Agriculture Commissioner, a position he was first elected to in 1996. While Agriculture Commissioner, Johnson served on the State Industrial Commission, the North Dakota Trade Office Advisory Board, and the State Board of Agricultural Research and Education, among many other boards and commissions. From 2007-2008, Johnson served as president of the National Association of State Departments of Agriculture (NASDA). He is a past president of the Midwestern Association of State Departments of Agriculture (MASDA), past president of the Food Export Association of the Midwest and a former chairman of the Interstate Pest Control Compact. Johnson graduated from North Dakota State University with a degree in agricultural economics. Johnson and his wife Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00013 AMERICAN SEED TRADE ASSOCIATION asta first-the - seed R Andrew W. "Andy" LaVigne President & CEO Andrew W. LaVigne is currently the President and CEO of the Ame rican Seed Trade Association. He joined ASTA in February, 2006. Andy has had a 30-year career i n government relations, industry representation, public affairs advocacy, and management. His C ore areas of expertise include agriculture, food policy and international trade. Prior to joining ASTA, Andy was Executive Vice President/CEC of Florida Citrus Mutual, representing citrus growers on issues affecting their business. Prejaiming tFdorida Citrus Mutual, Andy spent four years as Florida Fertilizer and Agrichemical Association's (FFAA) President and Executive Director. FFAA is a non-profit, agricultural trade organization representing companies that specialize in crop protection and plant nutrition products. Before his position at FFAA, Andy spent eight years in Washingt on, D.C. working in the U.S. Congress and the U.S. Department of Agriculture. He served as Legislative Director for Congressman Charles Canady, Agriculture Committee staffer for Congressman Tom Lewis , and on the staff of USDA Secretary Ed Madigan. Andy is a native of Florida with a BA degree in Political Scien ce, with a minor in economics, from the University of Florida. 1701 Duke Street Suite 275 Alexandria, VA 22314 Phone: (703)837-8140 Fax: (703)837-9365 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00014 Biotechnology Innovation Organization Dana O'Brien Executive Vice President, Food & Agriculture Dana O'Brien is Executive Vice President for Food and Agriculture and is responsible for the development of public policy and strategic advocacy, public affairo, and legal strategies that advance industry and stakeholder objectives in the United States. Prior to becoming EVP, Dana served bs BIO Food and Agriculture's chief legislative advocate as Senior Director of Federal Government Relations aince March 2011. Before BIO, Dana worked in Congress for the late Representative lke Skelton (D-MO) managing his legislative team and concentrating on a variety of agricultural, energy, and trade matters. A native of Sedalia, Missouri, and a graduate of Missouri University with a bachelor's degree in psychology, Dana joined the Skelton team immediately out of college and served there for nearly 14 years Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00015 UNITED FRESH is PRODUCE ASSOCIATION Tom Stenzel President and CEO United Fresh Produce Association 1901 Pennsylvania Avenue NW, Suite 1100 Washington, DC 20006 202/303-3400 tstenzel@unitedfresh.org Tom Stenzel is President and CEO of the United Fresh Produce Association, a position he has held since 1993. United Fresh is the pre-eminent trade association for the produce industry in shaping legislative and regulatory policies; providing scientific and technical leadership in food safety and nutrition; and developing educational programs for its members. Founded in 1904, United Fresh represents the interests of companies from small family businesses to the largest international corporations throughout the global fresh produce supply chain. United Fresh is widely known for its work in government affairs, agricultural policy, food safety and nutrition, working to promote political and environmental change to help the next generation of children double their consumption of fresh produce. The United Fresh Start Foundation is committed to increasing children's access to fresh fruits and vegetables, and is a founding partner of the Let's Move Salad Bars to Schools campaign. The campaign has donated salad bars to more than 6,000 schools across the country. Tom is a frequent speaker on industry issues and has been recognized often by the produce industry throughout his career. He was honored as the 2002 Produce Man of the Year by The Packer newspaper, and is the past Chairman of the International Federation for Produce Standards, a global body representing national produce associations around the world. He is a member of the U.S. Chamber of Commerce Committee of 100 leading association executives, the Advisory Board of the International Food Protection Training Institute, and the Key Industry Associations Committee of the American Society of Association Executives, from which he achieved the Certified Association Executive (CAE) designation in 1990. He has served in many government and industry leadership positions, including the first U.S. Department of Agriculture Fruit and Vegetable Industry Advisory Committee, President George W. Bush's Transition Advisory Team for Agriculture, and as an advisor on the U.S. Agricultural Policy Advisory Committee for Trade. Tom was the founding President of the International Food Information Council (IFIC) in 1986, and was previously director of public affairs for the National Soft Drink Association. Tom is a 1977 graduate of the University of Richmond. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00016 as of January 17, 2017 Jay Vroom has served as President and CEO of the trade association known as CropLife America (CLA) since 1989. CLA is the leading U.S. trade group for the crop protection industry in the U.S. Vroom is a founding member of the CropLife Foundation, serving as chairman since its inception in 2001, and now serves as the Foundation's Vice-Chair, since 2015. His sits of the Board of Directors for the Agricultural Retailers Association, Asmark, National Wheat Foundation, the National Association of Manufacturers Council of Manufacturing Associations, and the Soil Health Institute. He is also a member of the Farm Foundation Roundtable Steering Committee, and the North American Climate Smart Ag Alliance Steering Committee. Vroom was a member of the youth organization, Future Farmers of America, and served as an elected state officer in Illinois. Today, he is a member of the FFA Foundation's Individual Giving Council and Board of Trustees. Vroom co-chairs the Coalition for the Advancement of Precision Agriculture and the CEO Council. He is a member of the Friends of the National Arboretum (FONA) FONA Council. He graduated with honors from the College of Agriculture, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign. Vroom was raised on a grain and livestock farm in north-central Illinois and continues to own the farming operation. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00017 Elizabeth Ward Betsy Ward was appointed President & CEO of the USA Rice Federation in 2007. From 2003- 2005, Ward was the Vice President of International and Domestic Promotion at USA Rice where she was in charge of developing and implementing domestic and international promotion, and food aid programs. From 2005-2007, Ward served as the chief executive for the Hardwood Federation, a trade association representing over 15,000 hardwood producers across the United States. From 1995 to 2003, she ran the Wood Products International Group at the American Forest & Paper Association, directing the wood trade policy and global forestry agenda for the industry. In 2011, Ward was elected Chairman of the U.S. Agricultural Export Development Council (USAEDC) which represents the interests of more than 80 commodity organizations who grow and process a wide variety of U.S. agricultural products. She currently serves as Past Chair. Since 2011, Ward has also served on the Board of Directors of the Sustainable Fisheries Partnership, an independent non-governmental organization (NGO) working to ensure healthy marine and aquatic tecosystems; secure seafood supplies; and a thriving, responsible seafood economy. Ward served for six years as a cleared advisor on the Industry Trade Advisory Committee for forest and paper products (ITAC-7) and was appointed forest products representative to USDA's Agricultural Policy Advisory Committee (APAC) in 2001. Ward holds a Bachelor's degree in History and Political Science from the University of New Hampshire and a Master's degree in International Security Affairs from the School of International Affairs at Columbia University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00018 To: Brown, Byron[brown.byron@epa.gov]; Jackson, Ryan[jackson.ryan@epa.gov] From: Rebeckah Adcock Sent: Thur 3/30/2017 4:10:52 PM Subject: FW: FINAL CEO Council Meeting Agenda and Materials Pruitt Meeting Materials.pdf ATT00001.htm FYI - final materials for today's meeting. Reb From: "Mary Jo Tomalewski" <mjtomalewski@croplifeamerica.org> To: "Hupp, Sydney" <hupp.sydney@epa.gov> Cc: "Jay Vroom" <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00001 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobilé Ex. 6 Personal Privacy Fax (202) 466-5832 Email mitomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama. and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: :https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives on a small farm in Maryland with her husband: Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00011

What is the full form of TFI?

ffcn0226

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The Fertilizer Institute

To: Greenwalt, Sarah[greenwalt.sarah@epa.gov]; Dravis, Samantha[dravis.samantha@epa.gov] Brown, Byron[brown.byron@epa.gov];Wagner, Kenneth[wagner.kenneth@epa.gov] From: Hupp, Sydney Sent: Thur 3/30/2017 5:11:34 PM Subject: FW: FINAL Meeting Agenda and Materials Pruitt Meeting Materials.pd FYI. Sydney Hupp Office of the Administrator- Scheduling 202.816.1659 From: Mary Jo Tomalewski [mailto:mjtomalewski@croplifeamerica.org] Sent: Thursday, March 30, 2017 11:22 AM To: Hupp, Sydney <hupp.sydney@epa.gov> Cc: Jay Vroom <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000061-00001 MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobile Ex. 6 Personal Privacy Fax (202)466-5832 Email mjtomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000061-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00011 The Fertilizer Institute Nourish, Replenish, Grow BIOGRAPHY OF CHRISTOPHER JAHN President The Fertilizer Institute and the Nutrients for Life Foundation Christopher L. Jahn is president of The Fertilizer Institute (TFI), the fertilizer industry's national trade association. As TFI president, Jahn works to represent, promote and protect a sound fertilizer industry through legislative and regulatory activities and to promote a favorable public image of the fertilizer industry and agriculture. Jahn also serves as president of the Nutrients for Life Foundation (NFL). Jahn comes to TFI having served as president of the National Association of Chemical Distributors (NACD) since 2006. Prior to leading NACD, Jahn served as president of the Contract Services Association (CSA). Before joining CSA, Jahn had an active role in the United States Senate working for nearly 10 years for U.S. Senator Craig Thomas (R-Wyo.) in a variety of roles, including legislative assistant, legislative director and Chief of Staff. After graduating from Columbia University with a B.A. in Political Science, Jahn co-founded a book distribution business. He also earned an MBA from the University of Maryland. A native of Wyoming, Chris and his wife, Ex. 6 - Personal Privacy Ex. Personal Privacy Capitol View 202.962.0490 425 Third Street, S.W., Suite 950 202.962.0577 fax Washington, DC 20024 www.tfi.org Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00012 National Farmers Union Roger Johnson President Roger Johnson is president of the National Farmers Union (NFU), a grassroots organization that represents more than 200,000 family farmers, ranchers, fisherman and rural communities across the Unites States. Johnson was elected to lead the family farm organization at NFU's 107th anniversary convention in 2009. He has since expanded the education department by providing more programs for beginning, college-aged and women farmers, increased the number of Farmers Union state divisions, and developed a strategic plan for the organization. Johnson has also overseen a number of important policy initiatives important to family farmers including: passage of the 2014 Farm Bill; maintaining a strong Renewable Fuel Standard and Country-of-Origir Labeling, promoting policies that allow farmers to address the growing threat of climate change; and renewing the nation's focus on eliminating an overwhelming trade deficit that results in lost jobs and prosperity for rural America. Prior to leading National Farmers Union, Johnson, a third-generation family farmer from Turtle Lake, N.D., served as North Dakota Agriculture Commissioner, a position he was first elected to in 1996. While Agriculture Commissioner, Johnson served on the State Industrial Commission, the North Dakota Trade Office Advisory Board, and the State Board of Agricultural Research and Education, among many other boards and commissions. From 2007-2008, Johnson served as president of the National Association of State Departments of Agriculture (NASDA). He is a past president of the Midwestern Association of State Departments of Agriculture (MASDA), past president of the Food Export Association of the Midwest and a former chairman of the Interstate Pest Control Compact. Johnson graduated from North Dakota State University with a degree in agricultural economics. Johnson and his wife Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00013 AMERICAN SEED TRADE ASSOCIATION asta first-the - seed R Andrew W. "Andy" LaVigne President & CEO Andrew W. LaVigne is currently the President and CEO of the Ame rican Seed Trade Association. He joined ASTA in February, 2006. Andy has had a 30-year career i n government relations, industry representation, public affairs advocacy, and management. His C ore areas of expertise include agriculture, food policy and international trade. Prior to joining ASTA, Andy was Executive Vice President/CEC of Florida Citrus Mutual, representing citrus growers on issues affecting their business. Prejaiming tFdorida Citrus Mutual, Andy spent four years as Florida Fertilizer and Agrichemical Association's (FFAA) President and Executive Director. FFAA is a non-profit, agricultural trade organization representing companies that specialize in crop protection and plant nutrition products. Before his position at FFAA, Andy spent eight years in Washingt on, D.C. working in the U.S. Congress and the U.S. Department of Agriculture. He served as Legislative Director for Congressman Charles Canady, Agriculture Committee staffer for Congressman Tom Lewis , and on the staff of USDA Secretary Ed Madigan. Andy is a native of Florida with a BA degree in Political Scien ce, with a minor in economics, from the University of Florida. 1701 Duke Street Suite 275 Alexandria, VA 22314 Phone: (703)837-8140 Fax: (703)837-9365 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00014 Biotechnology Innovation Organization Dana O'Brien Executive Vice President, Food & Agriculture Dana O'Brien is Executive Vice President for Food and Agriculture and is responsible for the development of public policy and strategic advocacy, public affairo, and legal strategies that advance industry and stakeholder objectives in the United States. Prior to becoming EVP, Dana served bs BIO Food and Agriculture's chief legislative advocate as Senior Director of Federal Government Relations aince March 2011. Before BIO, Dana worked in Congress for the late Representative lke Skelton (D-MO) managing his legislative team and concentrating on a variety of agricultural, energy, and trade matters. A native of Sedalia, Missouri, and a graduate of Missouri University with a bachelor's degree in psychology, Dana joined the Skelton team immediately out of college and served there for nearly 14 years Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00015 UNITED FRESH is PRODUCE ASSOCIATION Tom Stenzel President and CEO United Fresh Produce Association 1901 Pennsylvania Avenue NW, Suite 1100 Washington, DC 20006 202/303-3400 tstenzel@unitedfresh.org Tom Stenzel is President and CEO of the United Fresh Produce Association, a position he has held since 1993. United Fresh is the pre-eminent trade association for the produce industry in shaping legislative and regulatory policies; providing scientific and technical leadership in food safety and nutrition; and developing educational programs for its members. Founded in 1904, United Fresh represents the interests of companies from small family businesses to the largest international corporations throughout the global fresh produce supply chain. United Fresh is widely known for its work in government affairs, agricultural policy, food safety and nutrition, working to promote political and environmental change to help the next generation of children double their consumption of fresh produce. The United Fresh Start Foundation is committed to increasing children's access to fresh fruits and vegetables, and is a founding partner of the Let's Move Salad Bars to Schools campaign. The campaign has donated salad bars to more than 6,000 schools across the country. Tom is a frequent speaker on industry issues and has been recognized often by the produce industry throughout his career. He was honored as the 2002 Produce Man of the Year by The Packer newspaper, and is the past Chairman of the International Federation for Produce Standards, a global body representing national produce associations around the world. He is a member of the U.S. Chamber of Commerce Committee of 100 leading association executives, the Advisory Board of the International Food Protection Training Institute, and the Key Industry Associations Committee of the American Society of Association Executives, from which he achieved the Certified Association Executive (CAE) designation in 1990. He has served in many government and industry leadership positions, including the first U.S. Department of Agriculture Fruit and Vegetable Industry Advisory Committee, President George W. Bush's Transition Advisory Team for Agriculture, and as an advisor on the U.S. Agricultural Policy Advisory Committee for Trade. Tom was the founding President of the International Food Information Council (IFIC) in 1986, and was previously director of public affairs for the National Soft Drink Association. Tom is a 1977 graduate of the University of Richmond. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00016 as of January 17, 2017 Jay Vroom has served as President and CEO of the trade association known as CropLife America (CLA) since 1989. CLA is the leading U.S. trade group for the crop protection industry in the U.S. Vroom is a founding member of the CropLife Foundation, serving as chairman since its inception in 2001, and now serves as the Foundation's Vice-Chair, since 2015. His sits of the Board of Directors for the Agricultural Retailers Association, Asmark, National Wheat Foundation, the National Association of Manufacturers Council of Manufacturing Associations, and the Soil Health Institute. He is also a member of the Farm Foundation Roundtable Steering Committee, and the North American Climate Smart Ag Alliance Steering Committee. Vroom was a member of the youth organization, Future Farmers of America, and served as an elected state officer in Illinois. Today, he is a member of the FFA Foundation's Individual Giving Council and Board of Trustees. Vroom co-chairs the Coalition for the Advancement of Precision Agriculture and the CEO Council. He is a member of the Friends of the National Arboretum (FONA) FONA Council. He graduated with honors from the College of Agriculture, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign. Vroom was raised on a grain and livestock farm in north-central Illinois and continues to own the farming operation. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00017 Elizabeth Ward Betsy Ward was appointed President & CEO of the USA Rice Federation in 2007. From 2003- 2005, Ward was the Vice President of International and Domestic Promotion at USA Rice where she was in charge of developing and implementing domestic and international promotion, and food aid programs. From 2005-2007, Ward served as the chief executive for the Hardwood Federation, a trade association representing over 15,000 hardwood producers across the United States. From 1995 to 2003, she ran the Wood Products International Group at the American Forest & Paper Association, directing the wood trade policy and global forestry agenda for the industry. In 2011, Ward was elected Chairman of the U.S. Agricultural Export Development Council (USAEDC) which represents the interests of more than 80 commodity organizations who grow and process a wide variety of U.S. agricultural products. She currently serves as Past Chair. Since 2011, Ward has also served on the Board of Directors of the Sustainable Fisheries Partnership, an independent non-governmental organization (NGO) working to ensure healthy marine and aquatic tecosystems; secure seafood supplies; and a thriving, responsible seafood economy. Ward served for six years as a cleared advisor on the Industry Trade Advisory Committee for forest and paper products (ITAC-7) and was appointed forest products representative to USDA's Agricultural Policy Advisory Committee (APAC) in 2001. Ward holds a Bachelor's degree in History and Political Science from the University of New Hampshire and a Master's degree in International Security Affairs from the School of International Affairs at Columbia University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00018 To: Brown, Byron[brown.byron@epa.gov]; Jackson, Ryan[jackson.ryan@epa.gov] From: Rebeckah Adcock Sent: Thur 3/30/2017 4:10:52 PM Subject: FW: FINAL CEO Council Meeting Agenda and Materials Pruitt Meeting Materials.pdf ATT00001.htm FYI - final materials for today's meeting. Reb From: "Mary Jo Tomalewski" <mjtomalewski@croplifeamerica.org> To: "Hupp, Sydney" <hupp.sydney@epa.gov> Cc: "Jay Vroom" <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00001 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobilé Ex. 6 Personal Privacy Fax (202) 466-5832 Email mitomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama. and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: :https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives on a small farm in Maryland with her husband: Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00011

For how many years did Christopher Jahn work for U.S. Senator Craig Thomas?

ffcn0226

ffcn0226_p0, ffcn0226_p1, ffcn0226_p2, ffcn0226_p3, ffcn0226_p4, ffcn0226_p5, ffcn0226_p6, ffcn0226_p7, ffcn0226_p8, ffcn0226_p9, ffcn0226_p10, ffcn0226_p11, ffcn0226_p12, ffcn0226_p13, ffcn0226_p14, ffcn0226_p15, ffcn0226_p16, ffcn0226_p17, ffcn0226_p18, ffcn0226_p19, ffcn0226_p20, ffcn0226_p21, ffcn0226_p22, ffcn0226_p23, ffcn0226_p24, ffcn0226_p25, ffcn0226_p26, ffcn0226_p27, ffcn0226_p28, ffcn0226_p29, ffcn0226_p30, ffcn0226_p31, ffcn0226_p32

nearly 10 years, 10, 10 years

To: Greenwalt, Sarah[greenwalt.sarah@epa.gov]; Dravis, Samantha[dravis.samantha@epa.gov] Brown, Byron[brown.byron@epa.gov];Wagner, Kenneth[wagner.kenneth@epa.gov] From: Hupp, Sydney Sent: Thur 3/30/2017 5:11:34 PM Subject: FW: FINAL Meeting Agenda and Materials Pruitt Meeting Materials.pd FYI. Sydney Hupp Office of the Administrator- Scheduling 202.816.1659 From: Mary Jo Tomalewski [mailto:mjtomalewski@croplifeamerica.org] Sent: Thursday, March 30, 2017 11:22 AM To: Hupp, Sydney <hupp.sydney@epa.gov> Cc: Jay Vroom <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000061-00001 MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobile Ex. 6 Personal Privacy Fax (202)466-5832 Email mjtomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000061-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00011 The Fertilizer Institute Nourish, Replenish, Grow BIOGRAPHY OF CHRISTOPHER JAHN President The Fertilizer Institute and the Nutrients for Life Foundation Christopher L. Jahn is president of The Fertilizer Institute (TFI), the fertilizer industry's national trade association. As TFI president, Jahn works to represent, promote and protect a sound fertilizer industry through legislative and regulatory activities and to promote a favorable public image of the fertilizer industry and agriculture. Jahn also serves as president of the Nutrients for Life Foundation (NFL). Jahn comes to TFI having served as president of the National Association of Chemical Distributors (NACD) since 2006. Prior to leading NACD, Jahn served as president of the Contract Services Association (CSA). Before joining CSA, Jahn had an active role in the United States Senate working for nearly 10 years for U.S. Senator Craig Thomas (R-Wyo.) in a variety of roles, including legislative assistant, legislative director and Chief of Staff. After graduating from Columbia University with a B.A. in Political Science, Jahn co-founded a book distribution business. He also earned an MBA from the University of Maryland. A native of Wyoming, Chris and his wife, Ex. 6 - Personal Privacy Ex. Personal Privacy Capitol View 202.962.0490 425 Third Street, S.W., Suite 950 202.962.0577 fax Washington, DC 20024 www.tfi.org Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00012 National Farmers Union Roger Johnson President Roger Johnson is president of the National Farmers Union (NFU), a grassroots organization that represents more than 200,000 family farmers, ranchers, fisherman and rural communities across the Unites States. Johnson was elected to lead the family farm organization at NFU's 107th anniversary convention in 2009. He has since expanded the education department by providing more programs for beginning, college-aged and women farmers, increased the number of Farmers Union state divisions, and developed a strategic plan for the organization. Johnson has also overseen a number of important policy initiatives important to family farmers including: passage of the 2014 Farm Bill; maintaining a strong Renewable Fuel Standard and Country-of-Origir Labeling, promoting policies that allow farmers to address the growing threat of climate change; and renewing the nation's focus on eliminating an overwhelming trade deficit that results in lost jobs and prosperity for rural America. Prior to leading National Farmers Union, Johnson, a third-generation family farmer from Turtle Lake, N.D., served as North Dakota Agriculture Commissioner, a position he was first elected to in 1996. While Agriculture Commissioner, Johnson served on the State Industrial Commission, the North Dakota Trade Office Advisory Board, and the State Board of Agricultural Research and Education, among many other boards and commissions. From 2007-2008, Johnson served as president of the National Association of State Departments of Agriculture (NASDA). He is a past president of the Midwestern Association of State Departments of Agriculture (MASDA), past president of the Food Export Association of the Midwest and a former chairman of the Interstate Pest Control Compact. Johnson graduated from North Dakota State University with a degree in agricultural economics. Johnson and his wife Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00013 AMERICAN SEED TRADE ASSOCIATION asta first-the - seed R Andrew W. "Andy" LaVigne President & CEO Andrew W. LaVigne is currently the President and CEO of the Ame rican Seed Trade Association. He joined ASTA in February, 2006. Andy has had a 30-year career i n government relations, industry representation, public affairs advocacy, and management. His C ore areas of expertise include agriculture, food policy and international trade. Prior to joining ASTA, Andy was Executive Vice President/CEC of Florida Citrus Mutual, representing citrus growers on issues affecting their business. Prejaiming tFdorida Citrus Mutual, Andy spent four years as Florida Fertilizer and Agrichemical Association's (FFAA) President and Executive Director. FFAA is a non-profit, agricultural trade organization representing companies that specialize in crop protection and plant nutrition products. Before his position at FFAA, Andy spent eight years in Washingt on, D.C. working in the U.S. Congress and the U.S. Department of Agriculture. He served as Legislative Director for Congressman Charles Canady, Agriculture Committee staffer for Congressman Tom Lewis , and on the staff of USDA Secretary Ed Madigan. Andy is a native of Florida with a BA degree in Political Scien ce, with a minor in economics, from the University of Florida. 1701 Duke Street Suite 275 Alexandria, VA 22314 Phone: (703)837-8140 Fax: (703)837-9365 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00014 Biotechnology Innovation Organization Dana O'Brien Executive Vice President, Food & Agriculture Dana O'Brien is Executive Vice President for Food and Agriculture and is responsible for the development of public policy and strategic advocacy, public affairo, and legal strategies that advance industry and stakeholder objectives in the United States. Prior to becoming EVP, Dana served bs BIO Food and Agriculture's chief legislative advocate as Senior Director of Federal Government Relations aince March 2011. Before BIO, Dana worked in Congress for the late Representative lke Skelton (D-MO) managing his legislative team and concentrating on a variety of agricultural, energy, and trade matters. A native of Sedalia, Missouri, and a graduate of Missouri University with a bachelor's degree in psychology, Dana joined the Skelton team immediately out of college and served there for nearly 14 years Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00015 UNITED FRESH is PRODUCE ASSOCIATION Tom Stenzel President and CEO United Fresh Produce Association 1901 Pennsylvania Avenue NW, Suite 1100 Washington, DC 20006 202/303-3400 tstenzel@unitedfresh.org Tom Stenzel is President and CEO of the United Fresh Produce Association, a position he has held since 1993. United Fresh is the pre-eminent trade association for the produce industry in shaping legislative and regulatory policies; providing scientific and technical leadership in food safety and nutrition; and developing educational programs for its members. Founded in 1904, United Fresh represents the interests of companies from small family businesses to the largest international corporations throughout the global fresh produce supply chain. United Fresh is widely known for its work in government affairs, agricultural policy, food safety and nutrition, working to promote political and environmental change to help the next generation of children double their consumption of fresh produce. The United Fresh Start Foundation is committed to increasing children's access to fresh fruits and vegetables, and is a founding partner of the Let's Move Salad Bars to Schools campaign. The campaign has donated salad bars to more than 6,000 schools across the country. Tom is a frequent speaker on industry issues and has been recognized often by the produce industry throughout his career. He was honored as the 2002 Produce Man of the Year by The Packer newspaper, and is the past Chairman of the International Federation for Produce Standards, a global body representing national produce associations around the world. He is a member of the U.S. Chamber of Commerce Committee of 100 leading association executives, the Advisory Board of the International Food Protection Training Institute, and the Key Industry Associations Committee of the American Society of Association Executives, from which he achieved the Certified Association Executive (CAE) designation in 1990. He has served in many government and industry leadership positions, including the first U.S. Department of Agriculture Fruit and Vegetable Industry Advisory Committee, President George W. Bush's Transition Advisory Team for Agriculture, and as an advisor on the U.S. Agricultural Policy Advisory Committee for Trade. Tom was the founding President of the International Food Information Council (IFIC) in 1986, and was previously director of public affairs for the National Soft Drink Association. Tom is a 1977 graduate of the University of Richmond. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00016 as of January 17, 2017 Jay Vroom has served as President and CEO of the trade association known as CropLife America (CLA) since 1989. CLA is the leading U.S. trade group for the crop protection industry in the U.S. Vroom is a founding member of the CropLife Foundation, serving as chairman since its inception in 2001, and now serves as the Foundation's Vice-Chair, since 2015. His sits of the Board of Directors for the Agricultural Retailers Association, Asmark, National Wheat Foundation, the National Association of Manufacturers Council of Manufacturing Associations, and the Soil Health Institute. He is also a member of the Farm Foundation Roundtable Steering Committee, and the North American Climate Smart Ag Alliance Steering Committee. Vroom was a member of the youth organization, Future Farmers of America, and served as an elected state officer in Illinois. Today, he is a member of the FFA Foundation's Individual Giving Council and Board of Trustees. Vroom co-chairs the Coalition for the Advancement of Precision Agriculture and the CEO Council. He is a member of the Friends of the National Arboretum (FONA) FONA Council. He graduated with honors from the College of Agriculture, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign. Vroom was raised on a grain and livestock farm in north-central Illinois and continues to own the farming operation. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00017 Elizabeth Ward Betsy Ward was appointed President & CEO of the USA Rice Federation in 2007. From 2003- 2005, Ward was the Vice President of International and Domestic Promotion at USA Rice where she was in charge of developing and implementing domestic and international promotion, and food aid programs. From 2005-2007, Ward served as the chief executive for the Hardwood Federation, a trade association representing over 15,000 hardwood producers across the United States. From 1995 to 2003, she ran the Wood Products International Group at the American Forest & Paper Association, directing the wood trade policy and global forestry agenda for the industry. In 2011, Ward was elected Chairman of the U.S. Agricultural Export Development Council (USAEDC) which represents the interests of more than 80 commodity organizations who grow and process a wide variety of U.S. agricultural products. She currently serves as Past Chair. Since 2011, Ward has also served on the Board of Directors of the Sustainable Fisheries Partnership, an independent non-governmental organization (NGO) working to ensure healthy marine and aquatic tecosystems; secure seafood supplies; and a thriving, responsible seafood economy. Ward served for six years as a cleared advisor on the Industry Trade Advisory Committee for forest and paper products (ITAC-7) and was appointed forest products representative to USDA's Agricultural Policy Advisory Committee (APAC) in 2001. Ward holds a Bachelor's degree in History and Political Science from the University of New Hampshire and a Master's degree in International Security Affairs from the School of International Affairs at Columbia University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00018 To: Brown, Byron[brown.byron@epa.gov]; Jackson, Ryan[jackson.ryan@epa.gov] From: Rebeckah Adcock Sent: Thur 3/30/2017 4:10:52 PM Subject: FW: FINAL CEO Council Meeting Agenda and Materials Pruitt Meeting Materials.pdf ATT00001.htm FYI - final materials for today's meeting. Reb From: "Mary Jo Tomalewski" <mjtomalewski@croplifeamerica.org> To: "Hupp, Sydney" <hupp.sydney@epa.gov> Cc: "Jay Vroom" <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00001 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobilé Ex. 6 Personal Privacy Fax (202) 466-5832 Email mitomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama. and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: :https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives on a small farm in Maryland with her husband: Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00011

What is the full form CSA?

ffcn0226

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Contract Services Association

To: Greenwalt, Sarah[greenwalt.sarah@epa.gov]; Dravis, Samantha[dravis.samantha@epa.gov] Brown, Byron[brown.byron@epa.gov];Wagner, Kenneth[wagner.kenneth@epa.gov] From: Hupp, Sydney Sent: Thur 3/30/2017 5:11:34 PM Subject: FW: FINAL Meeting Agenda and Materials Pruitt Meeting Materials.pd FYI. Sydney Hupp Office of the Administrator- Scheduling 202.816.1659 From: Mary Jo Tomalewski [mailto:mjtomalewski@croplifeamerica.org] Sent: Thursday, March 30, 2017 11:22 AM To: Hupp, Sydney <hupp.sydney@epa.gov> Cc: Jay Vroom <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000061-00001 MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobile Ex. 6 Personal Privacy Fax (202)466-5832 Email mjtomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000061-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00011 The Fertilizer Institute Nourish, Replenish, Grow BIOGRAPHY OF CHRISTOPHER JAHN President The Fertilizer Institute and the Nutrients for Life Foundation Christopher L. Jahn is president of The Fertilizer Institute (TFI), the fertilizer industry's national trade association. As TFI president, Jahn works to represent, promote and protect a sound fertilizer industry through legislative and regulatory activities and to promote a favorable public image of the fertilizer industry and agriculture. Jahn also serves as president of the Nutrients for Life Foundation (NFL). Jahn comes to TFI having served as president of the National Association of Chemical Distributors (NACD) since 2006. Prior to leading NACD, Jahn served as president of the Contract Services Association (CSA). Before joining CSA, Jahn had an active role in the United States Senate working for nearly 10 years for U.S. Senator Craig Thomas (R-Wyo.) in a variety of roles, including legislative assistant, legislative director and Chief of Staff. After graduating from Columbia University with a B.A. in Political Science, Jahn co-founded a book distribution business. He also earned an MBA from the University of Maryland. A native of Wyoming, Chris and his wife, Ex. 6 - Personal Privacy Ex. Personal Privacy Capitol View 202.962.0490 425 Third Street, S.W., Suite 950 202.962.0577 fax Washington, DC 20024 www.tfi.org Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00012 National Farmers Union Roger Johnson President Roger Johnson is president of the National Farmers Union (NFU), a grassroots organization that represents more than 200,000 family farmers, ranchers, fisherman and rural communities across the Unites States. Johnson was elected to lead the family farm organization at NFU's 107th anniversary convention in 2009. He has since expanded the education department by providing more programs for beginning, college-aged and women farmers, increased the number of Farmers Union state divisions, and developed a strategic plan for the organization. Johnson has also overseen a number of important policy initiatives important to family farmers including: passage of the 2014 Farm Bill; maintaining a strong Renewable Fuel Standard and Country-of-Origir Labeling, promoting policies that allow farmers to address the growing threat of climate change; and renewing the nation's focus on eliminating an overwhelming trade deficit that results in lost jobs and prosperity for rural America. Prior to leading National Farmers Union, Johnson, a third-generation family farmer from Turtle Lake, N.D., served as North Dakota Agriculture Commissioner, a position he was first elected to in 1996. While Agriculture Commissioner, Johnson served on the State Industrial Commission, the North Dakota Trade Office Advisory Board, and the State Board of Agricultural Research and Education, among many other boards and commissions. From 2007-2008, Johnson served as president of the National Association of State Departments of Agriculture (NASDA). He is a past president of the Midwestern Association of State Departments of Agriculture (MASDA), past president of the Food Export Association of the Midwest and a former chairman of the Interstate Pest Control Compact. Johnson graduated from North Dakota State University with a degree in agricultural economics. Johnson and his wife Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00013 AMERICAN SEED TRADE ASSOCIATION asta first-the - seed R Andrew W. "Andy" LaVigne President & CEO Andrew W. LaVigne is currently the President and CEO of the Ame rican Seed Trade Association. He joined ASTA in February, 2006. Andy has had a 30-year career i n government relations, industry representation, public affairs advocacy, and management. His C ore areas of expertise include agriculture, food policy and international trade. Prior to joining ASTA, Andy was Executive Vice President/CEC of Florida Citrus Mutual, representing citrus growers on issues affecting their business. Prejaiming tFdorida Citrus Mutual, Andy spent four years as Florida Fertilizer and Agrichemical Association's (FFAA) President and Executive Director. FFAA is a non-profit, agricultural trade organization representing companies that specialize in crop protection and plant nutrition products. Before his position at FFAA, Andy spent eight years in Washingt on, D.C. working in the U.S. Congress and the U.S. Department of Agriculture. He served as Legislative Director for Congressman Charles Canady, Agriculture Committee staffer for Congressman Tom Lewis , and on the staff of USDA Secretary Ed Madigan. Andy is a native of Florida with a BA degree in Political Scien ce, with a minor in economics, from the University of Florida. 1701 Duke Street Suite 275 Alexandria, VA 22314 Phone: (703)837-8140 Fax: (703)837-9365 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00014 Biotechnology Innovation Organization Dana O'Brien Executive Vice President, Food & Agriculture Dana O'Brien is Executive Vice President for Food and Agriculture and is responsible for the development of public policy and strategic advocacy, public affairo, and legal strategies that advance industry and stakeholder objectives in the United States. Prior to becoming EVP, Dana served bs BIO Food and Agriculture's chief legislative advocate as Senior Director of Federal Government Relations aince March 2011. Before BIO, Dana worked in Congress for the late Representative lke Skelton (D-MO) managing his legislative team and concentrating on a variety of agricultural, energy, and trade matters. A native of Sedalia, Missouri, and a graduate of Missouri University with a bachelor's degree in psychology, Dana joined the Skelton team immediately out of college and served there for nearly 14 years Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000062-00015 UNITED FRESH is PRODUCE ASSOCIATION Tom Stenzel President and CEO United Fresh Produce Association 1901 Pennsylvania Avenue NW, Suite 1100 Washington, DC 20006 202/303-3400 tstenzel@unitedfresh.org Tom Stenzel is President and CEO of the United Fresh Produce Association, a position he has held since 1993. United Fresh is the pre-eminent trade association for the produce industry in shaping legislative and regulatory policies; providing scientific and technical leadership in food safety and nutrition; and developing educational programs for its members. Founded in 1904, United Fresh represents the interests of companies from small family businesses to the largest international corporations throughout the global fresh produce supply chain. United Fresh is widely known for its work in government affairs, agricultural policy, food safety and nutrition, working to promote political and environmental change to help the next generation of children double their consumption of fresh produce. The United Fresh Start Foundation is committed to increasing children's access to fresh fruits and vegetables, and is a founding partner of the Let's Move Salad Bars to Schools campaign. The campaign has donated salad bars to more than 6,000 schools across the country. Tom is a frequent speaker on industry issues and has been recognized often by the produce industry throughout his career. He was honored as the 2002 Produce Man of the Year by The Packer newspaper, and is the past Chairman of the International Federation for Produce Standards, a global body representing national produce associations around the world. He is a member of the U.S. Chamber of Commerce Committee of 100 leading association executives, the Advisory Board of the International Food Protection Training Institute, and the Key Industry Associations Committee of the American Society of Association Executives, from which he achieved the Certified Association Executive (CAE) designation in 1990. He has served in many government and industry leadership positions, including the first U.S. Department of Agriculture Fruit and Vegetable Industry Advisory Committee, President George W. Bush's Transition Advisory Team for Agriculture, and as an advisor on the U.S. Agricultural Policy Advisory Committee for Trade. Tom was the founding President of the International Food Information Council (IFIC) in 1986, and was previously director of public affairs for the National Soft Drink Association. Tom is a 1977 graduate of the University of Richmond. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00016 as of January 17, 2017 Jay Vroom has served as President and CEO of the trade association known as CropLife America (CLA) since 1989. CLA is the leading U.S. trade group for the crop protection industry in the U.S. Vroom is a founding member of the CropLife Foundation, serving as chairman since its inception in 2001, and now serves as the Foundation's Vice-Chair, since 2015. His sits of the Board of Directors for the Agricultural Retailers Association, Asmark, National Wheat Foundation, the National Association of Manufacturers Council of Manufacturing Associations, and the Soil Health Institute. He is also a member of the Farm Foundation Roundtable Steering Committee, and the North American Climate Smart Ag Alliance Steering Committee. Vroom was a member of the youth organization, Future Farmers of America, and served as an elected state officer in Illinois. Today, he is a member of the FFA Foundation's Individual Giving Council and Board of Trustees. Vroom co-chairs the Coalition for the Advancement of Precision Agriculture and the CEO Council. He is a member of the Friends of the National Arboretum (FONA) FONA Council. He graduated with honors from the College of Agriculture, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign. Vroom was raised on a grain and livestock farm in north-central Illinois and continues to own the farming operation. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00017 Elizabeth Ward Betsy Ward was appointed President & CEO of the USA Rice Federation in 2007. From 2003- 2005, Ward was the Vice President of International and Domestic Promotion at USA Rice where she was in charge of developing and implementing domestic and international promotion, and food aid programs. From 2005-2007, Ward served as the chief executive for the Hardwood Federation, a trade association representing over 15,000 hardwood producers across the United States. From 1995 to 2003, she ran the Wood Products International Group at the American Forest & Paper Association, directing the wood trade policy and global forestry agenda for the industry. In 2011, Ward was elected Chairman of the U.S. Agricultural Export Development Council (USAEDC) which represents the interests of more than 80 commodity organizations who grow and process a wide variety of U.S. agricultural products. She currently serves as Past Chair. Since 2011, Ward has also served on the Board of Directors of the Sustainable Fisheries Partnership, an independent non-governmental organization (NGO) working to ensure healthy marine and aquatic tecosystems; secure seafood supplies; and a thriving, responsible seafood economy. Ward served for six years as a cleared advisor on the Industry Trade Advisory Committee for forest and paper products (ITAC-7) and was appointed forest products representative to USDA's Agricultural Policy Advisory Committee (APAC) in 2001. Ward holds a Bachelor's degree in History and Political Science from the University of New Hampshire and a Master's degree in International Security Affairs from the School of International Affairs at Columbia University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000062-00018 To: Brown, Byron[brown.byron@epa.gov]; Jackson, Ryan[jackson.ryan@epa.gov] From: Rebeckah Adcock Sent: Thur 3/30/2017 4:10:52 PM Subject: FW: FINAL CEO Council Meeting Agenda and Materials Pruitt Meeting Materials.pdf ATT00001.htm FYI - final materials for today's meeting. Reb From: "Mary Jo Tomalewski" <mjtomalewski@croplifeamerica.org> To: "Hupp, Sydney" <hupp.sydney@epa.gov> Cc: "Jay Vroom" <JVroom@croplifeamerica.org> Subject: FINAL Meeting Agenda and Materials Sydney, We have refined our proposed topics for today's CEO Council meeting with the administrator. Attached, please find: Revised "Final Proposed Agenda Topics," which includes the list of those CEO Council members who will attend our meeting today, and their short bios Introduction / Mission Overview of the CEO Council CEO Council Letter to President Trump, dated February 9, 2017 We assume we can skip a formal "round table of introductions" at the beginning of the meeting as our time is short and we want to maximize time spent talking about issues. MJ Mary Jo Tomalewski Executive Assistant to the President & CEO CropLife America Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00001 1156 15th Street, NW Suite 400 Washington, DC 20005 Direct Dial (202) 872-3849 Main Switchboard (202) 296-1585 Mobilé Ex. 6 Personal Privacy Fax (202) 466-5832 Email mitomalewski@croplifeamerica.org Web www.croplifeamerica.org How can I serve you today? Future Meetings 2017 Spring Regulator Conference - April 6-7, Arlington, VA 2017 Annual Meeting - September 22-27, Dana Point, CA 2018 Winter Board of Directors Meeting - March 5-7, Washington, DC 2018 Annual Meeting - September 21-26, The Ritz-Carlton Amelia Island Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000063-00002 FINAL PROPOSED AGENDA TOPICS Meeting Information: Office of EPA Administrator Scott Pruitt 1200 Pennsylvania Avenue, NW Washington, DC Thursday, March 30, 2017 3:45-4:30 PM Topic 1. Thanks to Trump Administration and Administrator Pruitt for early decisive actions: a. WOTUS b. Chlorpyrifos Petition 2. Top Priority Issues a. Ag Advisor Position - We recommend adding additional title of "Assistant Deputy Administrator" as a title b. Water i. Next steps to refine / clarify beyond WOTUS ii. NPDES permits (CAFO Program needs work; legislation to fix water permits NOT needed for lawful use of pesticides) c. Pesticides Policy i. Endangered Species Act conflicts with Pesticide Regulation and Biotech Regulation ii. Epidemiology Study Policy (as aftermath from Chlorpyrifos matter) iii. Reform Certification & Training and Worker Protection Rules - Suspend implementation and revise d. Renewable Fuels Standard - current program kept consistent e. Communication / Messaging / Opinion Polling - vital to all parties' ability to advance sound policy f. EPA and USDA Cooperation and Coordination - Already vast progress; more can be done! g. Environmental Justice, Research & Development, and Children's Health Offices - Better integration with and reform of EPA program offices; sound science h. Regulation of Manufacturing & Mining Facilities for Ag Inputs - Restore science and process i. Public and Science Advisory Panels at EPA - Balance, strategic agendas j. "Air Emissions" from farming operations CEO Attendees American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Corn Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Barb Glenn, CEO, ex-officio Departments of Agriculture Others American Farm Bureau Federation Dale Moore, Deputy Executive Director Corn Refiners Association John Bode, President & CEO National Farmers Union Rob Larew, Senior VP Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00001 Production Agriculture's CEO Council Introduction/Mission Statement: The production agriculture "CEO Council" coordinates alignment on core issues of modern agricultural systems through telling our story, sharing information and leveraging our strengths, while serving as a resource for government decision makers and others interested in USA food, fiber and renewable fuels. Core Focus of Interest Research and innovation Technology access Science and risk-based regulation Sustainability, environment, and weather Marketability, trade, and economic prosperity Government leadership and partnership with private sector Food access and food safety Plant and animal health Ag labor The Council supports principles/themes): Accelerating rural economic growth and improving productivity through innovation and technology Promoting research and innovation that enables development oftools and techniques necessary for discovering new products that hold tremendous potential for farmers and society at large Enabling a regulatory and commercial environment in which agricultural products are marketable, both domestically and internationally Appropriate balance between Federal and State Governments and a cooperative regulatory approach Access to essential labor in balance with an effective Federal immigration policy and adequate worker safety protections Support for all methods of agricultural production Transparency and dialogue with consumers Members of the CEO Council (see reversed) March 30, 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00002 CEO Council Members American Farm Bureau Vincent "Zippy" Duvall, President American Seed Trade Association Andrew "Andy" LaVigne, President and CEO American Soybean Association Steve Censky, Chief Executive Officer (Co-Chair) Biotechnology Innovation Organization Dana O'Brien, Executive Vice President CropLife America Jay Vroom, President and CEO (Co-Chair) The Fertilizer Institute Chris Jahn, President National Association of Wheat Growers Chandler Goule, CEO National Cattlemen's Beef Association Kendal Frazier, CEO National Chicken Council Michael Brown, President National Com Growers Association Chris Novak, CEO (Co-Chair) National Cotton Council Gary Adams, President and CEO National Council of Farmer Cooperatives Chuck Conner, President and CEO National Farmers Union Roger Johnson, President National Milk Producers Federation Jim Mulhern, President and CEO National Pork Producers Council Neil Dierks, CEO United Fresh Produce Association Tom Stenzel, President and CEO USA Rice Federation Betsy Ward, President & CEO National Association of State Departments of Barb Glenn, CEO, ex-officio Agriculture March 2017 Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00003 February 9, 2017 The President The White House Washington, D.C. 20500 Dear Mr. President, We, the CEO Council (undersigned herein), representing the production agricultural value chain, including many agricultural producers and farm input developers and suppliers, look forward to working with you and your Administration on matters of importance to American agriculture. The challenges we face in agriculture are significant. Many experts emphasize that producers must grow as much food in the next 50 years as was produced over all previous history to meet the demands of our expanding global population. A firm commitment by the U.S. government to aggressively support agricultural innovation and science-based regulatory decisions will be necessary to ensure farmers have the tools they need to produce a safe and abundant supply of nutritious food, in addition to feed, fuel and fiber, in an environmentally sound and sustainable manner. The policy and regulatory environment your Administration establishes can ensure that agricultural innovation flourishes and American farmers are able to meet the food production goals necessary to feed billions more people. We are ready to provide the White House and the Executive Branch Departments and Agencies, as well as Congress, with policy concepts that foster stability in the U.S. agriculture economy with a strong and predictable farm safety net and promotes American competitiveness through research; marketability and trade of agricultural commodities; rural economic growth; and plant, animal, and environmental health, among many other things. We appreciate your attention to these and other issues of value to American production agriculture and food consumers everywhere. Sincerely, American Farm Bureau Foundation, Zippy Duvall American Seed Trade Association, Andy LaVigne American Soybean Association, Steve Censky Biotechnology Innovation Organization, Dana O'Brien CropLife America, Jay Vroom The Fertilizer Institute, Chris Jahn National Association of Wheat Growers, Chandler Goule National Cattlemen's Beef Association, Kendal Frazier National Corn Growers Association, Chris Novak National Cotton Council, Gary Adams National Council of Farmer Cooperatives, Chuck Conner National Farmers Union, Roger Johnson National Milk Producers Federation, Jim Mulhern National Pork Producers Council, Neil Dierks United Fresh Produce Association, Tom Stenzel USA Rice Federation, Betsy Ward Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00004 National Gotton Council OF MERTOA Gary M. Adams President and Chief Executive Officer National Cotton Council of America Gary Adams assumed the position of President and Chief Executive Officer of the National Cotton Council in February 2015. He plays a key role in guiding the industry's seven segments to reach consensus on critical policies affecting U.S. cotton, with the mission of helping all U.S. cotton industry segments compete effectively and profitably in global markets. Prior to that, Gary served the Council for 13 years as the Vice President of Economic and Policy Analysis. As the Council's chief economist, he provided economic outlooks for global cotton markets, as well as analyzing the impacts of farm and trade policies. Gary also represents the U.S. cotton industry as a member of USDA's Agricultural Policy Advisory Committee. Previously, Gary served on USDA's Advisory Committee on Trade from 2005 through 2011 and the NASS Advisory Committee on Agricultural Statistics from 2003 through 2009. Prior to joining the Council, Gary was a Research Assistant Professor in the Department of Agricultural Economics at the University of Missouri. During his 13-year tenure at the university, Gary's primary responsibilities included policy analysis and market outlook for the Food and Agricultural Policy Research Institute, also known as FAPRI. While at FAPRI, Gary and his colleagues were recognized by the American Agricultural Economics Association for their distinguished policy contributions. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00005 Gary has B.S. and M.A. degrees in Applied Mathematics from the University of Alabama. and a Ph.D. in Agricultural Economics from the University of Missouri. Gary and his wife, Ex. 6 - Personal Privacy Ex. 6 - Personal Privacy Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00006 FASA American Soybean Associatión & Stephen L Censky Chief Executive Officer Stephen L. Censky is the American Soybean Association's (ASA) C hief Executive Officer, a staff position he accepted in April 1996. As ASA's top executive, Ce nsky is in charge of managing ASA's legislative, trade policy, membership and education and training programs. The American Soybean Association is a national, not-for-profit commodity organization with over 22,000 members. ASA works as the domestic and international policy advocate for soybean producer members. Prior to joining ASA, Censky worked in Washington, D.C. for ove a decade. He began his career on Capitol Hill as a legislative assistant for agricultural and transportation matters to Senator Jim Abdnor (R-SD). Later he served in both the Reagan and Bush Administrations at the U.S. Department of Agriculture, helping to craft the 1990 Farm Bill and eventually serving as Administrator of the Foreign Agricultural Service where he was involved in global trade negotiations and running our nation's export programs. Censky received his Bachelor's of Science degree of Agriculture from South Dakota State University and his Master's Diploma in Agriculture St of Melbourne, Australia. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00007 NCFC. National Council of Farmer Cooperatives Charles F. (Chuck) Conner President and CEO National Council of Farmer Cooperatives Charles F. (Chuck) Conner became president & CEO of the National Council of Farmer Cooperatives (NCFC) on January 22, 2009. As president of NCFC, Conner will oversee the organization's work to promote and protect the business and public policy interests of America's farmer-owned cooperatives. He will also provide the strategic vision for the trade association as it continues to seek new ways in which to add value for its membership. Prior to joining NCFC, Conner had served as the Deputy Secretary at the U.S. Department of Agriculture since mid-2005. In this capacity, he was the Chief Operating Officer (COO) overseeing day-to-day operations of the department. Conner interacted directly with President George W. Bush and his senior staff to formulate domestic and international food, trade, security and energy policy. He led development of the Bush Administration's $300 billion Farm Bill proposal and the strategy to educate and inform industry, constituents and Congress. From August 2007 to January 2008, Conner served as both USDA Secretary and Deputy Secretary. He played a key role in developing the Administration's immigration policy including important changes to the H2A program. Conner's experience also includes the assignment of Special Assistant to the President, Executive Office of the President, from October 2001 to May 2005, working on the 2001/2 Farm Bill to develop the strategy behind the transfer of several USDA agency functions to the newly formed Department of Homeland Security. From May 1997 to October 2001 Conner served as President of the Corn Refiners Association. He also served for 17 years as an advisor to U.S. Senator Richard Lugar of Indiana. Conner is a graduate of Purdue University, with a Bachelor's of Science degree and is the recipient of Purdue's Distinguished Alumni Award. He and his wife Ex. 6 - Personal Privacy Source: :https://www.industrydocuments.ucsf.edu/docs/ffcn0226_001225_00000065-00008 NATIONAL PORK PRODUCERS COUNCIL Neil Dierks, Chief Executive Officer Neil Dierks is Chief Executive Officer of the National Pork Producers Council (NPPC). In this position, he is responsible for the overall implementation of all NPPC programs. Dierks' position requires him to spend time in both Des Moines, Iowa, the national office of NPPC, and Washington, D.C. Beginning in 1990, Dierks served NPPC in a series of senior executive positions, including Executive Director of Operations, Vice President for Research and Education and Senior Vice President for Programs. Prior to his service with NPPC, Dierks was the Special Activities Director for the Iowa Pork Producers Association and Marketing Director for the Iowa Corn Promotion Board. Neil grew up on a livestock farm in eastern lowa and remains involved in a family farming operation. He is a graduate of Iowa State University. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00009 NASDA Dr. Barbara Glenn recently joined the National Association of State Departments of Agriculture (NASDA) as CEO on August 18, 2014. NASDA is a nonpartisan, nonprofit association which represents the elected and appointed commissioners, secretaries, and directors of the departments of agriculture in all fifty states and four U.S. territories. Dr. Glenn is a scientist with decades of experience as a policy researcher and advocate for agriculture. She previously served as Senior Vice President of Science and Regulatory Affairs for CropLife America, where she was responsible for developing policies and regulations to support agriculture through crop protection. Prior to joining CropLife America, Dr. Glenn served as Managing Director of the Animal Bi otechnology, Food and Agriculture Section of the Biotechnology Industry Association in Washington, DC. Dr. Glenn holds a B.S. in animal science and a Ph.D. in ruminan t nutrition from the University of Kentucky. She previously worked for the U.S. Department of Agriculture, Agric ultural Research Service and the Federation of Animal Science Societies. Born in Lincoln, Nebraska and raised in Centerville, Ohio, Dr. Glenn developed a passion for agriculture from her parents and her involvement in 4-H. She lives on a small farm in Maryland with her husband: Ex. 6 - Personal Privacy and serves on various boards for farm bureau and 4-H. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00010 National Association of Wheat Growers Chandler Goule CEO Chandler Goule assumed his responsibilities as CEO of the National Association of Wheat Growers on July 5, 2016. In addition, he also serves as the executive director of the National Wheat Foundation. Most recently, Goule served as senior vice president of programs at the National Farmers Union (NFU) where he was heavily involved in farm bill legislation. Originally from Texas, Goule holds degrees from Texas A&M and George Washington University and served as a subcommittee staff director for the House Agriculture Committee before moving to the National Farmers Union in 2009 as vice president of government relations. He was appointed senior vice president of NFU programs in 2014. Source: https://www.industrydocuments.ucsf.edu/docs/ffcn0226 001225 00000065-00011

what is in the appendix A?

fsbn0226

fsbn0226_p9, fsbn0226_p10, fsbn0226_p11, fsbn0226_p12, fsbn0226_p13, fsbn0226_p14, fsbn0226_p15, fsbn0226_p16, fsbn0226_p17, fsbn0226_p18, fsbn0226_p19, fsbn0226_p20, fsbn0226_p21, fsbn0226_p22, fsbn0226_p23, fsbn0226_p24, fsbn0226_p25, fsbn0226_p26, fsbn0226_p27, fsbn0226_p28, fsbn0226_p29, fsbn0226_p30, fsbn0226_p31, fsbn0226_p32, fsbn0226_p33, fsbn0226_p34, fsbn0226_p35, fsbn0226_p36, fsbn0226_p37

Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation, mode of action analysis for liver tumors based on NCI slide reread and Rfd derivation (Dourson et al. 2014)

Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications 2 USEPA APPROACH FOR EVALUATING CANCER RISHS POSED BY ORAL EXPOSURE TO 1,4-DIOXANE USEPA's Integrated Risk Information System (IRIS) published the Toxicological Review for 1,4-dioxane, in which it describes their approach and justification for deriving an oral CSF for this constituent. Below is a summary of USEPA's evaluation of available human toxicological data, weight of evidence evaluation, key study identification, critical effect selection, dose-response assessment, and the low-dose extrapolation procedure used to derive 1,4-dioxane's CSF. 2.1 USEPA's Evaluation of Evidence of Cancer in Humans USEPA evaluated the degree to which data provide evidence of carcinogenicity in humans (USEPA 2010). USEPA relied on two human occupational studies in their evaluation of potential impacts related to long-term exposure to 1,4-dioxane (Thiess et al. 1976; Buffler et al. 1978). USEPA concluded that neither study provided evidence that 1, ,4-dioxane causes cancer in humans. However, they noted "the cohort size and number of reported cases were small." 2.2 USEPA's Evaluation of Evidence of Cancer in Animal Bioassays USEPA followed its Guidelines for Carcinogen Risk Assessment (USEPA 2005) to conclude that 1,4- dioxane is "likely to be carcinogenic to humans" based on "evidence of liver carcinogenicity in several 2- year bioassays conducted in three strains of rats, two strains of mice, and in guinea pigs.' USEPA provided several reasons to justify its conclusion. For instance, USEPA concluded that the "available evidence is inadequate to establish a MOA by which 1,4-dioxane induces liver tumors in rats and mice" (USEPA 2010). Specifically, USEPA noted the "[c]onflicting data from rat and mouse bioassays (Japan Bioassay Research Center [JBRC] 1998; Kociba et al., 1974) suggest that cytotoxicity may not be a required precursor event for 1,4-dioxane-induced cell proliferation." USEPA (2010) noted that "[a]vailable data also do not clearly identify whether 1,4-dioxane or one of its metabolites is responsible for the observed effects. However, USEPA also reported that "the generally negative results for 1,4-dioxane in a number of genotoxicity assays indicates the carcinogenicity of 1,4-dioxane may not be mediated by a mutagenic MOA" (USEPA 2010). 2.3 Key Study Identification (Kano et al. 2009), Critical Effect Selection, Dose-Response Assessment, and Low-Dose Extrapolation Procedure USEPA (2010) concluded that the MOA by which 1,4-dioxane produces liver tumors is "unknown, and available evidence in support of any hypothetical mode of carcinogenic action for 1,4-dioxane is inconclusive." With this conclusion in mind, USEPA (2010) identified a 2-year drinking water study performed by Kano et al. (2009) as the key study of the oral CSF for 1,4-dioxane. Note that Kano et al. (2009) published findings originally reported by the JBRC (1990a). Although USEPA (2010) concurrently evaluated two other studies (Kociba et al. 1974; National Cancer Institute [NCI] 1978), the Kano et al. (2009) study was ultimately selected as the key study because USEPA (2010) noted that "[c]alculation of arcadis.com 3 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications a CSF for 1,4-dioxane is based upon the dose-response data for the most sensitive species and gender." The study was performed in accordance with the Organization of Economic Development's Principles for Good Laboratory Practices and involved exposing groups of rats (50 animals of each sex for each dose) and mice (50 animals of each sex for each dose) to 1,4-dioxane (>99% pure) in drinking water for 2 years. Rats were exposed to 1,4-dioxane in drinking water at 0, 200, 1,000, or 5,000 milligrams per liter (mg/L), while mice were exposed at 0, 500, 2,000, or 8,000 mg/L in drinking water. As reported by USEPA (2010): "The investigators used data from water consumption and BW [body weight] to calculate an estimate of the daily intake of 1,4-dioxane (mg/kg-day) by male and female rats and mice. Kano et al. (2009) reported a calculated mean + standard deviation for the daily doses of 1,4-dioxane for the duration of the study. Male rats received doses of approximately 0, 11+1, 55+3, or 274+18 mg/kg-day and female rats received 0, 183, 83+14, or 429+69 mg/kg-day. Male mice received doses of 0, 49+5, 191+21, or 677+74 mg/kg-day and female mice received 0, 66=10, 278+40, or 964+88 mg/kg-day." "The study by Kano et al. (2009) was used for development of an oral CSF. This was a well- designed study, conducted in both sexes in two species (rats and mice) with a sufficient number (N=50) of animals per dose group. The number of test animals allocated among three dose levels and an untreated control group was adequate, with examination of appropriate toxicological endpoints in both sexes of rats and mice. Alternative bioassays (Kociba et al., 1974; NCI, 1978) were available and were fully considered for the derivation of the oral CSF." USEPA identified increased incidence of liver adenomas or carcinomas as the critical effect in rats and mice exposed to 1,4-dioxane in the Kano et al. (2009) study. Following standard dose adjustment to a human equivalent dose using a default body weight (BW) scaling factor (USEPA 2005), USEPA performed dose-response modeling using Benchmark Dose Software and fit the suite of models available in the program to the incidence data for "either hepatocellular carcinoma or adenoma" (USEPA 2010). USEPA concluded that female mice are "more sensitive to liver carcinogenicity induced by 1,4-dioxane compared to other species or tumor types" and identified the lower 95% confidence bound on the benchmark dose associated with a 50% extra risk (benchmark response [BMR]) of developing "either hepatocellular carcinoma or adenoma" (4.95 milligrams per kilogram per day [mg/kg/d]) as the point of departure (POD) for calculating the oral CSF via linear low-dose extrapolation, as shown in Equation (1), below. USEPA (2010) again justified a linear low-dose extrapolation approach based on their conclusion that 1,4-dioxane's MOA for production of hepatic tumors in rodents is "unknown." BMR 0.5 Equation (1) CSF = = 0.1 (mg/kg/d)1 POD 4.95 mg/kg/d 2.4 Comments Provided to USEPA During External Peer Review When USEPA's IRIS program derives toxicity values, the Toxicological Review undergoes critical evaluation by individuals from within and outside the agency. A result of the outside review efforts indicated several external peer review panel members believed that available information for 1,4-dioxane could "support the use of a nonlinear extrapolation approach to estimate human carcinogenic risk" and arcadis.con 4 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications that "such an approach should be presented in the Toxicological Review.' Specifically, the USEPA (2010) notes: "[N]umerous short-term in vitro and a few in vivo tests were nonpositive for 1,4-dioxane-induced genotoxicity". Results from two-stage mouse skin tumor bioassays "suggest that a potential mode of action for 1,4- dioxane-induced tumors may involve proliferation of cells initiated spontaneously, or by some other agent, to become tumors." Additionally, a public commenter noted: "Low-dose linear extrapolation for the oral CSF is not appropriate nor justified by the data. The weight of evidence supports a threshold (nonlinear) MOA when metabolic pathway is saturated at high doses. Nonlinear extrapolations should be evaluated and presented for 1,4-dioxane." These statements indicated that some reviewers felt the toxicological data for 1,4-dioxane indicated that it may not behave in a linear manner, but rather as a threshold carcinogen. Nonetheless, USEPA (2010) ultimately concluded that there was insufficient information available to support any of the proposed MOAs and proceeded to adopt, albeit imprecisely in hindsight, the default linear low-dose extrapolation approach. arcadis.com 5 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications 3 DOURSON ET AL. (2014): MODE OF ACTION (MOA) ANALYSIS FOR LIVER TUMORS FROM ORAL 1,4- DIOXANE EXPOSURES AND EVIDENCE-BASED DOSE ss RESPONSE ASSESSMENT USEPA's (2010) conclusion to evaluate 1,4-dioxane as a non-threshold, linear, low-dose extrapolation carcinogen, was "based, in part, on the following: (1) apparent uncertainty in the toxic moiety for 1,4- dioxane; and, (2) apparent lack of noncancer toxicity data from several mouse bioassays at doses that evoke tumors, or that otherwise appear to have conflicting information concerning non-neoplastic lesions in the liver of rodents exposed orally to 1,4-dioxane" (Dourson et al. 2014). Recognizing that the key studies were performed over 3 decades, Dourson et al. (2014) hypothesized that "differences in histologic approaches for quantifying and reporting non-neoplastic changes may have been responsible for the differences noted across the studies" and would account for the apparent lack of non-cancer toxicity data reported in the key mouse bioassays. In addition to directly testing this hypothesis, Dourson et al. (2014) reviewed the database of genotoxicity studies, "which included DNA replication and promotion bioassays as well as mutation, initiation, and DNA repair studies," synthesized the genotoxicity database for 1,4- dioxane, and developed and analyzed a biologically plausible MOA for the formation of hepatic tumors in rodents by employing USEPA's (2005) carcinogen guidelines. Dourson et al.'s (2014) findings from the reread of the NCI (1978) mouse bioassay histopathology slides and review of the extensive genotoxicity database demonstrates that chronic exposure to 1,4-dioxane in drinking water is associated with a non-linear mode of carcinogenic action (threshold). which is contrary to USEPA's default linear low-dose extrapolation approach (non-threshold). The cancer MOA developed by Dourson et al. (2014) also afforded new data with which to perform an improved dose-response assessment for 1,4-dioxane using toxicological endpoints that protect against 1,4-dioxane's cancer MOA (refer to Appendix A for additional details). In regards to choosing a low-dose extrapolation approach, USEPA's Guidelines for Carcinogen Risk Assessment (2005) plainly state that "[a] nonlinear approach [i.e., derivation of a reference dose or concentration] should be selected when there are sufficient data to ascertain the mode of action and conclude that it is not linear at low doses and the agent does not demonstrate mutagenic or other activity consistent with linearity at low doses.' The information presented by USEPA (2010) and supplemented by the new information from Dourson et al. (2014) shows that: (1) 1,4-dioxane causes tumors at high doses through an MOA that involves cytotoxic effects, regenerative cell proliferation, and subsequent tumor formation; (2) the effects that precede tumor formation display non-linear dose-responses; and (3) 1,4- dioxane does not cause mutations at concentrations that are not cytotoxic. As a result, the RfD of 0.05 mg/kg/d developed by Dourson et al (2014) addressed key data gaps identified by USEPA (2010) and protects against the development of liver cancers following oral exposure to 1,4-dioxane. arcadis.com 6 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications 4 DOURSON ET AL. (2016 IN PEER REVIEM: UPDATED MODE OF ACTION ANALYSIS (MOA) FOR LIVER TUMORS FROM ORAL ,4-DIOXANE EXPOSURES AND EVIDENCE-BASED DOSE-RESPONSE ASSESSMENT While Dourson et al. (2014) demonstrated that a threshold-based, regenerative cell proliferation MOA accounted for the tumor findings in the NCI (1978) mouse bioassay, questions still remained about the tumor findings from a 2-year oral mouse bioassay and a 13-week precursor study reported by the JBRC (1990a,b), subsequently published as Kano et al. (2008, 2009). Similar to the NCI (1978) mouse bioassay discussed in Dourson et al. (2014), the Japanese work provided few details or findings regarding non- cancer toxicity in the mouse liver after long-term exposure to 1,4-dioxane. To address the remaining questions regarding the apparently discordant findings between the tumor MOA in mice and rats and enhance the investigation of the threshold-based MOA for hepatic tumor formation, Dourson et al. (2016 in peer review) performed a detailed evaluation of the translated Japanese rodent bioassay reports (JBRC 1990a,b) and integrated the findings with other lines of evidence for the regenerative cell proliferation MOA. This effort is summarized in Appendix B. In addition to the detailed evaluation of the JBRC (1990a,b) bioassays, Dourson et al. (2016 in peer review) also solicited opinions from several pathologists regarding the conflicting findings from the mouse bioassays. Dourson et al. (2016 in peer review) reported: "Collectively these pathology opinions support the hypothesized MOA discussed in U.S. EPA (2013) and Dourson et al. (2014) that the liver tumors from oral exposure to 1,4-dioxane occur after metabolic saturation, accumulation of the parent 1,4-dioxane molecule, liver toxicity and a regenerative hyperplasia. While additional live experimental animal testing might add confirmatory findings, a threshold for these tumors is expected if metabolism of the parent compound is not saturated, since subsequent liver toxicity does not occur." By integrating all lines of evidence, Dourson et al. (2016 in peer review) concluded: "When the many lines of evidence are taken together, the reevaluation of the Japanese studies show consistent findings in rats and consistent findings in mice other than liver histopathology not being fully recorded in the second chronic study. However, based on the number of studies conducted, the well established metabolic saturation of 1,4-dioxane metabolism in humans and experimental animals, the effects of higher dose exposures on target organ toxicity, the presence of proliferative lesions, the effect of dose and time on the progression of lesions, the time of appearance of tumors, the spectrum of tumors developed, the number and incidence of tumors at organ sites with high or low background historical incidence, and the shapes of the dose-response curve for key events and tumors, all lead to the conclusion that a regenerative hyperplasia MOA is operating with 1,4-dioxane induced liver tumors." arcadis.con 7 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications 5 IMPACT OF DOURSON ET AL.S UPDATED TOXICITY ASSESSMENT ON RISK-BASED DRINKING WATER CRITERIA An agency's choice to set risk-based criteria for 1,4-dioxane based on a threshold- or non-threshold- approach has the potential to drastically impact the value of the final criterion. An example of this is provided herein based on the approach used by the New Jersey Department of Environmental Protection (NJDEP) to derive groundwater quality criteria (NJDEP 2014). The risk-based equations NJDEP uses to derive groundwater criteria for threshold and non-threshold toxicants are shown below in Equations (2) and (3), respectively, while default exposure factors are shown in Table 1 below. Using the RfD of 0.05 mg/kg/d derived from Kociba et al. (1974) by Dourson et al. (2014) to protect against a regenerative cell proliferation MOA yields a risk-based criterion of 400 g/L Using USEPA's (2010) CSF of 0.1 (mg/kg/d)-¹ yields a risk-based criterion of 0.4 (0.35) g/L, corresponding to a 1 in 1,000,000 (1x10-6) excess lifetime cancer risk. Therefore, using the toxicity value derived based on a regenerative cell proliferation MOA (RfD, threshold approach) yields a criterion that is 1,000 times higher than the value derived using USEPA's CSF approach (linear low-dose extrapolation, non-threshold). The authors of this paper conclude that sites monitoring groundwater containing 1,4-dioxane at levels below 400 g/L would meet a reasonable groundwater quality criterion that is protective of human health. RfD x BW x CF x RSC Equation (2) Criterion = x UF BW x CF Equation (3) Criterion = x IRDW arcadis.com 8 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications Table 1. Toxicity Values and NJDEP's Exposure Factors for Calculating Risk-Based Groundwater Quality Criteria Exposure Pactor Units value bource RfD mg/kg/d 0.05 Dourson et al. (2014) CSF (mg/kg/d)-1 0.1 USEPA (2010) Target risk (TR) unitless 10-6 NJDEP default BW kg 70 NJDEP default Conversion factor (CF) g/mg 1,000 NJDEP default Relative source contribution (RSC) unitless 0.2 NJDEP default Drinking water ingestion rate (IRDw) L/d 2 NJDEP default Uncertainty factor (UF) unitless 1 NJDEP default Notes: kg = kilograms L/d = liters per day g/mg = micrograms per milligram arcadis.com 9 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications 6 SUMMARY AND CONCLUSIONS To support several state regulatory agencies, Dourson et al. (2016 in peer review) recently undertook additional scientific investigations to address data gaps identified in USEPA's (2010) Toxicological Review regarding 1,4-dioxane's cancer MOA and assessment approach. Collectively, Dourson et al.'s (2014, 2016 in peer review) cancer MOA evaluations and dose-response assessments addressed USEPA's uncertainties and indeed demonstrate that chronic exposure to 1,4-dioxane in drinking water is associated with a non-linear mode of carcinogenic action (threshold). These additional scientific findings provide new information that resolve 1,4- dioxane's cancer MOA and support use of a non-linear dose response approach to protect against development of cancer following low-dose oral exposures. USEPA's (2010) cancer evaluation showed that 1,4-dioxane is not mutagenic or genotoxic at non- cytotoxic doses. However, USEPA ultimately chose to use a linear low-dose extrapolation approach for estimating human cancer risk from oral exposure to 1, 4-dioxane because they concluded that the MOA for tumor formation was unknown. The recent scientific investigations by Dourson et al. (2014, 2016 in peer review) provide new information to address data gaps identified by USEPA (2010) and demonstrate that 1,4-dioxane causes liver tumors in rodents through a regenerative cell proliferation MOA. The regenerative cell proliferation MOA is characterized by: (1) metabolic saturation and accumulation of parent compound; (2) cellular swelling, hypertrophy, and liver weight increase; (3) necrosis and/or inflammation; (4) increased DNA synthesis, hyperplasia development, and foci development; and (5) development of liver adenoma and carcinomas. Specifically, 1,4-dioxane must accumulate in the liver to levels that cause inflammation and cell damage before liver tumors can form. If the first key event does not occur (metabolic saturation), then liver tumors will not form. Therefore, there is a threshold of exposure for 1,4-dioxane below which tumors do not form and it is appropriate to use a non-linear low-dose extrapolation procedure for estimating risks. The RfD of 0.05 mg/kg/d derived by Dourson et al. (2014) is protective against tumor formation through this series of events (MOA) and was calculated using USEPA's preferred methods and best available scientific practices. Using Dourson et al.'s (2014) peer-reviewed RfD, based on a regenerative cell proliferation MOA to derive a groundwater drinking water criterion results in a criterion (400 g/L) that is 1,000 times greater than the concentration derived using USEPA's default CSF approach (0.4 g/L). Based on Dourson et al.'s (2014, 2016 in peer review) studies, it is reasonable to conclude that sites that monitor groundwater containing 1,4-dioxane at levels below 400 g/L would meet a reasonable groundwater quality criteria. The recent scientific findings summarized in this report have major implications for sites that are currently or will be managing water resources impacted by 1,4-dioxane. Considering that 1,4-dioxane is emerging as a water resource contaminant, in part due to USEPA's default linear low-dose cancer evaluation approach for liver tumors in rodents (USEPA 2010), the updated toxicology evidence that 1,4-dioxane is a threshold carcinogen is significant, and suggests that many current regulatory guidelines and standards are unnecessarily low. As such, the authors of this paper conclude that sites that monitor groundwater containing 1,4-dioxane at levels below 400 g/L would meet a reasonable groundwater quality criteria that is protective of human health. arcadis.con 10 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications 7 REFERENCES ARA. 2016. 1,4-Dioxane Analysis. Available on line [Accessed Dec. 19] at: http://allianceforrisk.org/riskie- 2/. Buffler, P.A., S.M. Wood, L. Suarez, and D.J. Kilian. 1978. Mortality follow-up of workers exposed to 1,4- dioxane. J Occup Environ Med, 20: 255-259. Dourson, M., J. Reichard, P. Nance, H. Burleigh-Flayer, A. Parker, M. Vincent, and E.E. McConnell. 2014. Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment. Regul Toxicol Pharmacol. 68: 387-401. Dourson, M., J. Higginbotham, J. Crum, H. Burleigh-Flayer P, Nance, N. Forsberg, and M. Lafranconi. 2016 in peer review. Update: Mode of Action (MOA) for Liver Tumors Induced by Oral Exposure to 1,4-Dioxane. Regul Toxicol Pharmacol. Available online at: http://allianceforrisk.org/14-dioxane- analysis/. Health Canada. 2005. Drinking Water Guidance Value for 1,4-Dioxane. August 23. JBRC. 1990a. Report of Carcinogenicity Study by Oral Administration of 1,4-Dioxane (Mixed with Water) to Rats and Mice. Japan Industrial Safety and Health Association. December 28. JBRC. 1990b. Report of Preliminary Carcinogenicity Studies (Acute, Two-Week, and Thirteen-Week Studies) by Oral Administration of ,4-Dioxane (Mixed with Water) to Rats and Mice. Japan Industrial Safety and Health Association. December 28. Kano. H., Y. Umeda, M. Saito, H. Senoh, H. Ohbayashi, S. Aiso, K. Yamazaki, K. Nagano, and S. Fukushima. 2008. Thirteen-week oral toxicity of 1,4-dioxane in rats and mice. J Toxicol Sci. 33: 141- 153. Kano, H., Y, Umeda, T. Kasai, T. Sasaki, M. Matsumoto, K. Yamazaki, K. Nagano, H. Arito, and S. Fukushima. 2009. Carcinogenicity of 1,4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem Toxicol. 47:2776 - 2784. Kociba, R.J., S.B. McCollister, C. Park, T.R. Torkelson, and P.J. Gehring. 1974. 1,4-dioxane. I. Results of a 2-year ingestion study in rats. Toxicol Appl Pharmacol, 30: 275-286. doi:10.1016/0041- 008X(74)90099-4. McConnell, G. 2013. Report on the review of liver slides from the National Cancer Institute's Bioassay of 1,4-Dioxane for Possible Carcinogenicity Conducted in 1978 (NCI, 1978). Submitted to Toxicology Excellence for Risk Assessment. January/March 2013. NCI. 1978. Bioassay of 1,4-Dioxane for possible Carcinogenicity. Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute. NIH, Bethesda, MD, 78-1330. Netherlands. 1999. Risk Assessment: 1, 4-Dioxane. Netherlands Organization for Applied Scientific Research (TNO) and the National Institute of Public Health and the Environment (RIVM). Chemical Substances Bureau, Ministry of Housing, Spatial Planning and the Environment (VROM), Netherlands, Final Version, 5 November, EINECS-No.: 204-661-8. arcadis.con 11 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Update on Toxicity of 1,4-Dioxane and Potential Regulatory Implications Neumann, H.G., H.W. Thielmann, J.G. Filser, H.P. Gelbke, H. Griem, H. Kappus, K.H. Norpoth, U. Reuter, S. Vamvakas, P. Wardenbach, and H.E. Wichmann. 1977. Proposed changes in the classification of carcinogenic chemicals in the work area. Reg. Toxicol. Pharmacol., 26:288-295. National Industrial Chemicals Notification and Assessment Scheme (NICNAS). 1998. Priority Existing Chemical Assessment Reports: 1,4-dioxane. Sydney, Australia: Australia Department of Health and Ageing. June. Available online at: NJDEP. 2014. Ground Water Quality Standards. N.J.A.C 7:9C. Available online at: http://www.nj.gov/dep/rules/rules/njac7_9c.pd Office of Environmental Health Hazard Assessment (OEHHA). 2002. Air Toxics Hot Spots Program. Risk Assessment Guidelines. Part II. Technical Support Document for Describing Available Cancer Potency Factors. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency. December. Stickney, J.A., S.L. Sager, J.R. Clarkson, L.A. Smith, B.J. Locey, M.J. Bock, R. Hartung, and S.F. Olp. 2003. An updated evaluation of the carcinogenic potential of 1,4-dioxane. Regul Toxicol Pharmacol. 38(2):183-95. Thiess, A.M., E. Tress, and I. Fleig. 1976. Arbeitsmedizinische Untersuchungsergebnisse von Dioxan- exponierten Mitarbeitern [Industrial-medica investigation results in the case of workers exposed to dioxane]. Arbeitsmedizin, Sozialmedizin, Umweltmedizin, 11: 35-46. USEPA. 2005. Guidelines for carcinogen risk assessment, final report. EPA/630/P-03/001F. Risk Assessment Forum; U.S. Environmental Protection Agency. Washington, DC. March. USEPA. 2010. Toxicological Review of 1,4-Dioxane (CAS No. 123-91-1). EPA/635-R-09-005-F. Washington, D.C. August. USEPA. 2011. Recommended Use of Body Weight3/4 as the Default Method in Derivation of the Oral Reference Dose. EPA/100/R11/0001. Risk Assessment Forum. Washington, DC. USEPA. 2012. Benchmark Dose Technical Guidance. EPA/100/R-12/001. Risk Assessment Forum. Washington, DC. June 12. USEPA. 2013. Toxicological review of 1,4- Dioxane (with inhalation update) (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS) [EPA Report]. (EPA-635/R-11/003-F). Washington, DC. USEPA. 2016a. Drinking Water Contaminant Candidate List 4 - Final. Federal Register Notice, Volume 81, No. 2222, Thursday, November 17. USEPA. 2016b. The Third Unregulated Contaminant Monitoring Rule (UCMR 3): Data Summary, July 2016. Office of Water (MS-140). EPA 815-S-16-004, Available at: USEPA. 2016c. Conducting a Human Health Risk Assessment, Dose-Response. Available at: arcadis.com 12 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 APPENDIX A Mode of Action Analysis for Liver Tumors Based on NCI Siide Reread and RfD Derivation (Dourson et al. 2014) Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 ARCADIS Gesign & for natural and built assets Appendix A MODE OF ACTION ANALYSIS FOR LIVER TUMORS BASED ON NCI SLIDE REREAD AND RFD DERIVATION (DOURSON ET AL. 2014) January 2017 Source: :ttps://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) CONTENTS Acronyms and Abbreviations ii 1 Reread of NCI (1978) Histopathology Slides and Mode of Action Evaluation for Hepatic Tumors in Mice 3 1.1 Review of 1,4-Dioxane's Genotoxicity Database 4 1.2 Mode of Action Analysis 4 1.2.1 Key Event 1: Accumulation of Parent Compound 5 1.2.2 Key Event 2: Liver Cell Hypertrophy and Necrosis 5 1.2.3 Key Event 3: DNA Synthesis 5 1.2.4 Key Event 4: Regenerative Cell Proliferation 5 1.2.5 Key Event 5: Promotion of Endogenously Initiated Tumors 6 1.3 Updated Dose-Response Assessment and Reference Dose Derivation for 1,4-Dioxane 6 2 References 8 arcadis.com i Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) ACRONYMS AND ABBREVIATIONS BMD benchmark dose-modeling CUF composite uncertainty factor EPL Experimental Pathology Laboratories JBRC Japan Bioassay Research Center mg/kg/d milligrams per kilogram body weight per day MOA mode of action NCI National Cancer Institute NOAEL no-observable-adverse-effect level POD point of departure RfD oral reference dose g/L micrograms per liter USEPA United States Environmental Protection Agency arcadis.com ii Source: https://wwww.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) 1 REREAD OF NCI (1978) HISTOPATHOLOGY SLIDES AND MODE OF ACTION EVALUATION FOR HEPATIC TUMORS IN MICE To test their hypothesis and better understand the "sequence of events that maybe have contributed to the MOA of the observed liver tumors," Dourson et al. (2014) and McConnell (2013) performed a blinded reread of the mouse National Cancer Institute (NCI) (1978) liver histopathology slides, because that study did not report non-neoplastic lesions in livers of the high-dose group. Note this is one of the two long-term oral mouse bioassays that exist for 1,4-dioxane; the other chronic mouse bioassay was performed by the Japan Bioassay Research Center (JBRC) and is reported most recently by Kano et al. (2009). As noted by Dourson et al. (2014): "Because terminology and practices for reporting liver lesions has changed since the time of the NCI study (1978), and because EPA (2005) is focusing more on an understanding of a chemical's Mode of Action (MOA) prior to any determination of its dose response, a re-review of the liver slides of mice from the NCI study (1978) was performed. This reanalysis was performed at the Experimental Pathology Laboratories (EPL), Research Triangle Park, NC during September through November 2012. The objective of the slide review was to determine if any non-neoplastic lesions in the liver were present in an effort to understand the sequence of events that may have contributed to the MOA of the observed liver tumors in mice. Another reason for the slide review was because at the time of the original slide review (i.e., 1978) the NCI typically recorded only the most severe diagnosis on a given slide, (e.g., adenoma or carcinoma). During this timeframe, the focus of cancer bioassays was to determine the potential carcinogenic activity of the chemical, not its potential chronic toxicity. For example, if an adenoma, carcinoma, and evidence of chronic toxicity (e.g., hepatocellular hypertrophy), were all present on a given slide, only the tumor response was typically recorded. Thus, it was unclear whether non-neoplastic lesions were present in the livers of mice but were not recorded in the NCI carcinogenicity study. McConnell's (2013) reread of the NCI (1978) mouse liver histopathology slides and Dourson et al.'s (2014) summary report demonstrate that chronic exposure to 1,4-dioxane in drinking water is associated with a non-linear mode of carcinogenic action (contrary to the United States Environmental Protection Agency's [USEPA's] low-dose extrapolation conclusion) based on several hepatotoxic effects that preceded tumor formation, including: Dose-dependent hepatocellular glycogen depletion Dose-dependent hepatocellular hypotrophy Dose-related hepatocellular necrosis Dose-dependent hepatocellular inflammation associated with necrosis Dose-related hyperplasia in several non-neoplastic cell types arcadis.com 3 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) Dourson et al. (2014) states: "The appearance of the liver toxicity follows the pattern where glycogen depletion occurs either concurrently with, or preceding, hypertrophy in both sexes. This was followed closely by necrosis and inflammation in males, but a high control incidence of necrosis and inflammation clouded this overall pattern found in females In terms of dose-response behavior, hypertrophy preceded the formation of foci, which appeared to precede formation of tumors. This pattern was also evident in an individual animal analysis." 1.1 Review of ,4-Dioxane's Genotoxicity Database As a component of their mode of action (MOA) analysis, Dourson et al. (2014) reviewed 1,4-dioxane's genotoxicity database using the information presented in USEPA's (2010) Toxicological Review for 1,4- dioxane. Dourson et al. (2014) noted: '1,4-dioxane has been tested for genotoxicity using in vitro assay systems with prokaryotic organisms, non-mammalian eukaryotic organisms, and mammalian cells, both with and without metabolic activation.' "[A]II fifteen mutagenicity tests reported (8 without activation and 7 with metabolic activation) were negative." "22 in vitro genotoxicity assays, and 9 in vivo genotoxicity assays were negative." "Eight genotoxicity assays were noted to be positive but only at high or noted cytotoxic doses." Based on their review of 1,4-dioxane's genotoxicity database, Dourson et al. (2014) states "1,4-dioxane does not cause point mutations, DNA repair, or [tumor] initiation" when administered at non-cytotoxic doses, which is in general agreement with USEPA's conclusions (USEPA 2010). The authors noted their conclusions were similar to USEPA's, but differ in that "if mutations are caused by 1,4-dioxane, it is only at high cytotoxic doses." The authors concluded: "1,4-dioxane does not cause mutagenicity as evidenced by uniformly negative results in standard in vitro and in vivo genotoxicity bioassays at levels that are not overtly toxic, but it may be a clastogen in vivo, in light of the mixed results in the micronucleus assays. It follows that mutations needed for tumor formation are then likely from the known endogenously available pool of mutations, and that a regenerative hyperplasia evokes more of these endogenous mutations to form tumors. Mutation potentially caused by 1,4-dioxane at high doses is precluded as a key event in tumor formation." 1.2 Mode of Action Analysis Dourson et al. (2014) proposed five key events in the non-mutagenic MOA resulting in hepatic tumors in rodents; they include: "(1) accumulation of parent compound [at concentrations that saturate metabolic processes], (2) liver cell hypertrophy and necrosis, (3) DNA synthesis, (4) regenerative cell proliferation, and (5) promotion of endogenously-initiated tumors.' The regenerative cell proliferation MOA has a threshold below which hepatic tumors are not formed. Evidence supporting each key event is presented below. arcadis.com 4 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) 1.2.1 Key Event 1: Accumulation of Parent Compound "Humans, rats, and mice extensively metabolize 1,4-dioxane.' "[M]etabolism is a capacity-limited process." "When dose of 1,4-dioxane approaches or exceeds the metabolizing capacity, the unmetabolized fraction of the dose increases and target organ toxicity occurs." "Thus, there appears to be a threshold below which metabolism and elimination are rapid and with less or perhaps without toxicological effects." "Human environmental exposures to 1,4-dioxane are unlikely to approach doses that saturate metabolizing enzymes and which produce liver and nasal tumors in rats." "Hence, since humans, like rats, efficiently metabolize 1,4-dioxane at low doses, enzyme saturation is negligible at low exposure levels." 1.2.2 Key Event 2: Liver Cell Hypertrophy and Necrosis "Liver cell hypertrophy and necrosis are key events in the 1,4-dioxane MOA leading to regenerative cell proliferation and, with chronic exposures, liver tumors.' "Liver changes including centrilobular swelling, single cell necrosis coincide exclusively with saturating doses of 1,4-dioxane and occur in as little as 11 weeks." "Evidence of hepatocellular damage preceding evidence of hepatocellular tumors caused by higher doses of 1,4-dioxane has been provided by several studies." 1.2.3 Key Event 3: DNA Synthesis USEPA (2010) reported "that 1,4-dioxane does not cause DNA repair activity in five standard in vitro and in vivo bioassays that tested for the presence of DNA repair in various model systems." "Conversely, 1,4-dioxane does cause DNA replication as evidenced by in vitro bioassays in rat hepatocytes" "DNA synthesis appears to be a key event for a regenerative cell proliferation and/or tumor promotion and can occur in either the presence or absence of cytotoxicity." "DNA synthesis provides evidence that 1,4-dioxane promotes cell proliferation through cytotoxicity." 1.2.4 Key Event 4: Regenerative Cell Proliferation "Dose-response and temporal data support the occurrence of cell proliferation and hyperplasia prior to the development of liver tumors in the rat model." "Cell proliferation appears to be an early response with significant changes (1.5- to 2-fold) occurring in rats with as little as 2 weeks of exposure." arcadis.com 5 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) "Given time, proliferative changes manifest as pre-neoplastic foci in studies where the histopathology of such changes are reported." 1.2.5 Key Event 5: Promotion of Endogenously Initiated Tumors "Three studies relevant to tumor initiation and promotion establish that 1,4-dioxane does not cause initiation in standard in vivo bioassays, in agreement with the absence of observed mutagenic or genotoxic activity." "[T]umor promotion was associated with significant toxicity in rats when administered by either dermal or oral routes." 1.3 Updated Dose-Response Assessment and Reference Dose Derivation for 1,4-Dioxane Dourson et al. (2014) and USEPA (2010) both relied on the dose-response data reported by Kociba et al. (1974). This study provided data for liver and kidney degeneration and necrosis in 6- to 8-week-old male and female Sherman rats (60/sex/dose group) that were exposed to 1, ,4-dioxane at 0, 0.01, 0.1, or 1% (i.e., 9.6, 94, and 1,015 milligrams per kilogram body weight per day [mg/kg/d] and 19, 148, and 1,599 mg/kg/d for males and females, respectively) in drinking water for up to 716 days. The study reported a no-observed-adverse-effect level (NOAEL) of 9.6 mg/kg/d and provides "the most sensitive measure of adverse effects by 1,4-dioxane" (USEPA 2010). USEPA's Toxicological Review for 1,4-dioxane (USEPA 2010) provides a reference dose (RfD) of 0.03 mg/kg/d. This RfD was derived using the NOAEL of 9.6 mg/kg/d for liver and kidney degeneration and necrosis in rats reported by Kociba et al. (1974) as the point of departure (POD), in combination with a composite uncertainty factor (CUF) of 300 (10 for interspecies extrapolation, 10 for intraspecies extrapolation, and 3 for database deficiencies associated with the lack of a multigenerational reproductive toxicity study). The lowest-observable-adverse-effect level for this study was 94 mg/kg/d (USEPA 2010). USEPA derived the RfD using the NOAEL reported by Kociba et al. (1974) because the published study did not report incidence data for these effects, and therefore, they were unable to perform benchmark dose-modeling (BMD). Alternatively, Dourson et al. (2014) reported an updated RfD of 0.05 mg/kg/d that was derived using incidence data (laboratory report for the published study was provided to Dourson et al. [2014] by The Dow Chemical Company) for hepatocellular necrosis (combined across sexes) and USEPA's preferred approaches¹. Specifically, Dourson et al. (2014) utilized USEPA's preferred BMD approach (USEPA 2012) to derive a POD of 20 mg/kg/d (95% lower bound on the dose associated with a 10% extra risk), USEPA's preferred default bodyweight scaling factor (USEPA 2011), to estimate a human equivalent 1 USEPA (2010) used the NOAEL from Kociba et al. (1974) based on liver and kidney degeneration to derive the RfD, specifically because Kociba et al. (1974) did not provide quantitative incidence or severity data for liver and kidney degeneration and necrosis. However, when appropriate data are available, USEPA prefers using BMD to define the POD (USEPA 2012). Had the incidence data from Kociba et al. (1974) been available at the time of their review, USEPA would have used it to derive a benchmark dose to use as the POD for setting the RfD. arcadis.com 6 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) dose, in combination with a CUF of 100 (3 for interspecies toxicodynamic extrapolation, 10 for intraspecies extrapolation, and 3 due to the lack of a 2-generation reproductive study) to derive an RfD of 0.05 mg/kg/d. Dourson et al. (2014) concluded that "the choice of this endpoint [hepatocellular necrosis] is protective, since liver toxicity, resulting in liver tumors, is the clear apical effect of greatest intensity in the available array of toxic effects." Dourson et al. (2014) calculated their RfD using standard approaches, as shown in Equation (1), below: POD 20 mg/kg/d Equation (1) RfD = = 0.05 mg/kg/d CUF 3x10x3 arcadis.com 7 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix A - Mode of Action Analysis for Liver Tumors Based on NCI Slide Reread and RfD Derivation (Dourson et al. 2014) 2 REFERENCES Dourson, M., J. Reichard, P. Nance, H. Burleigh-Flayer, A. Parker, M. Vincent, and E.E. McConnell. 2014. Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment. Regul Toxicol Pharmacol. 68: 387-401. Kano, H., Y, Umeda, T. Kasai, T. Sasaki, M. Matsumoto, K. Yamazaki, K. Nagano, H. Arito, and S. Fukushima. 2009. Carcinogenicity of 1,4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem Toxicol. 47:2776 - 2784. Kociba, R.J., S.B. McCollister, C. Park, T.R. Torkelson, and P.J. Gehring. 1974. 1,4-dioxane. I. Results of a 2-year ingestion study in rats. Toxicol Appl Pharmacol, 30: 275-286. oi:10.1016/0041- 008X(74)90099-4. McConnell, G. 2013. Report on the review of liver slides from the National Cancer Institute's Bioassay of 1,4-Dioxane for Possible Carcinogenicity Conducted in 1978 (NCI, 1978). Submitted to Toxicology Excellence for Risk Assessment. January/March 2013. NCI. 1978. Bioassay of 1,4-Dioxane for possible Carcinogenicity. Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute. NIH, Bethesda, MD, 78-1330. USEPA. 2005. Guidelines for carcinogen risk assessment, final report. EPA/630/P-03/001F. Risk Assessment Forum; U.S. Environmental Protection Agency. Washington, DC. March. USEPA. 2010. Toxicological Review of 1,4-Dioxane (CAS No. 123-91-1). EPA/635-R-09-005-F. Washington, D.C. August. USEPA. 2012. Benchmark Dose Technical Guidance. EPA/100/R-12/001. Risk Assessment Forum. Washington, DC. June 12. arcadis.com 8 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 APPENDIX B Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) Source: https://www.industrydocuments.ucsf,edu/docs/fsbn0226 ARCADIS Desion & for natural and built assets Appendix B MODE OF ACTION ANALYSIS FOR LIVER TUMORS BASED ON JBRC REVIEW (DOURSONETAL.2016IN PEER REVIEW) January 2017 Source: :ttps://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix B - Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) CONTENTS Acronyms and Abbreviations ii 1 Findings from Detailed Review of JBRC Rat Bioassays 3 1.1 Findings from Detailed Review of JBRC Mouse Bioassays 3 1.2 Integration of Evidence Supporting Regenerative Cell Proliferation MOA for 1,4-Dioxane 4 2 References 6 TABLES Table 1. Integration and Comparison of Rat and Mouse Bioassay Data (Adapted from Dourson et al., 2016 in peer review) 5 arcadis.com i Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix B - Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) ACRONYMS AND ABEREVIATIONS JBRC Japan Bioassay Research Center mg/kg/d milligrams per kilogram body weight per day MOA mode of action NCI National Cancer Institute arcadis.com ii Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix B - Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) 1 FINDINGS FROM DETAILED REVIEW OF JBRC RAT BIOASSAYS Changes in the liver found in the Japan Bioassay Research Center (JBRC) rat bioassays provide strong evidence that hepatic tumors were modulated by a threshold-based regenerative cell proliferation mode of action (MOA). Dourson et al. (2016 in peer review) found that effects observed in rats were in the expected dose-sequence for a regenerative cell proliferation MOA. Specifically, Dourson et al. (2016 in peer review) observed the following sequence of effects: Dose: 42-55 milligrams per kilogram body weight per day (mg/kg/d) - Effect: Liver swelling, hypertrophy, and liver weight increase Dose: 94-219 mg/kg/d - Effect: Necrosis Dose: 55-389 mg/kg/d - Effect: Hyperplasia and foci development Dose: >200 mg/kg/d - Effect: Increased levels of enzymes associated with liver damage Dose: 274-1015 mg/kg/d - Effect: Adenomas and carcinomas 1.1 Findings from Detailed Review of JBRC Mouse Bioassays Dourson et al. (2016 in peer review) observed the following sequence of effects in the JBRC (1990a) mouse bioassays: Dose: 190-200 mg/kg/d - Effect: Liver swelling, hypertrophy, and liver weight increase Dose: 190-200 mg/kg/d - Effect: Necrosis Dose: Not reported - Effect: Hyperplasia and foci development not reported Dose: 200 mg/kg/d - Effect: Increased levels of enzymes associated with liver damage Dose: 66-964 mg/kg/d - Effect: Adenomas and carcinomas, females Surprisingly, effects in the liver found in the JBRC mouse bioassays conflict with those clearly reported by Dourson et al. (2014) and McConnell (2013) for the reread of the National Cancer Institute (NCI) (1978) mouse bioassay histopathology slides. Additionally, the progression of effects reported by JBRC for the 2- year chronic study is inconsistent with enzymatic changes indicative of liver damage noted in the same study, as well as findings from a 13-week precursor study performed by the same laboratory. As noted by Dourson et al. (2016 in peer review), "the lack of noncancer histopathology in the chronic mouse study is not consistent with the changes in liver enzymes in this same chronic study, nor is this lack of noncancer arcadis.com 3 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix B - Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) findings expected based on the histopathology of the precursor 13-week study" and "[n]or does the tumor response in the low dose female mice of JBRC (1990a) match the tumor findings in the McConnell (2013) re-read of NCI (1978). Dourson et al. (2016 in peer review) hypothesized that differences in mouse bioassay results between JBRC and McConnell (2013) may be due to differences in the interpretation of the histopathological data, and provided the following quote from JBRC (Kano et al. 2009) to substantiate their claim: "The hepatic hyperplasia of rats and mice diagnosed in the previous report (Yamazaki et al., 1994) [authors note: which was a presentation of the JBRC, 1990a] was re-examined histopathologically and changed to hepatocellular adenomas and altered hepatocellular foci including acidophilic, basophilic and clear cell foci in the present studies, according to the current diagnostic criteria of liver lesions in rats and mice." Unfortunately, slides from the original JBRC (1990a,b) bioassays were not available; therefore, the JBRC slides could not be reread as they were by McConnell (2013) for the NCI (1978) mouse liver slides. Additionally, JBRC did not archive sufficient numbers of pictures of histopathology slides to resolve the issue. While, it is impossible to know for sure from this dataset whether liver tumors formed prior to or following cytotoxic effects, the weight of evidence from the JBRC and NCI mouse bioassays supports a regenerative cell proliferation MOA. 1.2 Integration of Evidence Supporting Regenerative Cell Proliferation MOA for 1,4-Dioxane Following integration of key events from seven rat bioassays, three mouse bioassays, and 1,4-dioxane's genotoxicity profile, presented in Table 1 below, Dourson et al. (2016 in peer review) showed that 1,4- dioxane's toxicological database supports a threshold-based regenerative cell proliferation MOA for tumor formation in livers of rodents orally exposed to 1,4-dioxane. The authors reported that bioassay data for rats leads to the conclusion that "rat liver tumors are evoked by a regenerative hyperplasia," while the authors concluded the "sequence of events from two chronic mouse studies and a subchronic mouse study generally support the hypothesized regenerative hyperplasia MOA" (Dourson et al. 2016 in peer review). In regards to the conflicting mouse bioassay data (McConnell 2013; Dourson et al. 2014; JBRC 1990a), the difference is likely due in part to changes in the terminology and practices used for recording the liver lesions reported by Kano et al. (2009). arcadis.com 4 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix B - Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) Table 1. Integration and Comparison of Rat and Mouse Bioassay Data (Adapted from Dourson et al., 2016 in peer review) Key Events for Regenerative Call Proliferation MOA Rat (mg. kg/d) Mouse (mg/kg/d) 1. Metabolic saturation and accumulation of parent compound 30 100 ~200 2. Cellular swelling, hypertrophy, liver weight increase 42 55 190 - 200 3. Necrosis and/or inflammation 94 - 219 190 - 200 4a. Increased DNA synthesis 330 Not evaluated 380 in one study 4b. Hyperplasia development 55 330 but not the other 380 in one study 4c. Foci development 55 - 389 but not the other 5. Adenomas and carcinomas 274 - 1015 66 964 arcadis.com 5 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 Appendix B - Mode of Action Analysis for Liver Tumors Based on JBRC Review (Dourson et al. 2016 in peer review) 2 REFERENCES Dourson, M., J. Reichard, P. Nance, H. Burleigh-Flayer, A. Parker, M. Vincent, and E.E. McConnell. 2014. Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment. Regul Toxicol Pharmacol. 68:387-401. Dourson, M., J. Higginbotham, J. Crum, H. Burleigh-Flayer, P, Nance, N. Forsberg, and M. Lafranconi. 2016 in peer review. Update: Mode of Action (MOA) for Liver Tumors Induced by Oral Exposure to 1,4-Dioxane. Regul Toxicol Pharmacol. Available online at: http://allianceforrisk.org/14-dioxane analysis/. JBRC. 1990a. Report of Carcinogenicity Study by Oral Administration of 1,4-Dioxane (Mixed with Water) to Rats and Mice. Japan Industrial Safety and Health Association. December 28. JBRC. 1990b. Report of Preliminary Carcinogenicity Studies (Acute, Two-Week, and Thirteen-Week Studies) by Oral Administration of 1,4-Dioxane (Mixed with Water) to Rats and Mice. Japan Industrial Safety and Health Association. December 28. Kano, H., Y, Umeda, T. Kasai, T. Sasaki, M. Matsumoto, K. Yamazaki, K. Nagano, H. Arito, and S. Fukushima. 2009. Carcinogenicity of 1,4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem Toxicol. 47:2776 - 2784. McConnell, G. 2013. Report on the review of liver slides from the National Cancer Institute's Bioassay of 1,4-Dioxane for Possible Carcinogenicity Conducted in 1978 (NCI, 1978). Submitted to Toxicology Excellence for Risk Assessment. January/March 2013. NCI. 1978. Bioassay of 1,4-Dioxane for possible Carcinogenicity. Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute. NIH, Bethesda, MD, 78-1330. arcadis.com 6 Source: https://www.industrydocuments.ucsf.edu/docs/fsbn0226 ARCADIS Desion & Cansultancy for natural and bullt assets Arcadis U.S., Inc. 295 Woodcliff Drive Third Floor Suite 301 Fairport, New York 14450 Tel 585 385 0090 Fax 585 385 4198 www.arcadis.com Source: https://wwww.industrydocuments.ucsf.edu/docs/fsbn0226

What is the name of the President of BOARD OF TRUSTEES?

jgcn0226

jgcn0226_p0, jgcn0226_p1, jgcn0226_p2, jgcn0226_p3, jgcn0226_p4, jgcn0226_p5, jgcn0226_p6, jgcn0226_p7, jgcn0226_p8, jgcn0226_p9, jgcn0226_p10, jgcn0226_p11, jgcn0226_p12

Michael Leonard Dourson, PhD, DABT, ATS, Michael Leonard Dourson

238 From: Dourson. Michael (doursomi) To: Ann de Peyster: Nicole Soucy; Nditor Anthony JJBDUSI; William Farland; unab44@gmail.com Cc: Susie Masten; Toxicology Education Subject: Re: Toxicology Video Date: Friday, May 5, 2017 6:56:03 AM Attachments: image003.ong image002.ong image005.png image007.ong image004.ong image006.ong 2016 List of Trustees docx Dear Colleagues On the agenda for our Monday conference call is the assignment of various board members to our committees. Please feel free to add items to this agenda, of which I will otherwise send a draft later today. Cheers! Michael -- It is the mark of an instructed mind to rest satisfied with the degree of precision which the nature of the subject permits and not to seek an exactness where only an approximation of the truth is possible. Aristotle - Risk Science Center From: Ann de Peyster <adepeyst@mail.sdsu.edu> Date: Thursday, May 4, 2017 at 3:18 PM To: Nicole Soucy <nvsoucy@mmm.com> Cc: "Ndifor, Anthony [JRDUS]" <ANdifor@its.inj.com>, Michael Dourson <doursoml@ucmail.uc.edu>, William Farland <william.farland@colostate.edux Susie Masten <mastenmanagement@earthlink.net>, Toxicology Education > Ann de Peyster <adepeystermail.sdsu.edux Subject: Re: Re: Toxicology Video Ha ha! The fundraising committee consists of Tony and me at this point. The entire committee of 2 happens to have scheduled a rendezvous this Saturday in Tony's garage (TEF archives). We'll try to come up with some numbers. On Thu, May 4, 2017 at 11:22 AM, Nicole Soucy <nvsoucy@mmm.com> wrote: Hi everyone, Source: ttps://www.industrydocuments.ucsf.edu/docs/jgcn0226 239 Subtitles are definitely acceptable. If we are all in agreement to proceed please let me know how we should do so. We should have an idea of how much it will cost to create the subtitled video (and how much of a donation TEF would like) in order to take this on. Once the fundraising committee has determined that information I will share it with our group here at 3M to begin work on the translation. Nicole 3M Science. Applied to Life. Nicole V. Soucy, PhD, DABT | Senior Toxicology Specialist Medical Department I Toxicology & Compliance Solutions 3M Center, 220-06-E03 | St. Paul, MN 55144-1000 | United States Office: +1 651 733 8485 nvsoucy@mmm.com y in f 3M.com From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Thursday, April 27, 2017 7:24 PM To: Ndifor, Anthony [JRDUS] <ANdifor@its.ini.com> Cc: Dourson, Michael (doursoml) <doursoml@ucmailuc.edux; William Farland <william.farland@colostate.edux; Susie Masten <mastenmanagement@earthlink.net>; Nicole Soucy <nysoucy@mmm.com>; Toxicology Education >; Ann de Peyster <adepeyster@mail.sdsu.edu> Subject: [EXTERNAL] Re: Toxicology Video I retrieved a transcript from the Google Drive Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 240 Sent from my iPhone On Apr 27, 2017, at 2:47 PM, Ndifor, Anthony [JRDUS] kANdifor@its.inj.com> wrote: I am very supportive of Nicole's proposal. Thanks Nicole. I would not advocate for a voiceover. Adding subtitles would be much easier and I think equally effective. Voiceovers work well when the target audience looks like the actors but is distracting and appears phony when they don't. So all we need is the video transcripts. Regards Tony From: Dourson, Michael (doursoml) [ mailto:doursomi@ucmailuc.edu Sent: Thursday, April 27, 2017 2:30 PM To: Ndifor, Anthony [JRDUS]; William Farland Cc: Susie Masten; Nicole Soucy; 'Toxicology Education'; ; Ann de Peyster Subject: [EXTERNAL] Re: Toxicology Video Tony and Bill Sorry miss you on the original email. Michael -- Risk Science Center (formerly TERA Center) Integrating assessments for both human and environmental health. See htp://www.tera.org/ECoTERA/index.hml Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 241 W Risk Science Center Department 3 From: Michael Dourson <doursoml@ucmailuc.edu> Date: Thursday, April 27, 2017 at 11:29 PM To: Ann de Peyster <adepeyster@mailsdsu.edu) Cc: Susie Masten <mastenmanagement@earthlink.net. Nicole Soucy <nysoucy@mmm.com> 'Toxicology Education' " Subject: Re: Toxicology Video Ann Please caucus the fundraising committee. Whatever your committee decides will be fine. Ann, Bill and Tony, please feel free to weigh in here. Cheers! Michael -Alliance for Risk Assessment (ARA), building a risk assessment community Risk Science Center in From: Nicole Soucy <nysoucyommm.com> Date: Thursday, April 27, 2017 at 4:42 PM To: "Toxicology Education' Michael Dourson <doursoml@ucmailuc.edu, Ann de Peyster <adepeyster@mail.sdsu.edu>, Cc: Susie Masten <mastenmanagement@earthlink.net Subject: FW: Toxicology Video Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 242 Team, As part of an ongoing conversation with my management about making a donation to TEF, I shared the Is it Safe? video. The timing was advantageous in that we have been struggling with public perception about chemicals in the Korean market for some time. I think there is potential for a partnership between 3M and TEF related to translation of the video into Korean, and it sounds like 3M would be willing to do the translation (in addition to a donation to TEF). Should we have a call to discuss how to make this happen? ) do think we need to move fairly quickly on this to keep the momentum. Regards, Nicole <image019.gif> Nicole V. Soucy, PhD, DABT | Senior Toxicology Specialist Medical Department | Toxicology & Compliance Solutions 3M Center, 220-06-E03 | St. Paul, MN 55144-1000 | United States Office: +1 651 733 8485 nvsoucy@mmm.com in f <image024.ng><image025.png> From: James Zappia Sent: Thursday, April 27, 2017 6:55 AM To: Chideuk Kim <edkim@mmm.com>: JUNG-IM HUH <jhuh@mmun.com> Cc: YOHAN LEE <vlee@mmm.com>; Nicole Soucy <nvsoucy@mmm.com> Subject: Re: Toxicology Video Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 243 CD, I will find out. Are you proposing to do a translation that be used as a the audio portion or maybe using sub-titles? I expect the Toxicology Education Forum would want to maintain some control over the quality of the video. I'll talk with Nicole? Jim James Zappia Manager, Toxicology and Cpompliance Solutions 3M Medical Department Phone: 651 733 5180; Mobile: 612 735 0234 From: Chideuk Kim Sent: Thursday, April 27, 2017 12:01:24 AM To: JUNG-IM HUH; James Zappia Cc: YOHAN LEE Subject: RE: Toxicology Video Is this copyright or we can download for local language script ? <image019.gif> Chideuk(CD) Kim I Technical Director 3M Korea Technical Operations 7, Samsung 1-Ro, - 5- Gil, Hwaseong-si | Gyeonggi-do 18449, Korea Office: 82 31 8058 8301 I Mobile: 82 10 3859 5512 cdkim@mmm.com w in $ la <image026.gif><image025.ong> From: JUNG-IM HUH Sent: Thursday,April 27,2017 7:59 AM To: James Zappia <jizappial@mmm.com> Cc: YOHAN LEE <vlee@mmm.com>; Chideuk Kim <edkim@mmm.com> Subject: RE: Toxicology Video Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 244 Hi, Jim, This is a nice video to share for educational purposes. If needed, : can help translation it into Korean. Thanks, <image019.gif> Jung-Im Huh, Pho Manager-Produci EHS&R F&D Service 3M Korea Innovation Center, 7, Samsung U-Ro, 5-Gil I Hwaseong-si, Gyeonggi-do, 445-170 Republic of Korea Office: 82 31 8058 8645 Mobile: 82 10 3679 2354 Fax: 02 31 8058 8694 ihuh@mmm.com I www.3M.com (3M Internal Web site) krweb02.lapa.mmm.com/PrsPortal/index.jsr y in f bo <image026.gif> From: James Zappia Sent: Thursday, April 27, 2017 5:56 AM To: Chideuk Kim <edkim@mmm.com> JUNG-IM HUH <jhuh@mmm.com> Cc: YOHAN LEE <ylee@mmm.com> Subject: Toxicology Video Hi CD and JI, One of the toxicologist in our group, Nicole Soucy, is a board member of an organization called the Toxicology Education Foundation. One of their goals is to create and promote some great resources to help provide basic toxicology education to the general public, including an award winning video that 3M helped support and which featured the late John Doull (http://toxedfoundation.org/is-it-safe/) I watched the video and think that it is a very good educational tool that Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 245 talks about the importance of chemicals in our lives and how we evaluate safety. It is designed to be shared in the classroom or other places. I think this type of tool might have a place in Korea as it debates chemical safety in society. I am wondering if we should think about getting this translated into Korean and making it available to schools and other organizations. Please take a look and let me know your thoughts. Thanks, Jim <image034.png> James Zappia / Manager, Toxicology and Compliance Solutions 3M Medical Department 3M Center, Bidg 220-8E I St. Paul MN 55144 Office: 651 733 5180 izappia1@mmm.com www.3M.com 3M security scanners have not detected any malicious content in this message. Click here to report this email as spam Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 BOARD OF TRUSTEES 2016 President Suzanne C. Fitzpatrick, PhD, DABT U.S. Food and Drug Administration Michael Leonard Dourson, PhD, DABT, ATS Toxicology Excellence for Risk Assessment Stephen D. Gettings PhD, JD, DABT AVON Vice President Mark Lafranconi, PhD, DABT Elizabeth L. Anderson, Ph.D., FATS ToxHorizons Exponent A. Wallace Hayes, PhD, FATS, DABT Secretary/Treasurer Harvard School of Public Health Tony Ndifor, PhD Jeffrey Jenkins, PhD, Strategic Planning Johnson & Johnson Oregon State University Standing Committee Chairs and Other Trustees Gladys Ouédraogo, PharmD, PhD L'Oréal Research and Innovation Nancy B. Beck, PhD, DABT, Marketing/Media American Chemistry Council Richard D. Phillips, PhD ExxonMobil Biomedical Sciences, Inc. (Retired) Silvia Berlanga de Moraes Barros, MSc, PhD University of São Paulo Nicole V. Soucy, PhD, DABT 3M David W. Cragin, PhD, DABT Merk Sharp & Dohme David Steup, PhD, DABT Shell Oil Company (Retired) Ann de Peyster, PhD, ATS, Fundraising San Diego State University (Emeritus) Government Liaison William H. Farland, PhD, ATS, Website Content Philip Wexler, BS, MLS Colorado State University National Library of Medicine Source: :ttps://www.industrydocuments.ucsf.edu/docs/jgcn0226 TEF Committees 2016 NOTE: President is an ex officio member of all Committees FUNDRAISING Ann de Peyster, Chair Nicole Soucy Mark Lafranconi Tony Nfidor Wally Hayes MARKETING Nancy Beck, Chair Phil Wexler Gladys Ouédraogo Nicole Soucy Ann de Peyster WEBSITE Bill Farland, Chair Ann de Peyster Silvia Berlanga de Moraes Barros David Steup STRATEGIC PLANNING Jeffry Jenkins, Chair Betty Anderson Dick Phillips Bill Farland Mark Lafranconi Steve Gettings BYLAWS Nicole Soucy Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 CONTACT INFORMATION Elizabeth L. Anderson, Ph.D., FATS David W. Cragin, PhD, DABT William H. Farland, Ph.D., ATS Vice President 2014-2015 Trustee 2014-2017 Trustee 2014-2017 Trustee 2014-2017 - Merk Sharp & Dohme Senior Advisor to the Executive Vice Chief Science Officer and Principal Scientist Associate Director Chemical Notification and President & Professor, Environmental & Exponent Registration Radiological Health Sciences 1800 Diagonal Road, Suite 300 Product Stewardship and Science, Global College of Veterinary Medicine & Biomedical Alexandria, VA 22314 Safety & Environment Sciences Tel: 571-227-7205 770 Sumneytown Pike, WP20-205 Colorado State University Cell: 703-624-6561 West Point PA 19486 135 Physiology (1680 Campus Delivery) elanderson@exponent.com Tel:215-652-6615 Fort Collins, CO 80523-1680 Cell: 215-694-8249 Tel: 970-491-0280; Nancy B. Beck, Ph.D., DABT David_cragin@merck.com Cell: 970-222-3143 Trustee 2014-2017 William.Farland@ColoState.edu American Chemistry Council Ann de Peyster, PhD William H. Farland Consulting, LLC, Senior Director Regulatory Science Policy Trustee 2013-2016 88 Eastward, Rockport, ME 04856 Regulatory & Technical Affairs Professor (Emeritus) laughfox5@msn.com 700 2nd Street, NE Graduate School of Public Health Washington DC 20002 San Diego State University Suzanne C. Fitzpatrick, PhD, DABT Office: 202-249-6417 San Diego, CA 92182 Trustee 2013-2016 Nancy_Beck@americanchemistry.com Cell: 858-699-3599 Senior Science Policy Analyst adepeyst@mail.sdsu.edu Office of the Commissioner Silvia Berlanga de Moraes Barros, MSc, Office of the FDA Chief Scientist PhD Michael L. Dourson, Ph.D., DABT, ATS Trustee 2013-2016 President U.S. Food and Drug Administration 4917 Sunflower Drive School of Pharmaceutical Sciences Trustee 2012-2015 Rockville MD 20853 University of São Paulo Director, Toxicology Excellence for Risk Tel: 301-827-4591 Av. Prof.Lineu Prestes, Assessment (TERA) Center Professor of Environmental Health uzanne.fitzpatrick@fda.hhs.gov 580 - 05508-000 São Paulo - SP - Brasil University of Cincinnati, College of Medicine Tel: 55 11 30913631 160 Panzeca Way Stephen D. Gettings PhD, JD, DABT Trustee 2014-2017 or 30913632 Cincinnati OH 45267-0056 Cell: 55 11 991029301 Tel: 513-558-7949 Vice-President Product Safety, Integrity & smbarros@usp.br michael.dourson@uc.edu Regulatory Affairs Global Research & Development, silviaberlanga@gmail.com Suffern NY 10901 Tel: 845-369-2600 Cell: 845-664-4121 Steve.gettings@avon.com Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 A. Wallace Hayes, Ph.D., FATS, DABT Gladys Ouédraogo, Pharm.D, Ph.D Philip Wexler, B.S., M.L.S. Trustee 2013-2016 Trustee 2014-2017 Government Liaison Harvard School of Public Health Scientific Officer National Library of Medicine 298 South Main Street Predictive model and method development Toxicology Env Health Information Program Andover, Massachusetts 01810 Department 2 Democracy Plaza, Suite 510 Ph 978/749-3085 L'Oréal Research and Innovation 6707 Democracy Boulevard MSC 5467 Cell 978/302-3747 1 Avenue Eugène Schueller Bethesda, MD 20892-5467 awallacehayes@comcast.ne 93601 Aulnay sous-bois - France wexlerp@mail.nih.gov Tel : +33 (0) 1 48 68 92 56 Tel: 301-496-6346 Jeffrey Jenkins, PhD, Professor Email : gouedraogo@rd.loreal.com Cell:240-899-6514 President 2014-2015 Trustee 2014-2017 Richard D. Phillips, PhD, DABT TEF HEADQUARTERS Environmental and Molecular Toxicology Trustee 2014-2017 Toxicology Education Foundation 1007 Ag & Life Sciences ExxonMobil - retired PO Box 98224 Oregon State University 3667 Bridgewater Drive Raleigh, NC 27624 Corvallis, OR 97331-7301 Southport, NC 28461 toxedf@gmail.com Tel:541-737-5993 Cell: 908-391-9538 Masten Management Cell:541-740-6948 rdphill@ec.rr.com Susie Masten Jeffrey.Jenkins@oregonstate.edu Laurie Wood Nicole V. Soucy, Ph.D., DABT Email: mastenmanagement@earthlink.net Mark Lafranconi, Ph.D., DABT Trustee 2014-2017 Cell: 919-949-6667 Trustee 2013-2016 Advanced Toxicology Specialist Tox Horizons, LLC 3M Medical Department 7569 Kings Mills Road Toxicology Assessment and Compliance Maineville, OH 45039 Assurance Tel:513.312-8157 mark.lafranconi@gmail.com 3M Center, Building 220-6E-03 toxhorizons@gmail.com St Paul, MN 55144 Tel: 651 733 8485 Tony Ndifor, Ph.D. nvsoucy@mmm.com Secretary/Treasurer 2014-2015 Trustee 2014-2017 David Steup, Ph.D., DABT Preclinical Development &Safety Trustee 2014-2017 Janssen Research & Dev. Shell Oil Company (Retired) 3210 Merryfield Row, 4606 Echo Falls Dr. San Diego, CA 92121 Kingwood, TX 77345 Tel: 858-784-3260 Tel: 281-360-5451 Email: andifor@its.jnj.com drsteup@gmail.com Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 TOXICOLOGY EDUCATION FOUNDATION TRUSTEE TERMS Term Ended in 2015 Mike Dourson (1st term) Term ending in 2016 Suzanne Fitzpatrick (2nd term) Silvia Berlanga de Moraes Barros (2nd term) Ann de Peyster (2nd term) Mark Lafranconi (1st term) Wally Hayes (4th term) Term ending in 2017 Betty Anderson (4th term) Nancy Beck (1st term) David Cragin (1st term) Bill Farland (1st term) Stephen Gettings (1st term) Jeff Jenkins (2nd term) Tony Ndifor (2nd term) Gladys Ouédraogo (1st term) Dick Phillips (2nd term) Nicole Soucy (1st term) David Steup (1st term) Source: :ttps://www.industrydocuments.ucsf.edu/docs/jgcn0226

To which university did William H. Farland belong to?

jgcn0226

jgcn0226_p0, jgcn0226_p1, jgcn0226_p2, jgcn0226_p3, jgcn0226_p4, jgcn0226_p5, jgcn0226_p6, jgcn0226_p7, jgcn0226_p8, jgcn0226_p9, jgcn0226_p10, jgcn0226_p11, jgcn0226_p12

Colorado State University

238 From: Dourson. Michael (doursomi) To: Ann de Peyster: Nicole Soucy; Nditor Anthony JJBDUSI; William Farland; unab44@gmail.com Cc: Susie Masten; Toxicology Education Subject: Re: Toxicology Video Date: Friday, May 5, 2017 6:56:03 AM Attachments: image003.ong image002.ong image005.png image007.ong image004.ong image006.ong 2016 List of Trustees docx Dear Colleagues On the agenda for our Monday conference call is the assignment of various board members to our committees. Please feel free to add items to this agenda, of which I will otherwise send a draft later today. Cheers! Michael -- It is the mark of an instructed mind to rest satisfied with the degree of precision which the nature of the subject permits and not to seek an exactness where only an approximation of the truth is possible. Aristotle - Risk Science Center From: Ann de Peyster <adepeyst@mail.sdsu.edu> Date: Thursday, May 4, 2017 at 3:18 PM To: Nicole Soucy <nvsoucy@mmm.com> Cc: "Ndifor, Anthony [JRDUS]" <ANdifor@its.inj.com>, Michael Dourson <doursoml@ucmail.uc.edu>, William Farland <william.farland@colostate.edux Susie Masten <mastenmanagement@earthlink.net>, Toxicology Education > Ann de Peyster <adepeystermail.sdsu.edux Subject: Re: Re: Toxicology Video Ha ha! The fundraising committee consists of Tony and me at this point. The entire committee of 2 happens to have scheduled a rendezvous this Saturday in Tony's garage (TEF archives). We'll try to come up with some numbers. On Thu, May 4, 2017 at 11:22 AM, Nicole Soucy <nvsoucy@mmm.com> wrote: Hi everyone, Source: ttps://www.industrydocuments.ucsf.edu/docs/jgcn0226 239 Subtitles are definitely acceptable. If we are all in agreement to proceed please let me know how we should do so. We should have an idea of how much it will cost to create the subtitled video (and how much of a donation TEF would like) in order to take this on. Once the fundraising committee has determined that information I will share it with our group here at 3M to begin work on the translation. Nicole 3M Science. Applied to Life. Nicole V. Soucy, PhD, DABT | Senior Toxicology Specialist Medical Department I Toxicology & Compliance Solutions 3M Center, 220-06-E03 | St. Paul, MN 55144-1000 | United States Office: +1 651 733 8485 nvsoucy@mmm.com y in f 3M.com From: Ann de Peyster [mailto:adepeyst@mail.sdsu.edu Sent: Thursday, April 27, 2017 7:24 PM To: Ndifor, Anthony [JRDUS] <ANdifor@its.ini.com> Cc: Dourson, Michael (doursoml) <doursoml@ucmailuc.edux; William Farland <william.farland@colostate.edux; Susie Masten <mastenmanagement@earthlink.net>; Nicole Soucy <nysoucy@mmm.com>; Toxicology Education >; Ann de Peyster <adepeyster@mail.sdsu.edu> Subject: [EXTERNAL] Re: Toxicology Video I retrieved a transcript from the Google Drive Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 240 Sent from my iPhone On Apr 27, 2017, at 2:47 PM, Ndifor, Anthony [JRDUS] kANdifor@its.inj.com> wrote: I am very supportive of Nicole's proposal. Thanks Nicole. I would not advocate for a voiceover. Adding subtitles would be much easier and I think equally effective. Voiceovers work well when the target audience looks like the actors but is distracting and appears phony when they don't. So all we need is the video transcripts. Regards Tony From: Dourson, Michael (doursoml) [ mailto:doursomi@ucmailuc.edu Sent: Thursday, April 27, 2017 2:30 PM To: Ndifor, Anthony [JRDUS]; William Farland Cc: Susie Masten; Nicole Soucy; 'Toxicology Education'; ; Ann de Peyster Subject: [EXTERNAL] Re: Toxicology Video Tony and Bill Sorry miss you on the original email. Michael -- Risk Science Center (formerly TERA Center) Integrating assessments for both human and environmental health. See htp://www.tera.org/ECoTERA/index.hml Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 241 W Risk Science Center Department 3 From: Michael Dourson <doursoml@ucmailuc.edu> Date: Thursday, April 27, 2017 at 11:29 PM To: Ann de Peyster <adepeyster@mailsdsu.edu) Cc: Susie Masten <mastenmanagement@earthlink.net. Nicole Soucy <nysoucy@mmm.com> 'Toxicology Education' " Subject: Re: Toxicology Video Ann Please caucus the fundraising committee. Whatever your committee decides will be fine. Ann, Bill and Tony, please feel free to weigh in here. Cheers! Michael -Alliance for Risk Assessment (ARA), building a risk assessment community Risk Science Center in From: Nicole Soucy <nysoucyommm.com> Date: Thursday, April 27, 2017 at 4:42 PM To: "Toxicology Education' Michael Dourson <doursoml@ucmailuc.edu, Ann de Peyster <adepeyster@mail.sdsu.edu>, Cc: Susie Masten <mastenmanagement@earthlink.net Subject: FW: Toxicology Video Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 242 Team, As part of an ongoing conversation with my management about making a donation to TEF, I shared the Is it Safe? video. The timing was advantageous in that we have been struggling with public perception about chemicals in the Korean market for some time. I think there is potential for a partnership between 3M and TEF related to translation of the video into Korean, and it sounds like 3M would be willing to do the translation (in addition to a donation to TEF). Should we have a call to discuss how to make this happen? ) do think we need to move fairly quickly on this to keep the momentum. Regards, Nicole <image019.gif> Nicole V. Soucy, PhD, DABT | Senior Toxicology Specialist Medical Department | Toxicology & Compliance Solutions 3M Center, 220-06-E03 | St. Paul, MN 55144-1000 | United States Office: +1 651 733 8485 nvsoucy@mmm.com in f <image024.ng><image025.png> From: James Zappia Sent: Thursday, April 27, 2017 6:55 AM To: Chideuk Kim <edkim@mmm.com>: JUNG-IM HUH <jhuh@mmun.com> Cc: YOHAN LEE <vlee@mmm.com>; Nicole Soucy <nvsoucy@mmm.com> Subject: Re: Toxicology Video Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 243 CD, I will find out. Are you proposing to do a translation that be used as a the audio portion or maybe using sub-titles? I expect the Toxicology Education Forum would want to maintain some control over the quality of the video. I'll talk with Nicole? Jim James Zappia Manager, Toxicology and Cpompliance Solutions 3M Medical Department Phone: 651 733 5180; Mobile: 612 735 0234 From: Chideuk Kim Sent: Thursday, April 27, 2017 12:01:24 AM To: JUNG-IM HUH; James Zappia Cc: YOHAN LEE Subject: RE: Toxicology Video Is this copyright or we can download for local language script ? <image019.gif> Chideuk(CD) Kim I Technical Director 3M Korea Technical Operations 7, Samsung 1-Ro, - 5- Gil, Hwaseong-si | Gyeonggi-do 18449, Korea Office: 82 31 8058 8301 I Mobile: 82 10 3859 5512 cdkim@mmm.com w in $ la <image026.gif><image025.ong> From: JUNG-IM HUH Sent: Thursday,April 27,2017 7:59 AM To: James Zappia <jizappial@mmm.com> Cc: YOHAN LEE <vlee@mmm.com>; Chideuk Kim <edkim@mmm.com> Subject: RE: Toxicology Video Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 244 Hi, Jim, This is a nice video to share for educational purposes. If needed, : can help translation it into Korean. Thanks, <image019.gif> Jung-Im Huh, Pho Manager-Produci EHS&R F&D Service 3M Korea Innovation Center, 7, Samsung U-Ro, 5-Gil I Hwaseong-si, Gyeonggi-do, 445-170 Republic of Korea Office: 82 31 8058 8645 Mobile: 82 10 3679 2354 Fax: 02 31 8058 8694 ihuh@mmm.com I www.3M.com (3M Internal Web site) krweb02.lapa.mmm.com/PrsPortal/index.jsr y in f bo <image026.gif> From: James Zappia Sent: Thursday, April 27, 2017 5:56 AM To: Chideuk Kim <edkim@mmm.com> JUNG-IM HUH <jhuh@mmm.com> Cc: YOHAN LEE <ylee@mmm.com> Subject: Toxicology Video Hi CD and JI, One of the toxicologist in our group, Nicole Soucy, is a board member of an organization called the Toxicology Education Foundation. One of their goals is to create and promote some great resources to help provide basic toxicology education to the general public, including an award winning video that 3M helped support and which featured the late John Doull (http://toxedfoundation.org/is-it-safe/) I watched the video and think that it is a very good educational tool that Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 245 talks about the importance of chemicals in our lives and how we evaluate safety. It is designed to be shared in the classroom or other places. I think this type of tool might have a place in Korea as it debates chemical safety in society. I am wondering if we should think about getting this translated into Korean and making it available to schools and other organizations. Please take a look and let me know your thoughts. Thanks, Jim <image034.png> James Zappia / Manager, Toxicology and Compliance Solutions 3M Medical Department 3M Center, Bidg 220-8E I St. Paul MN 55144 Office: 651 733 5180 izappia1@mmm.com www.3M.com 3M security scanners have not detected any malicious content in this message. Click here to report this email as spam Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 BOARD OF TRUSTEES 2016 President Suzanne C. Fitzpatrick, PhD, DABT U.S. Food and Drug Administration Michael Leonard Dourson, PhD, DABT, ATS Toxicology Excellence for Risk Assessment Stephen D. Gettings PhD, JD, DABT AVON Vice President Mark Lafranconi, PhD, DABT Elizabeth L. Anderson, Ph.D., FATS ToxHorizons Exponent A. Wallace Hayes, PhD, FATS, DABT Secretary/Treasurer Harvard School of Public Health Tony Ndifor, PhD Jeffrey Jenkins, PhD, Strategic Planning Johnson & Johnson Oregon State University Standing Committee Chairs and Other Trustees Gladys Ouédraogo, PharmD, PhD L'Oréal Research and Innovation Nancy B. Beck, PhD, DABT, Marketing/Media American Chemistry Council Richard D. Phillips, PhD ExxonMobil Biomedical Sciences, Inc. (Retired) Silvia Berlanga de Moraes Barros, MSc, PhD University of São Paulo Nicole V. Soucy, PhD, DABT 3M David W. Cragin, PhD, DABT Merk Sharp & Dohme David Steup, PhD, DABT Shell Oil Company (Retired) Ann de Peyster, PhD, ATS, Fundraising San Diego State University (Emeritus) Government Liaison William H. Farland, PhD, ATS, Website Content Philip Wexler, BS, MLS Colorado State University National Library of Medicine Source: :ttps://www.industrydocuments.ucsf.edu/docs/jgcn0226 TEF Committees 2016 NOTE: President is an ex officio member of all Committees FUNDRAISING Ann de Peyster, Chair Nicole Soucy Mark Lafranconi Tony Nfidor Wally Hayes MARKETING Nancy Beck, Chair Phil Wexler Gladys Ouédraogo Nicole Soucy Ann de Peyster WEBSITE Bill Farland, Chair Ann de Peyster Silvia Berlanga de Moraes Barros David Steup STRATEGIC PLANNING Jeffry Jenkins, Chair Betty Anderson Dick Phillips Bill Farland Mark Lafranconi Steve Gettings BYLAWS Nicole Soucy Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 CONTACT INFORMATION Elizabeth L. Anderson, Ph.D., FATS David W. Cragin, PhD, DABT William H. Farland, Ph.D., ATS Vice President 2014-2015 Trustee 2014-2017 Trustee 2014-2017 Trustee 2014-2017 - Merk Sharp & Dohme Senior Advisor to the Executive Vice Chief Science Officer and Principal Scientist Associate Director Chemical Notification and President & Professor, Environmental & Exponent Registration Radiological Health Sciences 1800 Diagonal Road, Suite 300 Product Stewardship and Science, Global College of Veterinary Medicine & Biomedical Alexandria, VA 22314 Safety & Environment Sciences Tel: 571-227-7205 770 Sumneytown Pike, WP20-205 Colorado State University Cell: 703-624-6561 West Point PA 19486 135 Physiology (1680 Campus Delivery) elanderson@exponent.com Tel:215-652-6615 Fort Collins, CO 80523-1680 Cell: 215-694-8249 Tel: 970-491-0280; Nancy B. Beck, Ph.D., DABT David_cragin@merck.com Cell: 970-222-3143 Trustee 2014-2017 William.Farland@ColoState.edu American Chemistry Council Ann de Peyster, PhD William H. Farland Consulting, LLC, Senior Director Regulatory Science Policy Trustee 2013-2016 88 Eastward, Rockport, ME 04856 Regulatory & Technical Affairs Professor (Emeritus) laughfox5@msn.com 700 2nd Street, NE Graduate School of Public Health Washington DC 20002 San Diego State University Suzanne C. Fitzpatrick, PhD, DABT Office: 202-249-6417 San Diego, CA 92182 Trustee 2013-2016 Nancy_Beck@americanchemistry.com Cell: 858-699-3599 Senior Science Policy Analyst adepeyst@mail.sdsu.edu Office of the Commissioner Silvia Berlanga de Moraes Barros, MSc, Office of the FDA Chief Scientist PhD Michael L. Dourson, Ph.D., DABT, ATS Trustee 2013-2016 President U.S. Food and Drug Administration 4917 Sunflower Drive School of Pharmaceutical Sciences Trustee 2012-2015 Rockville MD 20853 University of São Paulo Director, Toxicology Excellence for Risk Tel: 301-827-4591 Av. Prof.Lineu Prestes, Assessment (TERA) Center Professor of Environmental Health uzanne.fitzpatrick@fda.hhs.gov 580 - 05508-000 São Paulo - SP - Brasil University of Cincinnati, College of Medicine Tel: 55 11 30913631 160 Panzeca Way Stephen D. Gettings PhD, JD, DABT Trustee 2014-2017 or 30913632 Cincinnati OH 45267-0056 Cell: 55 11 991029301 Tel: 513-558-7949 Vice-President Product Safety, Integrity & smbarros@usp.br michael.dourson@uc.edu Regulatory Affairs Global Research & Development, silviaberlanga@gmail.com Suffern NY 10901 Tel: 845-369-2600 Cell: 845-664-4121 Steve.gettings@avon.com Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 A. Wallace Hayes, Ph.D., FATS, DABT Gladys Ouédraogo, Pharm.D, Ph.D Philip Wexler, B.S., M.L.S. Trustee 2013-2016 Trustee 2014-2017 Government Liaison Harvard School of Public Health Scientific Officer National Library of Medicine 298 South Main Street Predictive model and method development Toxicology Env Health Information Program Andover, Massachusetts 01810 Department 2 Democracy Plaza, Suite 510 Ph 978/749-3085 L'Oréal Research and Innovation 6707 Democracy Boulevard MSC 5467 Cell 978/302-3747 1 Avenue Eugène Schueller Bethesda, MD 20892-5467 awallacehayes@comcast.ne 93601 Aulnay sous-bois - France wexlerp@mail.nih.gov Tel : +33 (0) 1 48 68 92 56 Tel: 301-496-6346 Jeffrey Jenkins, PhD, Professor Email : gouedraogo@rd.loreal.com Cell:240-899-6514 President 2014-2015 Trustee 2014-2017 Richard D. Phillips, PhD, DABT TEF HEADQUARTERS Environmental and Molecular Toxicology Trustee 2014-2017 Toxicology Education Foundation 1007 Ag & Life Sciences ExxonMobil - retired PO Box 98224 Oregon State University 3667 Bridgewater Drive Raleigh, NC 27624 Corvallis, OR 97331-7301 Southport, NC 28461 toxedf@gmail.com Tel:541-737-5993 Cell: 908-391-9538 Masten Management Cell:541-740-6948 rdphill@ec.rr.com Susie Masten Jeffrey.Jenkins@oregonstate.edu Laurie Wood Nicole V. Soucy, Ph.D., DABT Email: mastenmanagement@earthlink.net Mark Lafranconi, Ph.D., DABT Trustee 2014-2017 Cell: 919-949-6667 Trustee 2013-2016 Advanced Toxicology Specialist Tox Horizons, LLC 3M Medical Department 7569 Kings Mills Road Toxicology Assessment and Compliance Maineville, OH 45039 Assurance Tel:513.312-8157 mark.lafranconi@gmail.com 3M Center, Building 220-6E-03 toxhorizons@gmail.com St Paul, MN 55144 Tel: 651 733 8485 Tony Ndifor, Ph.D. nvsoucy@mmm.com Secretary/Treasurer 2014-2015 Trustee 2014-2017 David Steup, Ph.D., DABT Preclinical Development &Safety Trustee 2014-2017 Janssen Research & Dev. Shell Oil Company (Retired) 3210 Merryfield Row, 4606 Echo Falls Dr. San Diego, CA 92121 Kingwood, TX 77345 Tel: 858-784-3260 Tel: 281-360-5451 Email: andifor@its.jnj.com drsteup@gmail.com Source: https://www.industrydocuments.ucsf.edu/docs/jgcn0226 TOXICOLOGY EDUCATION FOUNDATION TRUSTEE TERMS Term Ended in 2015 Mike Dourson (1st term) Term ending in 2016 Suzanne Fitzpatrick (2nd term) Silvia Berlanga de Moraes Barros (2nd term) Ann de Peyster (2nd term) Mark Lafranconi (1st term) Wally Hayes (4th term) Term ending in 2017 Betty Anderson (4th term) Nancy Beck (1st term) David Cragin (1st term) Bill Farland (1st term) Stephen Gettings (1st term) Jeff Jenkins (2nd term) Tony Ndifor (2nd term) Gladys Ouédraogo (1st term) Dick Phillips (2nd term) Nicole Soucy (1st term) David Steup (1st term) Source: :ttps://www.industrydocuments.ucsf.edu/docs/jgcn0226

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202 From: Erraguntla, Neeraja To: White. Kimberly; Admon. Smadar: Anderson Steven; Batoon Audrey; Bradley, Kevin: de Lacy Catharine; Elkan, Han; Goodman. Bryan; Hochschwender. Lane Jacobi Svlvia. B: Kannah. Kasturirangan; Levan, Steve: Levchik, Sergei; Little, Barbara; Manor. Orit: Prero. Judab; Rothenbacher. Klaus; Saunders Eric L.; Scherrer, Steve: Simon. Robert; Tavior. Jennifer: Tenney, Joel; Thorn, Amelia: West Jay; Hayes, A. Wallace; Rein. Guillermo; info@sroitzsch.com Troitzsch, Jurgen; Blais, Matthew; Dourson. Michael (doursomi); Kacew Sam; Osimitz, Thomas Cc: Erraguntia. Neeraia Subject: RE: Clarification -Updated Smoke Toxicity Proposal -SAC May 2017 - Meeting Materials Date: Tuesday, May 16, 2017 11:11:42 AM Attachments: Update - Smoke Toxicity Project - April 2017 to NAFRA. pdf Re-sending the proposal to follow Tom's discussion on Smoke toxicity right now at the SAC mtg on May 16. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT| American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE Washington, DC | 20002 O: (202) 249-6712 C (202) 779-0524 www.americanchemistry.com From: Erraguntla, Neeraja Sent: Tuesday, May 16, 2017 9:08 AM To: White, Kimberly; Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com; Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmail.uc.edu); Kacew, Sam; Osimitz, Thomas Cc: Erraguntla, Neeraja Subject: RE: Clarification - -Updated Smoke Toxicity Proposal - -SAC May 2017 - Meeting Materials Dear All, Tom provided additional clarification on the updated smoke toxicity proposal. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE I Washington, DC I 20002 O: (202) 249-6712 C: (202)779-0524 www.americanchemistry.com Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 203 From: Erraguntla, Neeraja Sent: Sunday, May 14, 2017 4:38 PM To: White, Kimberly; Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmailuc.edu); Kacew, Sam; Osimitz, Thomas Subject: RE: Updated Smoke Toxicity Proposal -SAC May 2017 - Meeting Materials Dear All, Please see the attached Updated Smoke Toxicity Proposal from Tom for consideration and action at the SAC meeting this week. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE Washington DO I 20002 O: (202) 249-6712 C: (202) 779-0524 www.americanchemistry.cor From: White, Kimberly Sent: Tuesday, May 9, 2017 5:28 PM To: Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Erraguntla, Neeraja; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; White, Kimberly; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com; Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmailuc.edu); Kacew, Sam; Osimitz, Thomas Subject: SAC May 2017 - Meeting Materials Dear NAFRA, BSEF and SAC members: In preparation for the May 16th-17th SAC meeting, attached are associated meeting materials. Hard copies will also be available onsite. In addition to the attached materials, we also anticipate additional information on the dermal exposure project, the smoke toxicity project and the baby monitor combustion project to be disseminated in the coming days. Below are general meeting logistics. General Logistics Meeting Dates/Times: May 16, 2017 (Meeting from 9:00 a.m. -5:00 p.m. ET) May 17, 2017 ( Meeting from 9:00 a.m. -2:00 p.m. ET) Meeting/Hotel Location: DoubleTree by Hilton Hotel Metropolitan -New York City, 569 Lexington Avenue, New York, New York 10022 Dinner on May 15, 2017 at 6:30pm (ET) - The Modern; Address: 9 W 53rd St. New York, NY 10019 Dinner on May 16, 2017 at 6:30pm (ET) Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 204 SAC Members Only - The Smith; Address: 956 2nd Ave, New York, NY 10022 NAFRA/ BSEF Members Only - Mitae: Address: 4 East 46th Street, New York, NY 10017 I look forward to seeing everyone next week and feel free to contact me if you have any questions. Kind Regards, Kimberly Wise White, Ph.I D. | American Chemistry Council Senior Director, Chemical Products & Technology Division Kimberly Whitelamericanchemistry.com 700 2nd Street NE Washington, DC | 20002 O: (202) 249-6707 C: (202) 341-7602 www.americanchemistry.com + This message may contain confidential information and is intended only for the individual named. If you are not the named addressee do not disseminate, distribute or copy this email. Please notify the sender immediately by email if you have received this email by mistake and delete this email from your system. E-mail transmission cannot be guaranteed to be secure or error-free as information could be intercepted, corrupted, lost, destroyed, arrive late or incomplete, or contain viruses. The sender therefore does not accept liability for any errors or omissions in the contents of this message which arise as a result of email transmission. American Chemistry Council, 700 - 2nd Street NE, Washington, DC 20002, www.americanchemistry.com Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Relative Toxicity of Combustion Products from Various Materials Effect of Flame Retardants T.G. Osimitz (Science Strategies) and M.S. Blais (Southwest Research Institute) April 18, 2017 Background Recent studies haves shown the presence of flame retardants (esp. polybrominated diphenyl ethers (PBDEs)) and/or possible flame retardant (FR) combustion products (halogenated dioxins and furans), and other polyaromatic hydrocarbons (PAHs) in the serum of firefighters and/or on their clothing (Shaw et al. 2013). In their study, polychlorinated and polybrominated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs and PBDD/Fs) were measured in the serum of twelve firefighters sampled after a fire event in San Francisco, California, along with PBDEs, polychlorinated biphenyls (PCBs), p,p'- DDE, hexachlorobenzene (HCB), perfluorinated chemicals (PFCs), bisphenol-A (BPA) and tetrabromobisphenol-A (TBBPA). Given the elevated rates of some cancers in firefighters and general concern about firefighter health, it is important to understand the significance of these findings. While it is not certain that the PBDEs can survive a fire and end up posing a potential exposure to firefighters as suggested by Shaw et al. (2013), halogenated dioxins and furans are known products of incomplete combustion. The extent to which the presence of halogenated flame retardants contribute to or accelerate the formation of the dioxins and furans in house fires is not clear. However, a recent report by Zhang et al. (Zhang, Buekens, and Li 2016) shows that an increase in the bromine content of electrical/electronic waste (presumably from flame retardants) is associated with an increase in the presence of halogenated dioxins and furans in the combustion products. They also state that: "Other forms of open burning (landfill fires and accidental fires) are also donors of PBDD/F emissions.' Although not surprising, this evidence will be used to support the general statement often made by opponents of flame retardants that flame retardants make smoke more toxic and that this poses an increased risk to firefighters. The Issue to Address There is widespread agreement that smoke (regardless of the presence of flame retardants) is acutely toxic and may contain numerous chemicals with the potential to cause chronic effects such as cancer. The unanswered question is: "Is smoke/soot from combustion of materials with flame retardants more toxic than smoke/soot from materials without flame retardants? 1 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 For the project being conducted here, we are not concerned with acute toxicity, which is reasonably well understood, but rather chronic effects including cancer. Numerous studies have documented the presence of poly aromatic hydrocarbons as well as polychlorinated and polybrominated dibenzodioxins and dibenzonfurans in smoke from combusted materials. The open question is whether flame retardants enhance the carcinogenicity and chronic toxicity of the already hazardous smoke from a fire. Experimental Approach We combusted four test articles. Smoke condensate was collected during the combustion and wipe samples of soot were collected after combustion. The samples were analyzed for a wide variety of chemicals commonly associated with combustion. The combustion and chemical analysis were performed at Southwest Research Institute (San Antonio, TX). The samples were also sent to Cyprotex Laboratories (Watertown, MA) for evaluation of the biological activity. We chose a battery of vitro assays that could be conducted quickly without the use of live animals. The hypothesis being tested was whether the biological activity of the smoke condensates and soot is identical and whether the combusted materials contain a flame retardant or not. Combustion of Materials and Collection and Analysis of Smoke and Soot In Phase I (Pilot Study), two materials were combusted: High Impact Polystyrene (HIPS) - without flame retardant and with the flame retardants decabromodipdhenylethane and antimony trioxide added. Br Br Br Br Br Br Br Br Br Br Flexible Poly Urethane Foam (PUF) - without flame retardant and with the flame retardant tris(dichloroisopropyl) phosphate (TDCP). 2 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 CI CI o ; +++++++++ CI o CI C CI Combustion took place in a National Bureau of Standards (NBS) smoke chamber at 50 kW/m² radiant energy. A 100 mm x100 mm x <50 mm piece of selected material was pyrolyzed. Smoke opacity was measured using a calibrated light source in the smoke chamber. Samples were collected through the heated sample transfer line (HSTL) at a fixed and measured flow rate and analyzed by Fourier transform infrared spectroscopy (FTIR) in a 2 meter gas cell. The FTIR particulate filter was analyzed for halogens. Samples were also collected through a separate HSTL, fitted with a stainless steel cooling line and cooled solvent impingers, from the chamber at a flow of 1 standard liters/minute (SLPM) over the duration of the burn (30 min). There were two impingers in series, the first impinger filled with DMSO and the second filled with water. Both impingers were chilled in a 0°C cold bath. The stainless steel cooled sample line was rinsed with dimethyl sulfoxide (DMSO) and rinsate added to the DMSO impinger solvent and mass measured of total solvent. A second wash with water was performed and the two rinsates added together and the total mass measured. Soot was collected from the inside surfaces of the smoke chamber by use of latex wipes. The DMSO and water rinsates as well as extracts from the wipes used to collect the soot were combined for each pyrolysis experiment and the combined materials were used for the characterization of biological activity (described below). Samples were frozen at a temperature of - -70°C and shipped overnight on dry ice to the biological testing laboratory. Note: All collection materials (such as the wipes, solvents and containers) were confirmed prior to use not to have been contaminated with any known FR by analysis of quality blanks. Results Chemical Analysis of Samples The comprehensive chemical analysis of the samples included: 3 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 A screen for over 200 volatile and semi-volatile target compounds in EPA method TO-15 (Target Compounds). In addition, any peak showing an area count greater than 1% of the sample was also tentatively identified (referred to as a Tentatively Identified Compound - TIC) and a semi-quantitative analysis was also performed; An array of both brominated and chlorinated dioxins and dibenzofurans. Note: Analytical difficulties beset the analysis of brominated dioxins and dibenzofurans. Thus, those data are not reported. Target Compounds Diethylphthalate was detected in approximately equal concentrations from both non-FR and FR HIPS samples. Other than benzoic acid (in DMSO samples from polyurethane foam (PUF) with FR), no other target chemicals were detected. In contrast to flexible PUF, numerous target compounds were detected from the combustion of HIPS. Although the FR and non-FR versions of HIPS produced some of the above chemicals, more such individual chemicals were produced in the presence of FR (Table 1). Moreover, for the chemicals detected in both FR and non-FR samples, concentrations were generally higher in the FR-containing samples. Nonetheless, this does not suggest that these differences are toxicologically significant. Table 1: Target Compounds - HIPS with and without FR FRI IIIPS HIPS 1 FRJ HIPS HIPS Impinger Impinger Rasio Impinger Impinger Raties DI 1120 DE 1120 FR/Non FR DMSO DAISO FR/Non FR Name (ug/l) (mg/l.) ND ND 26.2 ND 19.1 NO 46,7 13.4 3,5 76 23.3 3.3 160 56.8 3.8 39.6 20.4 1.9 89 56 135 50.6 2.7 377 146 1.9 26.6 ND 58.4 33.4 1.7 33 ND 28.6 23.5 1.3 Acid 37.6 NO 109 67.3 1.6 13.8 17.4 0.8 ND ND 319 29.3 7.3 429 78.1 5.5 43.6 ND 91,7 34,5 2.7 ND ND 14 ND 31.6 28.9 1.1 33 35.6 0.9 ND ND 38.5 ND 107 13,7 7.8 220 40 3,5 18.4 ND 50.6 18.5 2.7 ryyrene 87.8 19.3 4,6 195 56.1 3.5 (Naphthalene 20.7 NO NO ND 204 26.3 7,8 446 5.0 Pyreme 41.1 ND 80.5 22.4 3.6 TOTAL como (ug/L) 1142.00 229,78 5.0 171.60 3.1 Tentatively Identified Compounds (TIC) TDCP was detected in samples from the combustion products from both flexible PUF samples. No TIC were detected in the samples collected in water. 4 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Table 2: Tentatively Identified Compounds - PUF with and without FR Tentativa compounds in Flexible PUF: DMSO Impinger and Wipe Samples Concentration in pg/l. Compound Name CAS # Flexible PUF FR Flexible PUF Trist 13674-87-8 536 1210 For HIPS, significantly more individual TICs were identified in the FR-containing material (Tables 3, 4). For the chemicals detected in both FR and non-FR samples; concentrations were generally higher in the FR-containing samples. As with the target compounds, it is not possible to make inferences about the toxicological significance of these results. Unexpectedly, TDCP was detected in samples from the combustion products from both HIPS samples. The source of the contamination is uncertain, although it can most likely be attributed to the experimental and sampling set up. In the future, special attention will be paid to scrupulously clean the apparatus to eliminate such confounding results. Table 3: Tentatively Identified Compounds - HIPS with and without FR (water collection) Tentative compounds in HIPS: DI Water Impinger and Wipe Samples Concentration in pg/L Compound Name HIPS I FRI HIPS 1-Propente, 22.4 686 58.4 528 Naphthalene, 2-phenyl- ND 464 ND 249 ND 144 Naphthalene, -pheny)- ND 128 Heracnemethanamine, 225 46.6 Bennene, ND 90.6 glycal in DMSO Finit 62.7 85.2 Pyrene, 1-phenyl- ND 85.2 4: Tentatively Identified Compounds - HIPS with and without FR (DMSO collection) Tentative compounds in HIPS: DMSO Impinger and Wipe Samples Concentration in mg/l. Compound Name HIPS 1 FR3 HIPS Tris(1,3-dichloroisopropyi)phosphatel 788 ND ND 1280 1,17:3', ND 1160 Naphthalene, ND 912 ND 779 5 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Chlorinated Dioxins and Benzofurans For the Flexible PUF, only 3 of the 50 samples analyzed showed detectable levels of the analytes (data not presented). All values were below the Limit of Quantitation (LOQ). In contrast to the flexible PUF, many more individual chlorinated dioxins and furans were reported, most of them below the Limit of Quantitation (LOQ). Nonetheless, the total amounts of chlorinated dioxins and furans (collected in either water or DMSO) were essentially identical between FR and non-FR samples. Table 5 Chlorinated Dioxins and Benzofurans from HIPS with and without FR HIPS (blank cells are non-detects) Chiorinated Dinxins and in HIPS: DI Water Cblorinated Dioxins and Furans in HIPS: DMSO Impinger and Wipe Samples Impinges and Wipe Samples Concentration in us/T. Concentración in ug/L Compound Name HIPS 1 FR3 HIPS Compowad Name IIIPS 1 FR3 HIPS 2,3,7,8-TCDO 2,3,7,8-TCDD 1,2,3,7,8-PeCOD 1,2,3,7,8-PeCDD 1,2,3,4,7,8-MxCDD 1,2,3,4,7,8-HxCDO 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDO 1,2,3,7,8,9-HxCOD 1,2,3,4,6,7,8-HpC00 1,2,3,4,6,7,8-HpC00 OCDO OCDO 2,3,7,8-TCDF 1.05 1.2 2,3,7,8-TCDF 2.39 3.59 1,2,3,7,8-PeCDF -LOQ 1,2,3,7,8-PeCOF -LOQ 2,3,4,7,8-PeCOF 2,3,4,7,8-PeCDF HLOC 1,2,3,4,7,8-HxCDF <LOQ <LOQ 1,2,3,4,7,8-HxCDF KLOC <LOQ 1,2,3,6,7,8-HxCOF 1,2,3,6,7,8-HxCDF -LOQ 1,2,3,7,8,9-HxCOF 1,2,3,7,8,9-HxCDF 2,3,4,6,7,8-14xCDF <LOQ 1,2,3,4,6,7,8-HpCOF <LOQ 1,2,3,4,6,7,&-HpCDF <LOQ 1,2,3,4,7,8,9-HpCDF 1,2,3,4,7,8,9-HpCOF OCDF OCDF Total Tetra-Dioxins 0.838 Total Tetra-Dioxins 2.21 Total Penta-Diaxins Total Penta-Dioxins KLOC <LOC Total Hexa-Dioxins Total Hexa-Dioxins <LOQ Total Hepta-Dioxins Total Hepta-Dioxins LOQ Total Tetra-Furans 3.18 5.42 Total Tetra-Furans 12.9 22.1 Total Penta-Furans 3.41 2.46 Total Penta-Furans 7.97 9.66 Total Hexa-Furans <LOQ <LOQ Total Hexa-Furans 2.38 2.79 Total Hepta-Furans CLOQ Total Hepta-Furans 4,00 -LOQ Total a dioxins and furans 7.428 7.88 Total a dioxins and furans 25.46 34,55 No Change Decrease with FR (either >2X reduction or going to a non-detett) Increase with FR (>2X increase) 6 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Assessment of Biological Activity (Cyrprotex Labortories) Genotoxicity In Vitro Micronucleus Screen (MNT) None of the test articles exhibited genotoxicity in the absence or presence of S9 metabolic activation. Ames Genotoxicity Screen (two test strains) No genotoxicity was observed for any of the test articles. Note: we ran Cyprotex's most popular option for non-GLP testing ("mini-Ames"). The two bacterial strains used allow for detection of two of the most common mutations (i.e. frame-shift mutations with strain TA98, and base-pair substitutions with strain TA100). Assessment of Indicators of General Toxicity CellCiphr TM Premier Tox Profiling CellCiphrTM was the Cellular Systems Biology approach used to screen compounds for broad-ranging toxic effects using tissue-specific cell models. The CellCiphrTM Profiling used a combination of toxicity-relevant cells and toxicity biomarkers to monitor the effects of test compounds on many cellular systems responses known to be correlated with toxic challenge. These were surveyed using primary rat hepatocytes (metabolically competent) and the HepG2 (human) cell line, to take advantage of the specific biology present in these cell types and the toxicity endpoints associated with them. The smoke condensate samples were profiled in an expanded CellCiphrTM panel which includes both HepG2 and primary rat hepatocytes at two time points. It also included a Glutathione assay, ROS assay and a 5-day toxicity assay in rat hepatocytes. A combined 21 toxicity endpoints at multiple time points were measured to create the CellCiphrTM profile (38 total measured endpoints). The output (when applicable) included the maximum tolerated dose, AC50 curves and rank order and safety risks for prioritization. A summary of the results is below in Table 6. 7 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Table 6: Summary of CellCiphr Results - 0 NH Foam FR Ras O NO C : 049 1.08 (10% 1% Rat : * CA 31 : 1.29 07% 1% HepG2 8 72h NS : 1.10 (22% Mat 3 400 MIMIP : 0.00 (91% 1 0.5% C NO Riank Rat e NR C NR Rai o NR * 8 3 de - * The - - - - Res - No responses were see with the blank (as expected), PUF, and PUF with FR samples. Minimal responses were observed for HIPS and HIPS with FR. The responses are such that the effect of FR in either of the samples could not be distinguished. It is possible that this is a true reflection of the properties of the samples. But, more likely, the test samples may have been too diluted to produce a significant response. This is also suggested by the fact that, for several endpoints, the concentration-response curves began to develop at the highest concentrations (Figure 1). Figure 1: Representative Concentration-Response Curves Showing Apparent Onset of Effect at High Concentrations 48h 72h S a 2 2 18 8 & $ : * * & * $ 83 ses 8.8 : 0.00 88 (%) a ACA 31% 3° 0,778 No MEC MIN 8 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Biological Indicators of Presence of Dioxins and Dibenzofurans Dioxins and furans have been shown to be carcinogenic, immunotoxic, and toxic to reproduction in various animal models. The Adverse Outcome Pathway for these effects begins with their high affinity binding of the chemical to the Aryl Hydrocarbon Receptor (AhR). Subsequent translocation of the complex into the nucleus of the cell, dimerization of the AhR with the AhR nuclear translocator (Arnt) protein, and binding of the ligand:AhR:1 complex to its DNA recognition sequence leads to increased transcription and translation of certain genes, including that of cytochrome P4501A1 (CYP1A1). All dioxin-like compounds are assumed to act through this AhR signal transduction pathway. The test system we used consisted of transformed tumor cells plated on 96-well microtiter plates. An expression vector harboring human AhR plus the appropriate enhancers and promoters linked to the luciferase reporter gene have been integrated into the tumor cells. Receptor activation was assessed by monitoring reporter gene activity, and by comparing the results to vehicle-treated cells. The results were reported as the fold increase in transcriptional activation of AhR above vehicle control for each test article. Foam FR, HIPS, and HIPS FR exhibited levels of AhR induction of approximately 5, 7, and 9-fold, respectively. The levels of activation for both HIPS and Flexible PUF correspond to less than 20% of the positive control compound (3- methylcholanthrene, at 10 M) as shown in Figures 2 and 3, respectively. Cyprotex, the testing laboratory, indicated that for drug discovery screening programs, they typically flag compounds that show >40% induction relative to the positive control. The maximum level of induction we observed could therefore be considered modest by such screening criteria standards. Thus, although there is an apparent increase in Ah Receptor activity in FR-containing samples but, because of the relatively low response, it is not possible to assess the toxicological significance, if any of these observations. 9 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Figure 2: Ah Receptor Activation - HIPS with and without FR Ah Receptor Activity HIPS HIPS FR 100 80 60 40 16 20 8 9 12 1 1 2 2 4 4 6 6 - 0 - 0.03125 0.0625 0.125 0.25 0,5 1 Test Concentration Range (%) Figure 3: Ah Receptor Activation - Flexible PUF with and without FR Ah Receptor Actvity Flexible PUF Plexible POF FR 100 90 80 70 60 50 40 30 20 011 3 5 8 10 0 0 0 0 0 1 3 0 asse 0.03125 0.0625 0.125 0,25 0.5 1 Test Concentration Range (%) 10 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Summary of Pilot Study and Future Needs No indication of adverse responses, but data are inconclusive due to need to optimize concentration of samples being tested; Sample collection and preparation needs to be revised to provide more concentrated sample for both analytical characterization and biological testing; Extra efforts will be undertaken to avoid contamination with FRs from other sources. Recommendations for Follow-up The pilot study provided important insight to steps we need to take to maximize the robustness of this program. In addition to the sampling and sample preparation (concentrating of samples) discussed above, we recommend moving from the CellCiphrTM assay to ToxTracker by Toxys. Why move to the Toxys System? Cells Used: Cyprotex uses HepG2 cells which are immortal human liver carcinoma line as well as rat hepatocytes. That is fine, but the stems cells used by Toxys are better, as they are less organ specific; Experience with Lipophilic Molecules: CellCiphrTM system has primarily been used for relatively water-soluble pharmaceuticals and not complex mixtures like we are dealing with. The Toxys system has been used with lipophilic mixtures as in the petroleum-related project; Regulatory Utility: The system is undergoing validation for screening for carcinogenicity be the European Union; ToxTracker generally predicts very well (>90%) the outcome of the standard battery of GLP in vitro genotoxicity (Ames, Mouse Lymphoma Assay, Micronucleus - In vitro, Chromosome aberrations). Proposed Project This is essentially a repeat of the pilot project with the same test articles (plus red oak). In contrast to the pilot study: Sampling volume and handling will be modified to produce a more concentrated sample to be sure that we are well within the dynamic range of the assays; Because of the special focus that Toxys has on carcinogenesis (by several modes of action - genotoxic and non-genotoxic), we will not run the Ames nor the micronucleus assays. We will still run the Ah Receptor assay as a sensitive biological indicator of halogenated dioxins and furans. 11 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Budget: For 5 Test Articles - Phase 18 (definitive) Assay $/test Article Total Cost Combustion set up and collection 3,000 15,000 Analytical chemistry on the above 2,600 13,000 Cell Tracker 3,000 15,000 Ah Receptor 800 4,000 Subtotal Laboratory Costs 47,000 *Study management and oversight (0.2) 9,400 Total Project Cost 56,400 *Science Strategies Timing: Toxys offers a one week turnaround, depending upon availability. 12 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 References Shaw, S. D., M. L. Berger, J. H. Harris, S. H. Yun, Q. Wu, C. Liao, A. Blum, A. Stefani, and K. Kannan. 2013. 'Persistent organic pollutants including polychlorinated and polybrominated dibenzo-p-dioxins and dibenzofurans in firefighters from Northern California', Chemosphere, 91: 1386-94. Zhang, M., A. Buekens, and X. Li. 2016. 'Brominated flame retardants and the formation of dioxins and furans in fires and combustion', J Hazard Mater, 304: 26-39. 13 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226

What is the Total Project Cost?

mxcn0226

mxcn0226_p0, mxcn0226_p1, mxcn0226_p2, mxcn0226_p3, mxcn0226_p4, mxcn0226_p5, mxcn0226_p6, mxcn0226_p7, mxcn0226_p8, mxcn0226_p9, mxcn0226_p10, mxcn0226_p11, mxcn0226_p12, mxcn0226_p13, mxcn0226_p14, mxcn0226_p15

56,400

202 From: Erraguntla, Neeraja To: White. Kimberly; Admon. Smadar: Anderson Steven; Batoon Audrey; Bradley, Kevin: de Lacy Catharine; Elkan, Han; Goodman. Bryan; Hochschwender. Lane Jacobi Svlvia. B: Kannah. Kasturirangan; Levan, Steve: Levchik, Sergei; Little, Barbara; Manor. Orit: Prero. Judab; Rothenbacher. Klaus; Saunders Eric L.; Scherrer, Steve: Simon. Robert; Tavior. Jennifer: Tenney, Joel; Thorn, Amelia: West Jay; Hayes, A. Wallace; Rein. Guillermo; info@sroitzsch.com Troitzsch, Jurgen; Blais, Matthew; Dourson. Michael (doursomi); Kacew Sam; Osimitz, Thomas Cc: Erraguntia. Neeraia Subject: RE: Clarification -Updated Smoke Toxicity Proposal -SAC May 2017 - Meeting Materials Date: Tuesday, May 16, 2017 11:11:42 AM Attachments: Update - Smoke Toxicity Project - April 2017 to NAFRA. pdf Re-sending the proposal to follow Tom's discussion on Smoke toxicity right now at the SAC mtg on May 16. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT| American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE Washington, DC | 20002 O: (202) 249-6712 C (202) 779-0524 www.americanchemistry.com From: Erraguntla, Neeraja Sent: Tuesday, May 16, 2017 9:08 AM To: White, Kimberly; Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com; Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmail.uc.edu); Kacew, Sam; Osimitz, Thomas Cc: Erraguntla, Neeraja Subject: RE: Clarification - -Updated Smoke Toxicity Proposal - -SAC May 2017 - Meeting Materials Dear All, Tom provided additional clarification on the updated smoke toxicity proposal. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE I Washington, DC I 20002 O: (202) 249-6712 C: (202)779-0524 www.americanchemistry.com Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 203 From: Erraguntla, Neeraja Sent: Sunday, May 14, 2017 4:38 PM To: White, Kimberly; Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmailuc.edu); Kacew, Sam; Osimitz, Thomas Subject: RE: Updated Smoke Toxicity Proposal -SAC May 2017 - Meeting Materials Dear All, Please see the attached Updated Smoke Toxicity Proposal from Tom for consideration and action at the SAC meeting this week. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE Washington DO I 20002 O: (202) 249-6712 C: (202) 779-0524 www.americanchemistry.cor From: White, Kimberly Sent: Tuesday, May 9, 2017 5:28 PM To: Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Erraguntla, Neeraja; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; White, Kimberly; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com; Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmailuc.edu); Kacew, Sam; Osimitz, Thomas Subject: SAC May 2017 - Meeting Materials Dear NAFRA, BSEF and SAC members: In preparation for the May 16th-17th SAC meeting, attached are associated meeting materials. Hard copies will also be available onsite. In addition to the attached materials, we also anticipate additional information on the dermal exposure project, the smoke toxicity project and the baby monitor combustion project to be disseminated in the coming days. Below are general meeting logistics. General Logistics Meeting Dates/Times: May 16, 2017 (Meeting from 9:00 a.m. -5:00 p.m. ET) May 17, 2017 ( Meeting from 9:00 a.m. -2:00 p.m. ET) Meeting/Hotel Location: DoubleTree by Hilton Hotel Metropolitan -New York City, 569 Lexington Avenue, New York, New York 10022 Dinner on May 15, 2017 at 6:30pm (ET) - The Modern; Address: 9 W 53rd St. New York, NY 10019 Dinner on May 16, 2017 at 6:30pm (ET) Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 204 SAC Members Only - The Smith; Address: 956 2nd Ave, New York, NY 10022 NAFRA/ BSEF Members Only - Mitae: Address: 4 East 46th Street, New York, NY 10017 I look forward to seeing everyone next week and feel free to contact me if you have any questions. Kind Regards, Kimberly Wise White, Ph.I D. | American Chemistry Council Senior Director, Chemical Products & Technology Division Kimberly Whitelamericanchemistry.com 700 2nd Street NE Washington, DC | 20002 O: (202) 249-6707 C: (202) 341-7602 www.americanchemistry.com + This message may contain confidential information and is intended only for the individual named. If you are not the named addressee do not disseminate, distribute or copy this email. Please notify the sender immediately by email if you have received this email by mistake and delete this email from your system. E-mail transmission cannot be guaranteed to be secure or error-free as information could be intercepted, corrupted, lost, destroyed, arrive late or incomplete, or contain viruses. The sender therefore does not accept liability for any errors or omissions in the contents of this message which arise as a result of email transmission. American Chemistry Council, 700 - 2nd Street NE, Washington, DC 20002, www.americanchemistry.com Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Relative Toxicity of Combustion Products from Various Materials Effect of Flame Retardants T.G. Osimitz (Science Strategies) and M.S. Blais (Southwest Research Institute) April 18, 2017 Background Recent studies haves shown the presence of flame retardants (esp. polybrominated diphenyl ethers (PBDEs)) and/or possible flame retardant (FR) combustion products (halogenated dioxins and furans), and other polyaromatic hydrocarbons (PAHs) in the serum of firefighters and/or on their clothing (Shaw et al. 2013). In their study, polychlorinated and polybrominated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs and PBDD/Fs) were measured in the serum of twelve firefighters sampled after a fire event in San Francisco, California, along with PBDEs, polychlorinated biphenyls (PCBs), p,p'- DDE, hexachlorobenzene (HCB), perfluorinated chemicals (PFCs), bisphenol-A (BPA) and tetrabromobisphenol-A (TBBPA). Given the elevated rates of some cancers in firefighters and general concern about firefighter health, it is important to understand the significance of these findings. While it is not certain that the PBDEs can survive a fire and end up posing a potential exposure to firefighters as suggested by Shaw et al. (2013), halogenated dioxins and furans are known products of incomplete combustion. The extent to which the presence of halogenated flame retardants contribute to or accelerate the formation of the dioxins and furans in house fires is not clear. However, a recent report by Zhang et al. (Zhang, Buekens, and Li 2016) shows that an increase in the bromine content of electrical/electronic waste (presumably from flame retardants) is associated with an increase in the presence of halogenated dioxins and furans in the combustion products. They also state that: "Other forms of open burning (landfill fires and accidental fires) are also donors of PBDD/F emissions.' Although not surprising, this evidence will be used to support the general statement often made by opponents of flame retardants that flame retardants make smoke more toxic and that this poses an increased risk to firefighters. The Issue to Address There is widespread agreement that smoke (regardless of the presence of flame retardants) is acutely toxic and may contain numerous chemicals with the potential to cause chronic effects such as cancer. The unanswered question is: "Is smoke/soot from combustion of materials with flame retardants more toxic than smoke/soot from materials without flame retardants? 1 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 For the project being conducted here, we are not concerned with acute toxicity, which is reasonably well understood, but rather chronic effects including cancer. Numerous studies have documented the presence of poly aromatic hydrocarbons as well as polychlorinated and polybrominated dibenzodioxins and dibenzonfurans in smoke from combusted materials. The open question is whether flame retardants enhance the carcinogenicity and chronic toxicity of the already hazardous smoke from a fire. Experimental Approach We combusted four test articles. Smoke condensate was collected during the combustion and wipe samples of soot were collected after combustion. The samples were analyzed for a wide variety of chemicals commonly associated with combustion. The combustion and chemical analysis were performed at Southwest Research Institute (San Antonio, TX). The samples were also sent to Cyprotex Laboratories (Watertown, MA) for evaluation of the biological activity. We chose a battery of vitro assays that could be conducted quickly without the use of live animals. The hypothesis being tested was whether the biological activity of the smoke condensates and soot is identical and whether the combusted materials contain a flame retardant or not. Combustion of Materials and Collection and Analysis of Smoke and Soot In Phase I (Pilot Study), two materials were combusted: High Impact Polystyrene (HIPS) - without flame retardant and with the flame retardants decabromodipdhenylethane and antimony trioxide added. Br Br Br Br Br Br Br Br Br Br Flexible Poly Urethane Foam (PUF) - without flame retardant and with the flame retardant tris(dichloroisopropyl) phosphate (TDCP). 2 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 CI CI o ; +++++++++ CI o CI C CI Combustion took place in a National Bureau of Standards (NBS) smoke chamber at 50 kW/m² radiant energy. A 100 mm x100 mm x <50 mm piece of selected material was pyrolyzed. Smoke opacity was measured using a calibrated light source in the smoke chamber. Samples were collected through the heated sample transfer line (HSTL) at a fixed and measured flow rate and analyzed by Fourier transform infrared spectroscopy (FTIR) in a 2 meter gas cell. The FTIR particulate filter was analyzed for halogens. Samples were also collected through a separate HSTL, fitted with a stainless steel cooling line and cooled solvent impingers, from the chamber at a flow of 1 standard liters/minute (SLPM) over the duration of the burn (30 min). There were two impingers in series, the first impinger filled with DMSO and the second filled with water. Both impingers were chilled in a 0°C cold bath. The stainless steel cooled sample line was rinsed with dimethyl sulfoxide (DMSO) and rinsate added to the DMSO impinger solvent and mass measured of total solvent. A second wash with water was performed and the two rinsates added together and the total mass measured. Soot was collected from the inside surfaces of the smoke chamber by use of latex wipes. The DMSO and water rinsates as well as extracts from the wipes used to collect the soot were combined for each pyrolysis experiment and the combined materials were used for the characterization of biological activity (described below). Samples were frozen at a temperature of - -70°C and shipped overnight on dry ice to the biological testing laboratory. Note: All collection materials (such as the wipes, solvents and containers) were confirmed prior to use not to have been contaminated with any known FR by analysis of quality blanks. Results Chemical Analysis of Samples The comprehensive chemical analysis of the samples included: 3 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 A screen for over 200 volatile and semi-volatile target compounds in EPA method TO-15 (Target Compounds). In addition, any peak showing an area count greater than 1% of the sample was also tentatively identified (referred to as a Tentatively Identified Compound - TIC) and a semi-quantitative analysis was also performed; An array of both brominated and chlorinated dioxins and dibenzofurans. Note: Analytical difficulties beset the analysis of brominated dioxins and dibenzofurans. Thus, those data are not reported. Target Compounds Diethylphthalate was detected in approximately equal concentrations from both non-FR and FR HIPS samples. Other than benzoic acid (in DMSO samples from polyurethane foam (PUF) with FR), no other target chemicals were detected. In contrast to flexible PUF, numerous target compounds were detected from the combustion of HIPS. Although the FR and non-FR versions of HIPS produced some of the above chemicals, more such individual chemicals were produced in the presence of FR (Table 1). Moreover, for the chemicals detected in both FR and non-FR samples, concentrations were generally higher in the FR-containing samples. Nonetheless, this does not suggest that these differences are toxicologically significant. Table 1: Target Compounds - HIPS with and without FR FRI IIIPS HIPS 1 FRJ HIPS HIPS Impinger Impinger Rasio Impinger Impinger Raties DI 1120 DE 1120 FR/Non FR DMSO DAISO FR/Non FR Name (ug/l) (mg/l.) ND ND 26.2 ND 19.1 NO 46,7 13.4 3,5 76 23.3 3.3 160 56.8 3.8 39.6 20.4 1.9 89 56 135 50.6 2.7 377 146 1.9 26.6 ND 58.4 33.4 1.7 33 ND 28.6 23.5 1.3 Acid 37.6 NO 109 67.3 1.6 13.8 17.4 0.8 ND ND 319 29.3 7.3 429 78.1 5.5 43.6 ND 91,7 34,5 2.7 ND ND 14 ND 31.6 28.9 1.1 33 35.6 0.9 ND ND 38.5 ND 107 13,7 7.8 220 40 3,5 18.4 ND 50.6 18.5 2.7 ryyrene 87.8 19.3 4,6 195 56.1 3.5 (Naphthalene 20.7 NO NO ND 204 26.3 7,8 446 5.0 Pyreme 41.1 ND 80.5 22.4 3.6 TOTAL como (ug/L) 1142.00 229,78 5.0 171.60 3.1 Tentatively Identified Compounds (TIC) TDCP was detected in samples from the combustion products from both flexible PUF samples. No TIC were detected in the samples collected in water. 4 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Table 2: Tentatively Identified Compounds - PUF with and without FR Tentativa compounds in Flexible PUF: DMSO Impinger and Wipe Samples Concentration in pg/l. Compound Name CAS # Flexible PUF FR Flexible PUF Trist 13674-87-8 536 1210 For HIPS, significantly more individual TICs were identified in the FR-containing material (Tables 3, 4). For the chemicals detected in both FR and non-FR samples; concentrations were generally higher in the FR-containing samples. As with the target compounds, it is not possible to make inferences about the toxicological significance of these results. Unexpectedly, TDCP was detected in samples from the combustion products from both HIPS samples. The source of the contamination is uncertain, although it can most likely be attributed to the experimental and sampling set up. In the future, special attention will be paid to scrupulously clean the apparatus to eliminate such confounding results. Table 3: Tentatively Identified Compounds - HIPS with and without FR (water collection) Tentative compounds in HIPS: DI Water Impinger and Wipe Samples Concentration in pg/L Compound Name HIPS I FRI HIPS 1-Propente, 22.4 686 58.4 528 Naphthalene, 2-phenyl- ND 464 ND 249 ND 144 Naphthalene, -pheny)- ND 128 Heracnemethanamine, 225 46.6 Bennene, ND 90.6 glycal in DMSO Finit 62.7 85.2 Pyrene, 1-phenyl- ND 85.2 4: Tentatively Identified Compounds - HIPS with and without FR (DMSO collection) Tentative compounds in HIPS: DMSO Impinger and Wipe Samples Concentration in mg/l. Compound Name HIPS 1 FR3 HIPS Tris(1,3-dichloroisopropyi)phosphatel 788 ND ND 1280 1,17:3', ND 1160 Naphthalene, ND 912 ND 779 5 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Chlorinated Dioxins and Benzofurans For the Flexible PUF, only 3 of the 50 samples analyzed showed detectable levels of the analytes (data not presented). All values were below the Limit of Quantitation (LOQ). In contrast to the flexible PUF, many more individual chlorinated dioxins and furans were reported, most of them below the Limit of Quantitation (LOQ). Nonetheless, the total amounts of chlorinated dioxins and furans (collected in either water or DMSO) were essentially identical between FR and non-FR samples. Table 5 Chlorinated Dioxins and Benzofurans from HIPS with and without FR HIPS (blank cells are non-detects) Chiorinated Dinxins and in HIPS: DI Water Cblorinated Dioxins and Furans in HIPS: DMSO Impinger and Wipe Samples Impinges and Wipe Samples Concentration in us/T. Concentración in ug/L Compound Name HIPS 1 FR3 HIPS Compowad Name IIIPS 1 FR3 HIPS 2,3,7,8-TCDO 2,3,7,8-TCDD 1,2,3,7,8-PeCOD 1,2,3,7,8-PeCDD 1,2,3,4,7,8-MxCDD 1,2,3,4,7,8-HxCDO 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDO 1,2,3,7,8,9-HxCOD 1,2,3,4,6,7,8-HpC00 1,2,3,4,6,7,8-HpC00 OCDO OCDO 2,3,7,8-TCDF 1.05 1.2 2,3,7,8-TCDF 2.39 3.59 1,2,3,7,8-PeCDF -LOQ 1,2,3,7,8-PeCOF -LOQ 2,3,4,7,8-PeCOF 2,3,4,7,8-PeCDF HLOC 1,2,3,4,7,8-HxCDF <LOQ <LOQ 1,2,3,4,7,8-HxCDF KLOC <LOQ 1,2,3,6,7,8-HxCOF 1,2,3,6,7,8-HxCDF -LOQ 1,2,3,7,8,9-HxCOF 1,2,3,7,8,9-HxCDF 2,3,4,6,7,8-14xCDF <LOQ 1,2,3,4,6,7,8-HpCOF <LOQ 1,2,3,4,6,7,&-HpCDF <LOQ 1,2,3,4,7,8,9-HpCDF 1,2,3,4,7,8,9-HpCOF OCDF OCDF Total Tetra-Dioxins 0.838 Total Tetra-Dioxins 2.21 Total Penta-Diaxins Total Penta-Dioxins KLOC <LOC Total Hexa-Dioxins Total Hexa-Dioxins <LOQ Total Hepta-Dioxins Total Hepta-Dioxins LOQ Total Tetra-Furans 3.18 5.42 Total Tetra-Furans 12.9 22.1 Total Penta-Furans 3.41 2.46 Total Penta-Furans 7.97 9.66 Total Hexa-Furans <LOQ <LOQ Total Hexa-Furans 2.38 2.79 Total Hepta-Furans CLOQ Total Hepta-Furans 4,00 -LOQ Total a dioxins and furans 7.428 7.88 Total a dioxins and furans 25.46 34,55 No Change Decrease with FR (either >2X reduction or going to a non-detett) Increase with FR (>2X increase) 6 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Assessment of Biological Activity (Cyrprotex Labortories) Genotoxicity In Vitro Micronucleus Screen (MNT) None of the test articles exhibited genotoxicity in the absence or presence of S9 metabolic activation. Ames Genotoxicity Screen (two test strains) No genotoxicity was observed for any of the test articles. Note: we ran Cyprotex's most popular option for non-GLP testing ("mini-Ames"). The two bacterial strains used allow for detection of two of the most common mutations (i.e. frame-shift mutations with strain TA98, and base-pair substitutions with strain TA100). Assessment of Indicators of General Toxicity CellCiphr TM Premier Tox Profiling CellCiphrTM was the Cellular Systems Biology approach used to screen compounds for broad-ranging toxic effects using tissue-specific cell models. The CellCiphrTM Profiling used a combination of toxicity-relevant cells and toxicity biomarkers to monitor the effects of test compounds on many cellular systems responses known to be correlated with toxic challenge. These were surveyed using primary rat hepatocytes (metabolically competent) and the HepG2 (human) cell line, to take advantage of the specific biology present in these cell types and the toxicity endpoints associated with them. The smoke condensate samples were profiled in an expanded CellCiphrTM panel which includes both HepG2 and primary rat hepatocytes at two time points. It also included a Glutathione assay, ROS assay and a 5-day toxicity assay in rat hepatocytes. A combined 21 toxicity endpoints at multiple time points were measured to create the CellCiphrTM profile (38 total measured endpoints). The output (when applicable) included the maximum tolerated dose, AC50 curves and rank order and safety risks for prioritization. A summary of the results is below in Table 6. 7 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Table 6: Summary of CellCiphr Results - 0 NH Foam FR Ras O NO C : 049 1.08 (10% 1% Rat : * CA 31 : 1.29 07% 1% HepG2 8 72h NS : 1.10 (22% Mat 3 400 MIMIP : 0.00 (91% 1 0.5% C NO Riank Rat e NR C NR Rai o NR * 8 3 de - * The - - - - Res - No responses were see with the blank (as expected), PUF, and PUF with FR samples. Minimal responses were observed for HIPS and HIPS with FR. The responses are such that the effect of FR in either of the samples could not be distinguished. It is possible that this is a true reflection of the properties of the samples. But, more likely, the test samples may have been too diluted to produce a significant response. This is also suggested by the fact that, for several endpoints, the concentration-response curves began to develop at the highest concentrations (Figure 1). Figure 1: Representative Concentration-Response Curves Showing Apparent Onset of Effect at High Concentrations 48h 72h S a 2 2 18 8 & $ : * * & * $ 83 ses 8.8 : 0.00 88 (%) a ACA 31% 3° 0,778 No MEC MIN 8 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Biological Indicators of Presence of Dioxins and Dibenzofurans Dioxins and furans have been shown to be carcinogenic, immunotoxic, and toxic to reproduction in various animal models. The Adverse Outcome Pathway for these effects begins with their high affinity binding of the chemical to the Aryl Hydrocarbon Receptor (AhR). Subsequent translocation of the complex into the nucleus of the cell, dimerization of the AhR with the AhR nuclear translocator (Arnt) protein, and binding of the ligand:AhR:1 complex to its DNA recognition sequence leads to increased transcription and translation of certain genes, including that of cytochrome P4501A1 (CYP1A1). All dioxin-like compounds are assumed to act through this AhR signal transduction pathway. The test system we used consisted of transformed tumor cells plated on 96-well microtiter plates. An expression vector harboring human AhR plus the appropriate enhancers and promoters linked to the luciferase reporter gene have been integrated into the tumor cells. Receptor activation was assessed by monitoring reporter gene activity, and by comparing the results to vehicle-treated cells. The results were reported as the fold increase in transcriptional activation of AhR above vehicle control for each test article. Foam FR, HIPS, and HIPS FR exhibited levels of AhR induction of approximately 5, 7, and 9-fold, respectively. The levels of activation for both HIPS and Flexible PUF correspond to less than 20% of the positive control compound (3- methylcholanthrene, at 10 M) as shown in Figures 2 and 3, respectively. Cyprotex, the testing laboratory, indicated that for drug discovery screening programs, they typically flag compounds that show >40% induction relative to the positive control. The maximum level of induction we observed could therefore be considered modest by such screening criteria standards. Thus, although there is an apparent increase in Ah Receptor activity in FR-containing samples but, because of the relatively low response, it is not possible to assess the toxicological significance, if any of these observations. 9 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Figure 2: Ah Receptor Activation - HIPS with and without FR Ah Receptor Activity HIPS HIPS FR 100 80 60 40 16 20 8 9 12 1 1 2 2 4 4 6 6 - 0 - 0.03125 0.0625 0.125 0.25 0,5 1 Test Concentration Range (%) Figure 3: Ah Receptor Activation - Flexible PUF with and without FR Ah Receptor Actvity Flexible PUF Plexible POF FR 100 90 80 70 60 50 40 30 20 011 3 5 8 10 0 0 0 0 0 1 3 0 asse 0.03125 0.0625 0.125 0,25 0.5 1 Test Concentration Range (%) 10 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Summary of Pilot Study and Future Needs No indication of adverse responses, but data are inconclusive due to need to optimize concentration of samples being tested; Sample collection and preparation needs to be revised to provide more concentrated sample for both analytical characterization and biological testing; Extra efforts will be undertaken to avoid contamination with FRs from other sources. Recommendations for Follow-up The pilot study provided important insight to steps we need to take to maximize the robustness of this program. In addition to the sampling and sample preparation (concentrating of samples) discussed above, we recommend moving from the CellCiphrTM assay to ToxTracker by Toxys. Why move to the Toxys System? Cells Used: Cyprotex uses HepG2 cells which are immortal human liver carcinoma line as well as rat hepatocytes. That is fine, but the stems cells used by Toxys are better, as they are less organ specific; Experience with Lipophilic Molecules: CellCiphrTM system has primarily been used for relatively water-soluble pharmaceuticals and not complex mixtures like we are dealing with. The Toxys system has been used with lipophilic mixtures as in the petroleum-related project; Regulatory Utility: The system is undergoing validation for screening for carcinogenicity be the European Union; ToxTracker generally predicts very well (>90%) the outcome of the standard battery of GLP in vitro genotoxicity (Ames, Mouse Lymphoma Assay, Micronucleus - In vitro, Chromosome aberrations). Proposed Project This is essentially a repeat of the pilot project with the same test articles (plus red oak). In contrast to the pilot study: Sampling volume and handling will be modified to produce a more concentrated sample to be sure that we are well within the dynamic range of the assays; Because of the special focus that Toxys has on carcinogenesis (by several modes of action - genotoxic and non-genotoxic), we will not run the Ames nor the micronucleus assays. We will still run the Ah Receptor assay as a sensitive biological indicator of halogenated dioxins and furans. 11 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Budget: For 5 Test Articles - Phase 18 (definitive) Assay $/test Article Total Cost Combustion set up and collection 3,000 15,000 Analytical chemistry on the above 2,600 13,000 Cell Tracker 3,000 15,000 Ah Receptor 800 4,000 Subtotal Laboratory Costs 47,000 *Study management and oversight (0.2) 9,400 Total Project Cost 56,400 *Science Strategies Timing: Toxys offers a one week turnaround, depending upon availability. 12 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 References Shaw, S. D., M. L. Berger, J. H. Harris, S. H. Yun, Q. Wu, C. Liao, A. Blum, A. Stefani, and K. Kannan. 2013. 'Persistent organic pollutants including polychlorinated and polybrominated dibenzo-p-dioxins and dibenzofurans in firefighters from Northern California', Chemosphere, 91: 1386-94. Zhang, M., A. Buekens, and X. Li. 2016. 'Brominated flame retardants and the formation of dioxins and furans in fires and combustion', J Hazard Mater, 304: 26-39. 13 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226

What is the heading of the budget table?

mxcn0226

mxcn0226_p0, mxcn0226_p1, mxcn0226_p2, mxcn0226_p3, mxcn0226_p4, mxcn0226_p5, mxcn0226_p6, mxcn0226_p7, mxcn0226_p8, mxcn0226_p9, mxcn0226_p10, mxcn0226_p11, mxcn0226_p12, mxcn0226_p13, mxcn0226_p14, mxcn0226_p15

For 5 Test Articles - Phase IB (definitive)

202 From: Erraguntla, Neeraja To: White. Kimberly; Admon. Smadar: Anderson Steven; Batoon Audrey; Bradley, Kevin: de Lacy Catharine; Elkan, Han; Goodman. Bryan; Hochschwender. Lane Jacobi Svlvia. B: Kannah. Kasturirangan; Levan, Steve: Levchik, Sergei; Little, Barbara; Manor. Orit: Prero. Judab; Rothenbacher. Klaus; Saunders Eric L.; Scherrer, Steve: Simon. Robert; Tavior. Jennifer: Tenney, Joel; Thorn, Amelia: West Jay; Hayes, A. Wallace; Rein. Guillermo; info@sroitzsch.com Troitzsch, Jurgen; Blais, Matthew; Dourson. Michael (doursomi); Kacew Sam; Osimitz, Thomas Cc: Erraguntia. Neeraia Subject: RE: Clarification -Updated Smoke Toxicity Proposal -SAC May 2017 - Meeting Materials Date: Tuesday, May 16, 2017 11:11:42 AM Attachments: Update - Smoke Toxicity Project - April 2017 to NAFRA. pdf Re-sending the proposal to follow Tom's discussion on Smoke toxicity right now at the SAC mtg on May 16. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT| American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE Washington, DC | 20002 O: (202) 249-6712 C (202) 779-0524 www.americanchemistry.com From: Erraguntla, Neeraja Sent: Tuesday, May 16, 2017 9:08 AM To: White, Kimberly; Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com; Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmail.uc.edu); Kacew, Sam; Osimitz, Thomas Cc: Erraguntla, Neeraja Subject: RE: Clarification - -Updated Smoke Toxicity Proposal - -SAC May 2017 - Meeting Materials Dear All, Tom provided additional clarification on the updated smoke toxicity proposal. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE I Washington, DC I 20002 O: (202) 249-6712 C: (202)779-0524 www.americanchemistry.com Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 203 From: Erraguntla, Neeraja Sent: Sunday, May 14, 2017 4:38 PM To: White, Kimberly; Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmailuc.edu); Kacew, Sam; Osimitz, Thomas Subject: RE: Updated Smoke Toxicity Proposal -SAC May 2017 - Meeting Materials Dear All, Please see the attached Updated Smoke Toxicity Proposal from Tom for consideration and action at the SAC meeting this week. Kind regards, Neera Neeraja Erraguntia, Ph.D., DABT American Chemistry Council Director, Chemical Products & Technology Division Neeraja erraguntla@americanchemistry.com 700 2nd Street NE Washington DO I 20002 O: (202) 249-6712 C: (202) 779-0524 www.americanchemistry.cor From: White, Kimberly Sent: Tuesday, May 9, 2017 5:28 PM To: Admon, Smadar; Anderson, Steven; Batoon, Audrey; Bradley, Kevin; de Lacy, Catharine; Elkan, Ilan; Erraguntla, Neeraja; Goodman, Bryan; Hochschwender, Lane; Jacobi, Sylvia R.; Kannah, Kasturirangan; LeVan, Steve; Levchik, Sergei; Little, Barbara; Manor, Orit; Prero, Judah; Rothenbacher, Klaus; Saunders, Eric L.; Scherrer, Steve; Simon, Robert; Taylor, Jennifer; Tenney, Joel; Thorn, Amelia; West, Jay; White, Kimberly; Hayes, A. Wallace; Rein, Guillermo; info@troitzsch.com; Troitzsch, Jurgen; Blais, Matthew; Michael Dourson (doursoml@ucmailuc.edu); Kacew, Sam; Osimitz, Thomas Subject: SAC May 2017 - Meeting Materials Dear NAFRA, BSEF and SAC members: In preparation for the May 16th-17th SAC meeting, attached are associated meeting materials. Hard copies will also be available onsite. In addition to the attached materials, we also anticipate additional information on the dermal exposure project, the smoke toxicity project and the baby monitor combustion project to be disseminated in the coming days. Below are general meeting logistics. General Logistics Meeting Dates/Times: May 16, 2017 (Meeting from 9:00 a.m. -5:00 p.m. ET) May 17, 2017 ( Meeting from 9:00 a.m. -2:00 p.m. ET) Meeting/Hotel Location: DoubleTree by Hilton Hotel Metropolitan -New York City, 569 Lexington Avenue, New York, New York 10022 Dinner on May 15, 2017 at 6:30pm (ET) - The Modern; Address: 9 W 53rd St. New York, NY 10019 Dinner on May 16, 2017 at 6:30pm (ET) Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 204 SAC Members Only - The Smith; Address: 956 2nd Ave, New York, NY 10022 NAFRA/ BSEF Members Only - Mitae: Address: 4 East 46th Street, New York, NY 10017 I look forward to seeing everyone next week and feel free to contact me if you have any questions. Kind Regards, Kimberly Wise White, Ph.I D. | American Chemistry Council Senior Director, Chemical Products & Technology Division Kimberly Whitelamericanchemistry.com 700 2nd Street NE Washington, DC | 20002 O: (202) 249-6707 C: (202) 341-7602 www.americanchemistry.com + This message may contain confidential information and is intended only for the individual named. If you are not the named addressee do not disseminate, distribute or copy this email. Please notify the sender immediately by email if you have received this email by mistake and delete this email from your system. E-mail transmission cannot be guaranteed to be secure or error-free as information could be intercepted, corrupted, lost, destroyed, arrive late or incomplete, or contain viruses. The sender therefore does not accept liability for any errors or omissions in the contents of this message which arise as a result of email transmission. American Chemistry Council, 700 - 2nd Street NE, Washington, DC 20002, www.americanchemistry.com Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Relative Toxicity of Combustion Products from Various Materials Effect of Flame Retardants T.G. Osimitz (Science Strategies) and M.S. Blais (Southwest Research Institute) April 18, 2017 Background Recent studies haves shown the presence of flame retardants (esp. polybrominated diphenyl ethers (PBDEs)) and/or possible flame retardant (FR) combustion products (halogenated dioxins and furans), and other polyaromatic hydrocarbons (PAHs) in the serum of firefighters and/or on their clothing (Shaw et al. 2013). In their study, polychlorinated and polybrominated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs and PBDD/Fs) were measured in the serum of twelve firefighters sampled after a fire event in San Francisco, California, along with PBDEs, polychlorinated biphenyls (PCBs), p,p'- DDE, hexachlorobenzene (HCB), perfluorinated chemicals (PFCs), bisphenol-A (BPA) and tetrabromobisphenol-A (TBBPA). Given the elevated rates of some cancers in firefighters and general concern about firefighter health, it is important to understand the significance of these findings. While it is not certain that the PBDEs can survive a fire and end up posing a potential exposure to firefighters as suggested by Shaw et al. (2013), halogenated dioxins and furans are known products of incomplete combustion. The extent to which the presence of halogenated flame retardants contribute to or accelerate the formation of the dioxins and furans in house fires is not clear. However, a recent report by Zhang et al. (Zhang, Buekens, and Li 2016) shows that an increase in the bromine content of electrical/electronic waste (presumably from flame retardants) is associated with an increase in the presence of halogenated dioxins and furans in the combustion products. They also state that: "Other forms of open burning (landfill fires and accidental fires) are also donors of PBDD/F emissions.' Although not surprising, this evidence will be used to support the general statement often made by opponents of flame retardants that flame retardants make smoke more toxic and that this poses an increased risk to firefighters. The Issue to Address There is widespread agreement that smoke (regardless of the presence of flame retardants) is acutely toxic and may contain numerous chemicals with the potential to cause chronic effects such as cancer. The unanswered question is: "Is smoke/soot from combustion of materials with flame retardants more toxic than smoke/soot from materials without flame retardants? 1 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 For the project being conducted here, we are not concerned with acute toxicity, which is reasonably well understood, but rather chronic effects including cancer. Numerous studies have documented the presence of poly aromatic hydrocarbons as well as polychlorinated and polybrominated dibenzodioxins and dibenzonfurans in smoke from combusted materials. The open question is whether flame retardants enhance the carcinogenicity and chronic toxicity of the already hazardous smoke from a fire. Experimental Approach We combusted four test articles. Smoke condensate was collected during the combustion and wipe samples of soot were collected after combustion. The samples were analyzed for a wide variety of chemicals commonly associated with combustion. The combustion and chemical analysis were performed at Southwest Research Institute (San Antonio, TX). The samples were also sent to Cyprotex Laboratories (Watertown, MA) for evaluation of the biological activity. We chose a battery of vitro assays that could be conducted quickly without the use of live animals. The hypothesis being tested was whether the biological activity of the smoke condensates and soot is identical and whether the combusted materials contain a flame retardant or not. Combustion of Materials and Collection and Analysis of Smoke and Soot In Phase I (Pilot Study), two materials were combusted: High Impact Polystyrene (HIPS) - without flame retardant and with the flame retardants decabromodipdhenylethane and antimony trioxide added. Br Br Br Br Br Br Br Br Br Br Flexible Poly Urethane Foam (PUF) - without flame retardant and with the flame retardant tris(dichloroisopropyl) phosphate (TDCP). 2 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 CI CI o ; +++++++++ CI o CI C CI Combustion took place in a National Bureau of Standards (NBS) smoke chamber at 50 kW/m² radiant energy. A 100 mm x100 mm x <50 mm piece of selected material was pyrolyzed. Smoke opacity was measured using a calibrated light source in the smoke chamber. Samples were collected through the heated sample transfer line (HSTL) at a fixed and measured flow rate and analyzed by Fourier transform infrared spectroscopy (FTIR) in a 2 meter gas cell. The FTIR particulate filter was analyzed for halogens. Samples were also collected through a separate HSTL, fitted with a stainless steel cooling line and cooled solvent impingers, from the chamber at a flow of 1 standard liters/minute (SLPM) over the duration of the burn (30 min). There were two impingers in series, the first impinger filled with DMSO and the second filled with water. Both impingers were chilled in a 0°C cold bath. The stainless steel cooled sample line was rinsed with dimethyl sulfoxide (DMSO) and rinsate added to the DMSO impinger solvent and mass measured of total solvent. A second wash with water was performed and the two rinsates added together and the total mass measured. Soot was collected from the inside surfaces of the smoke chamber by use of latex wipes. The DMSO and water rinsates as well as extracts from the wipes used to collect the soot were combined for each pyrolysis experiment and the combined materials were used for the characterization of biological activity (described below). Samples were frozen at a temperature of - -70°C and shipped overnight on dry ice to the biological testing laboratory. Note: All collection materials (such as the wipes, solvents and containers) were confirmed prior to use not to have been contaminated with any known FR by analysis of quality blanks. Results Chemical Analysis of Samples The comprehensive chemical analysis of the samples included: 3 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 A screen for over 200 volatile and semi-volatile target compounds in EPA method TO-15 (Target Compounds). In addition, any peak showing an area count greater than 1% of the sample was also tentatively identified (referred to as a Tentatively Identified Compound - TIC) and a semi-quantitative analysis was also performed; An array of both brominated and chlorinated dioxins and dibenzofurans. Note: Analytical difficulties beset the analysis of brominated dioxins and dibenzofurans. Thus, those data are not reported. Target Compounds Diethylphthalate was detected in approximately equal concentrations from both non-FR and FR HIPS samples. Other than benzoic acid (in DMSO samples from polyurethane foam (PUF) with FR), no other target chemicals were detected. In contrast to flexible PUF, numerous target compounds were detected from the combustion of HIPS. Although the FR and non-FR versions of HIPS produced some of the above chemicals, more such individual chemicals were produced in the presence of FR (Table 1). Moreover, for the chemicals detected in both FR and non-FR samples, concentrations were generally higher in the FR-containing samples. Nonetheless, this does not suggest that these differences are toxicologically significant. Table 1: Target Compounds - HIPS with and without FR FRI IIIPS HIPS 1 FRJ HIPS HIPS Impinger Impinger Rasio Impinger Impinger Raties DI 1120 DE 1120 FR/Non FR DMSO DAISO FR/Non FR Name (ug/l) (mg/l.) ND ND 26.2 ND 19.1 NO 46,7 13.4 3,5 76 23.3 3.3 160 56.8 3.8 39.6 20.4 1.9 89 56 135 50.6 2.7 377 146 1.9 26.6 ND 58.4 33.4 1.7 33 ND 28.6 23.5 1.3 Acid 37.6 NO 109 67.3 1.6 13.8 17.4 0.8 ND ND 319 29.3 7.3 429 78.1 5.5 43.6 ND 91,7 34,5 2.7 ND ND 14 ND 31.6 28.9 1.1 33 35.6 0.9 ND ND 38.5 ND 107 13,7 7.8 220 40 3,5 18.4 ND 50.6 18.5 2.7 ryyrene 87.8 19.3 4,6 195 56.1 3.5 (Naphthalene 20.7 NO NO ND 204 26.3 7,8 446 5.0 Pyreme 41.1 ND 80.5 22.4 3.6 TOTAL como (ug/L) 1142.00 229,78 5.0 171.60 3.1 Tentatively Identified Compounds (TIC) TDCP was detected in samples from the combustion products from both flexible PUF samples. No TIC were detected in the samples collected in water. 4 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Table 2: Tentatively Identified Compounds - PUF with and without FR Tentativa compounds in Flexible PUF: DMSO Impinger and Wipe Samples Concentration in pg/l. Compound Name CAS # Flexible PUF FR Flexible PUF Trist 13674-87-8 536 1210 For HIPS, significantly more individual TICs were identified in the FR-containing material (Tables 3, 4). For the chemicals detected in both FR and non-FR samples; concentrations were generally higher in the FR-containing samples. As with the target compounds, it is not possible to make inferences about the toxicological significance of these results. Unexpectedly, TDCP was detected in samples from the combustion products from both HIPS samples. The source of the contamination is uncertain, although it can most likely be attributed to the experimental and sampling set up. In the future, special attention will be paid to scrupulously clean the apparatus to eliminate such confounding results. Table 3: Tentatively Identified Compounds - HIPS with and without FR (water collection) Tentative compounds in HIPS: DI Water Impinger and Wipe Samples Concentration in pg/L Compound Name HIPS I FRI HIPS 1-Propente, 22.4 686 58.4 528 Naphthalene, 2-phenyl- ND 464 ND 249 ND 144 Naphthalene, -pheny)- ND 128 Heracnemethanamine, 225 46.6 Bennene, ND 90.6 glycal in DMSO Finit 62.7 85.2 Pyrene, 1-phenyl- ND 85.2 4: Tentatively Identified Compounds - HIPS with and without FR (DMSO collection) Tentative compounds in HIPS: DMSO Impinger and Wipe Samples Concentration in mg/l. Compound Name HIPS 1 FR3 HIPS Tris(1,3-dichloroisopropyi)phosphatel 788 ND ND 1280 1,17:3', ND 1160 Naphthalene, ND 912 ND 779 5 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Chlorinated Dioxins and Benzofurans For the Flexible PUF, only 3 of the 50 samples analyzed showed detectable levels of the analytes (data not presented). All values were below the Limit of Quantitation (LOQ). In contrast to the flexible PUF, many more individual chlorinated dioxins and furans were reported, most of them below the Limit of Quantitation (LOQ). Nonetheless, the total amounts of chlorinated dioxins and furans (collected in either water or DMSO) were essentially identical between FR and non-FR samples. Table 5 Chlorinated Dioxins and Benzofurans from HIPS with and without FR HIPS (blank cells are non-detects) Chiorinated Dinxins and in HIPS: DI Water Cblorinated Dioxins and Furans in HIPS: DMSO Impinger and Wipe Samples Impinges and Wipe Samples Concentration in us/T. Concentración in ug/L Compound Name HIPS 1 FR3 HIPS Compowad Name IIIPS 1 FR3 HIPS 2,3,7,8-TCDO 2,3,7,8-TCDD 1,2,3,7,8-PeCOD 1,2,3,7,8-PeCDD 1,2,3,4,7,8-MxCDD 1,2,3,4,7,8-HxCDO 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDO 1,2,3,7,8,9-HxCOD 1,2,3,4,6,7,8-HpC00 1,2,3,4,6,7,8-HpC00 OCDO OCDO 2,3,7,8-TCDF 1.05 1.2 2,3,7,8-TCDF 2.39 3.59 1,2,3,7,8-PeCDF -LOQ 1,2,3,7,8-PeCOF -LOQ 2,3,4,7,8-PeCOF 2,3,4,7,8-PeCDF HLOC 1,2,3,4,7,8-HxCDF <LOQ <LOQ 1,2,3,4,7,8-HxCDF KLOC <LOQ 1,2,3,6,7,8-HxCOF 1,2,3,6,7,8-HxCDF -LOQ 1,2,3,7,8,9-HxCOF 1,2,3,7,8,9-HxCDF 2,3,4,6,7,8-14xCDF <LOQ 1,2,3,4,6,7,8-HpCOF <LOQ 1,2,3,4,6,7,&-HpCDF <LOQ 1,2,3,4,7,8,9-HpCDF 1,2,3,4,7,8,9-HpCOF OCDF OCDF Total Tetra-Dioxins 0.838 Total Tetra-Dioxins 2.21 Total Penta-Diaxins Total Penta-Dioxins KLOC <LOC Total Hexa-Dioxins Total Hexa-Dioxins <LOQ Total Hepta-Dioxins Total Hepta-Dioxins LOQ Total Tetra-Furans 3.18 5.42 Total Tetra-Furans 12.9 22.1 Total Penta-Furans 3.41 2.46 Total Penta-Furans 7.97 9.66 Total Hexa-Furans <LOQ <LOQ Total Hexa-Furans 2.38 2.79 Total Hepta-Furans CLOQ Total Hepta-Furans 4,00 -LOQ Total a dioxins and furans 7.428 7.88 Total a dioxins and furans 25.46 34,55 No Change Decrease with FR (either >2X reduction or going to a non-detett) Increase with FR (>2X increase) 6 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Assessment of Biological Activity (Cyrprotex Labortories) Genotoxicity In Vitro Micronucleus Screen (MNT) None of the test articles exhibited genotoxicity in the absence or presence of S9 metabolic activation. Ames Genotoxicity Screen (two test strains) No genotoxicity was observed for any of the test articles. Note: we ran Cyprotex's most popular option for non-GLP testing ("mini-Ames"). The two bacterial strains used allow for detection of two of the most common mutations (i.e. frame-shift mutations with strain TA98, and base-pair substitutions with strain TA100). Assessment of Indicators of General Toxicity CellCiphr TM Premier Tox Profiling CellCiphrTM was the Cellular Systems Biology approach used to screen compounds for broad-ranging toxic effects using tissue-specific cell models. The CellCiphrTM Profiling used a combination of toxicity-relevant cells and toxicity biomarkers to monitor the effects of test compounds on many cellular systems responses known to be correlated with toxic challenge. These were surveyed using primary rat hepatocytes (metabolically competent) and the HepG2 (human) cell line, to take advantage of the specific biology present in these cell types and the toxicity endpoints associated with them. The smoke condensate samples were profiled in an expanded CellCiphrTM panel which includes both HepG2 and primary rat hepatocytes at two time points. It also included a Glutathione assay, ROS assay and a 5-day toxicity assay in rat hepatocytes. A combined 21 toxicity endpoints at multiple time points were measured to create the CellCiphrTM profile (38 total measured endpoints). The output (when applicable) included the maximum tolerated dose, AC50 curves and rank order and safety risks for prioritization. A summary of the results is below in Table 6. 7 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Table 6: Summary of CellCiphr Results - 0 NH Foam FR Ras O NO C : 049 1.08 (10% 1% Rat : * CA 31 : 1.29 07% 1% HepG2 8 72h NS : 1.10 (22% Mat 3 400 MIMIP : 0.00 (91% 1 0.5% C NO Riank Rat e NR C NR Rai o NR * 8 3 de - * The - - - - Res - No responses were see with the blank (as expected), PUF, and PUF with FR samples. Minimal responses were observed for HIPS and HIPS with FR. The responses are such that the effect of FR in either of the samples could not be distinguished. It is possible that this is a true reflection of the properties of the samples. But, more likely, the test samples may have been too diluted to produce a significant response. This is also suggested by the fact that, for several endpoints, the concentration-response curves began to develop at the highest concentrations (Figure 1). Figure 1: Representative Concentration-Response Curves Showing Apparent Onset of Effect at High Concentrations 48h 72h S a 2 2 18 8 & $ : * * & * $ 83 ses 8.8 : 0.00 88 (%) a ACA 31% 3° 0,778 No MEC MIN 8 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Biological Indicators of Presence of Dioxins and Dibenzofurans Dioxins and furans have been shown to be carcinogenic, immunotoxic, and toxic to reproduction in various animal models. The Adverse Outcome Pathway for these effects begins with their high affinity binding of the chemical to the Aryl Hydrocarbon Receptor (AhR). Subsequent translocation of the complex into the nucleus of the cell, dimerization of the AhR with the AhR nuclear translocator (Arnt) protein, and binding of the ligand:AhR:1 complex to its DNA recognition sequence leads to increased transcription and translation of certain genes, including that of cytochrome P4501A1 (CYP1A1). All dioxin-like compounds are assumed to act through this AhR signal transduction pathway. The test system we used consisted of transformed tumor cells plated on 96-well microtiter plates. An expression vector harboring human AhR plus the appropriate enhancers and promoters linked to the luciferase reporter gene have been integrated into the tumor cells. Receptor activation was assessed by monitoring reporter gene activity, and by comparing the results to vehicle-treated cells. The results were reported as the fold increase in transcriptional activation of AhR above vehicle control for each test article. Foam FR, HIPS, and HIPS FR exhibited levels of AhR induction of approximately 5, 7, and 9-fold, respectively. The levels of activation for both HIPS and Flexible PUF correspond to less than 20% of the positive control compound (3- methylcholanthrene, at 10 M) as shown in Figures 2 and 3, respectively. Cyprotex, the testing laboratory, indicated that for drug discovery screening programs, they typically flag compounds that show >40% induction relative to the positive control. The maximum level of induction we observed could therefore be considered modest by such screening criteria standards. Thus, although there is an apparent increase in Ah Receptor activity in FR-containing samples but, because of the relatively low response, it is not possible to assess the toxicological significance, if any of these observations. 9 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Figure 2: Ah Receptor Activation - HIPS with and without FR Ah Receptor Activity HIPS HIPS FR 100 80 60 40 16 20 8 9 12 1 1 2 2 4 4 6 6 - 0 - 0.03125 0.0625 0.125 0.25 0,5 1 Test Concentration Range (%) Figure 3: Ah Receptor Activation - Flexible PUF with and without FR Ah Receptor Actvity Flexible PUF Plexible POF FR 100 90 80 70 60 50 40 30 20 011 3 5 8 10 0 0 0 0 0 1 3 0 asse 0.03125 0.0625 0.125 0,25 0.5 1 Test Concentration Range (%) 10 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Summary of Pilot Study and Future Needs No indication of adverse responses, but data are inconclusive due to need to optimize concentration of samples being tested; Sample collection and preparation needs to be revised to provide more concentrated sample for both analytical characterization and biological testing; Extra efforts will be undertaken to avoid contamination with FRs from other sources. Recommendations for Follow-up The pilot study provided important insight to steps we need to take to maximize the robustness of this program. In addition to the sampling and sample preparation (concentrating of samples) discussed above, we recommend moving from the CellCiphrTM assay to ToxTracker by Toxys. Why move to the Toxys System? Cells Used: Cyprotex uses HepG2 cells which are immortal human liver carcinoma line as well as rat hepatocytes. That is fine, but the stems cells used by Toxys are better, as they are less organ specific; Experience with Lipophilic Molecules: CellCiphrTM system has primarily been used for relatively water-soluble pharmaceuticals and not complex mixtures like we are dealing with. The Toxys system has been used with lipophilic mixtures as in the petroleum-related project; Regulatory Utility: The system is undergoing validation for screening for carcinogenicity be the European Union; ToxTracker generally predicts very well (>90%) the outcome of the standard battery of GLP in vitro genotoxicity (Ames, Mouse Lymphoma Assay, Micronucleus - In vitro, Chromosome aberrations). Proposed Project This is essentially a repeat of the pilot project with the same test articles (plus red oak). In contrast to the pilot study: Sampling volume and handling will be modified to produce a more concentrated sample to be sure that we are well within the dynamic range of the assays; Because of the special focus that Toxys has on carcinogenesis (by several modes of action - genotoxic and non-genotoxic), we will not run the Ames nor the micronucleus assays. We will still run the Ah Receptor assay as a sensitive biological indicator of halogenated dioxins and furans. 11 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 Budget: For 5 Test Articles - Phase 18 (definitive) Assay $/test Article Total Cost Combustion set up and collection 3,000 15,000 Analytical chemistry on the above 2,600 13,000 Cell Tracker 3,000 15,000 Ah Receptor 800 4,000 Subtotal Laboratory Costs 47,000 *Study management and oversight (0.2) 9,400 Total Project Cost 56,400 *Science Strategies Timing: Toxys offers a one week turnaround, depending upon availability. 12 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226 References Shaw, S. D., M. L. Berger, J. H. Harris, S. H. Yun, Q. Wu, C. Liao, A. Blum, A. Stefani, and K. Kannan. 2013. 'Persistent organic pollutants including polychlorinated and polybrominated dibenzo-p-dioxins and dibenzofurans in firefighters from Northern California', Chemosphere, 91: 1386-94. Zhang, M., A. Buekens, and X. Li. 2016. 'Brominated flame retardants and the formation of dioxins and furans in fires and combustion', J Hazard Mater, 304: 26-39. 13 Source: https://www.industrydocuments.ucsf.edu/docs/mxcn0226

Who are the Publication co-authors?

kqbn0226

kqbn0226_p21, kqbn0226_p22, kqbn0226_p23, kqbn0226_p24, kqbn0226_p25, kqbn0226_p26, kqbn0226_p27, kqbn0226_p28, kqbn0226_p29, kqbn0226_p30, kqbn0226_p31, kqbn0226_p32, kqbn0226_p33

Michael Dourson, Bernard Gadagbui, John Lowe and Rod Thompson

Hazard Range Intermediate Value It is a plausible estimate of the concentration or dose that is likely to be protective of the general population, including sensitive subpopulations Is a judgment that meshes four considerations: Collective magnitude of the UFs Steepness of the hazard slope describing exposures above the RfC/RfD The confidence in the selection of the critical effect The confidence in the POD 20 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Hazard Range Intermediate Value Intermediates values are closer to the floor, the RfC, if: The UF is small The hazard slope is steep The confidence is high in the critical effect, and The confidence is high in the POD Intermediate values are further from the RfC if: The uncertainty factor is large, Hazard slope is shallow, and Confidence is low in the critical effect and in the POD 21 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Developing the Safety Range for TCE In the IRIS Summary for TCE, U.S. EPA identified three candidate RfC values from principal and supporting studies for the noncancer inhalation toxicity of TCE. These are: Candidate RfC of 2 g/m³ based on decreased thymus weight in female mice (Keil et al., 2009); Candidate RfC of 2 g/m³ based on fetal heart malformations in rats (Johnson et al., 2003); and Candidate RfC of 3 g/m³, based on toxic nephropathy in female rats (NTP, 1988). Each of these candidate RfCs may be evaluated with respect to the imprecision and the uncertainty inherent in its derivation. 22 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 TCE Safety Range, 2013. All values g/m³. Table 7. Different uncertainty ranges for different TCE RfC's. All values are in g/m³. Shaded areas indicate best overall uncertainty range for risk management purposes. Endpoint Confidence Uncertainty Ranges Study IRIS Steep 6 C Critical Point of a Floor Intermediate Ceiling UF Slope Effect Departure Johnson et al Fetal Lower Low 10 20 10 Low 2 (2003) malformation Toxic nephropathy Medium NTP (1988) 10 Higher Medium 3 9 30 to Low Decreased thymus Medium Keil et al. 2009 100 NA Medium 2 20 60 weight to Low a. Size of the uncertainty factor as on IRIS b. Steepness of the hazard slope (i.e., the slope of the line describing hypothetical population responses at concentrations above the RfC), as per Section 3. c. Confidence in the choices of critical effect, as per Section 4. d. Confidence in the POD, as per Section 4. 23 Source: Ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Limitations of the Johnson et al. study and the FCM endpoint as basis for quantitative assessment of the RfC High rate of observations in control group Lack of robust dose-response relationship Lack of repeatability of results Study based on oral exposure (five other inhalation studies with negative response) 1% benchmark response level, HEC99 for point of departure in RfC derivation 24 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Revised Safety TCE Range, 2016: All values are in g/m³. Confidence Uncertainty Ranges Study IRIS Steep b Critical c Point of d Floor Intermediat Ceiling UF a Slope Effect Departure e Johnson et Lower 10 10 Low 2 al (2003) Low 20 Higher Medium Medium to 9 NTP (1988) 10 3 Low 30 Keil et al. 100 NA Medium Medium to 2 20 2009 Low 190 a. a. Size of the uncertainty factor as on IRIS b. b. Steepness of the hazard slope (i.e., the slope of the line describing hypothetical population responses at concentrations above the RfC). c. c. Confidence in the choices of critical effect. d. d. Confidence in the POD. Source: ttps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Safety Range for TCE Short-Term Action Levels. All values are in g/m³ Confidence Uncertainty Ranges Study IRIS Steep b Critical c Point of d Floor Intermediat Ceiling UF a Slope Effect Departure e Johnson et 10 Lower Low 2 10 al (2003) Low 20 Medium to NTP (1988) 10 Higher Medium 3 9 Low 30 Keil et al. NA Medium Medium to 100 2 20 2009 Low 190 a. a. Size of the uncertainty factor as on IRIS b. b. Steepness of the hazard slope (i.e., the slope of the line describing hypothetical population responses at concentrations above the RfC). c. c. Confidence in the choices of critical effect. d. d. Confidence in the POD. Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 TCE Short-term Action Levels Normal Response Accelerated Response Prompt Response Exposure Scenario Action Action Action Residential Observed Concentrations > 3.2 and 9.4 g/m³ 3 > 9.4 and 21 g/m³ > 21 g/m³ Response Timeframe < I year < 6 months < 10 days Remedial Objective* 3.2 - 4.8 g/m³ 3.2 - 4.8 g/m³ 3.2 - 4.8 Mg/m3 Commercial/Industrial Observed Concentrations > 13 and 39 g/m³ > 39 and < 88 Mg/m3 > 88 g/m³ Response Timeframe < I year < 6 months < 10 days Remedial Objective* 13 - 30 Mg/m3 13 - 30 g/m³ 13 - 30 g/m³ upper end of remedial objective range based on cancer endpoint 27 Source: Ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Risk Communication Essential component in accelerated and prompt response actions Engagement of public health and environmental agencies with public and stakeholders Safety range considerations in risk communication Comparison to cancer risk range Contrast with bright line of RfC Association of the bright line with the threshold concentration (experimental NOEC) 28 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Safety Range as a Risk Management Tool Chemical-specific evaluation Assessment of the uncertainty of the following factors associated with each critical study: Point of departure Critical effect Nature of dose-response relationship Magnitude of the composite uncertainty factor Provides a tool for quantifying the uncertainty and confidence associated with each RfD or RfC 29 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Next Steps Continue dialogue regarding vapor intrusion risk assessment issues, including agencies and responsible parties. Study the proposed method for the noncancer safety range. Resolve discrepancies in TCE fetal heart findings from one lab compared with negative findings in all other labs. Determine appropriate averaging time for TCE concentrations. 30 Source: ttps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Alliance for Risk Assessment For more information go to: http://www.allianceforrisk.org/Proje cts/TCE.html 31 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Thank You MSECA Conference organizers, esp. Megan Hamilton and Brian Lewis Panel Participants Alliance for Risk Assessment Publication co-authors Michael Dourson, Bernard Gadagbui, John Lowe and Rod Thompson 32 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226

what is the full form of ppe?

hlcn0226

hlcn0226_p0, hlcn0226_p1, hlcn0226_p2, hlcn0226_p3, hlcn0226_p4, hlcn0226_p5, hlcn0226_p6, hlcn0226_p7, hlcn0226_p8, hlcn0226_p9, hlcn0226_p10, hlcn0226_p11

Personal Protective Equipment, personal protective equipment

129 From: Jürgen Troitzsch To: Osimitz Thomas; Dr. Blais Matthew; Prof. Rein Guillermo; Dr. Hayes Wallace; Dourson. Michael (doursomi); Kacew Sam; Dr. Wise Kimberly Subject: Fwd: Project on FF PPE Cleaning Validation Date: Monday, June 12, 2017 1:11:46 PM Attachments: PROU PANEL - PPE Cleaning (33) pdf PROJ SUMMARY - PPE Cleaning (7) pot FLYER FF Contam Control Workshop (6) odf HOTELS - Contam Control Wrkshp on 2017Jul19.pd PROJS JMMARY- FE Cancer Cohort Study (4) odf Dear All, I came across this project, which may be of interest in the frame of our fire fighters cancer activities. Kind regards/Viele Grüße Jürgen Dr. Jürgen Troitzsch Fire and Environment Protection Service FEPS Via Patrizia 32 CH-6612 Ascona, Switzerland Mobile: +41 79 289 17 16 Phone: +41 91 791 14 22 Email: itroitzsch@troitzsch.com Web: www.troitzsch.com De : Grant, Casey Envoyé : lundi 22 mai 2017 17:58 À : Safety@local67.com; kenblock@edmonton.ca. tis.com; mlambetamallN u.edu; dwardmecarthyebostengoy ark.a.miller@ehoen ix.gov; james.riley@bosta nagov; mrilev@ybgov.com Thomas Smith@fdnv.nyc.gov; ;timügearcleaningsolutions.s om KTvson@FCSN.net; Ken.Wiles @fire.jacounty.gov Farrell, Christopher cobtlogiobefiresuits.com; pattogiobefiresults.com; Diane.Hess@ Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 130 PBIProducts.com; Kebtonen@lionprotedscon leur.gouv.fr; GUILLAUME Eric <eric guillaume@EFECTIS.COM ;ilames.hoar@boston.gov; mamiefortunes-collide.com Cc : lasonallendintertekeor vfe2@cdc.gov; ckf7@codc.gov wlindslev@ cdc.gov; stmp@adc.edu ivr2@cdc.gov; drc3@cdc.gov; ; istendice OY; Objet : Project on FF PPE Cleaning Validation To: Panel, Research Team and Liaisons for Project on "Fire Fighter PPE Cleaning Validation" It has been some time since we last spoke, and I have the following three items to be addressed: 1) A lot has been happening with our project and we want to hold a 90 minute conference call in early August 2017 to bring everyone up-to-date. I've created a scheduling poll to determine the optimum date/time Please respond before Noon ET on Wednesday 31/May/2017 so that we can get this on our calendars. I've attached the Project Roster and Project Summary in case anyone needs a refresher for this project addressing "how clean is clean". Thanks. 2) I've been asked to participate in a webinar tomorrow (23/Mav/2017) from noon ET to 1:30 pm ET on "Factors Relating to Cancer and Contamination in the US Fire Service". I've been assigned a portion of this webinar (among two other speakers) to address on-going research and I'm planning to address our project among several other on-going efforts. The link is on the NFPA home page at: FYI.. 3) Some of you are already aware of the Workshop in Columbus, Ohio on 19- 20/Julv/2017, and if not I want to call it to your attention. This is for the separate one year AFG project on "Campaign for Fire Service Contamination Control". Attached is a Flyer that provides additional details, and also attached is a list of hotels in the area to assist with travel. The workshop will be held from Noon to Noon on 19-20/July and we still have room if you would like to attend. In addition, the separate project (i.e., a third related project) on "Fire Fighter Cancer Cohort Study" will hold a separate planning meeting on the afternoon of 20/July from 1 pm to 5 pm (Project Summary is attached). All are welcome to attend this as well. If you are a fire service panel member we can cover your travel, and I can send follow-up instructions to you separately. For anyone interested in attending the Columbus meetings on 19-20/July, please let us know by email to cgrant@nfoa.org and Thanks.. Casey C. Grant, P.E. Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION "CAMPAIGN FOR FIRE SERVICE CONTAMINATION CONTROL" WORKSHOP Location: Columbus Fire Fighters Union Hall, 379 W Broad St, Columbus, OH 43215 Workshop Dates: 19-20 July 2017 (Last Updated: 21 April 2017; subject to update) Background: Exposure to chemical and biological contaminants on the fire ground is an increasing concern for long-term fire fighter health. Cancer and other diseases resulting from chronic exposures has become a leading concern for the fire service. This is presumed to be associated with fireground exposures relating to protection/hygiene practices and persistent harmful contamination found in fire fighter equipment, apparatus carrying that equipment, and stations where the equipment resides. Workshop Goal and Objectives: The goal of this Workshop is to identify concepts and materials that are or can be useful to control the spread of harmful fire ground contaminants, ultimately in support of improved fire fighter long-term health. The following objectives support this goal (and reflect anticipated deliverables): Identify, review and recommend baseline materials (existing and proposed) addressing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and prioritize gaps that are barriers to enhancing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and review key characteristics for effective promotion and communication. Clarify target audiences for outreach and consider stakeholder research prior to developing a comprehensive communications plan to improve outcome. Prioritize messages for year one. Agenda: Wed; 19/July 1:00 pm Day One: Welcome and Call to Order Casey Grant, FPRF 1:15 pm Overview of Baseline Materials and Review of Gaps Jeff Stull, IPP 2:00 pm Review of Outreach Peg, Paul, PPA 2:30 pm Case Study: Best Practice Information Beth Gallup, KFD 3:00 pm PM Break 3:15 pm Casey Study: Standards Revisions Dave Bernzweig, CFD 3:45 pm Case Study: Equipment & Facilities Paul Erickson, LEWA 4:15 pm Breakout Groups Workshop Attendees 5:00 pm Adjourn for Day One (& Evening Networking Reception) Thur; 20/July 8:30 am Day Two: Group Review of Baseline Materials Jeff Stull, IPP 8:45 am Breakout Groups Continue Workshop Attendees 9:45 am AM Break 10:00 am Breakout Group Report Workshop Attendees 11:00 am Plenary Discussion Workshop Attendees 11:30 am Workshop Wrap-up & Summary Observations Casey Grant, FPRF 12:00 pm Adjournment Registration: Workshop attendance is limited to the first 50 attendees, and others will be placed the on a waiting list. To request attendance or for more information, please contact epeterson@nfpa.org. After the Workshop a report will be available. This Workshop is funded through an AFG Fire Prevention & Safety Grant from U.S.DHS/FEMA. 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 WORKSHOP ON FIRE SERVICE CONTAMINATION CONTROL 19-20 July 2017 (Noon to Noon ET) Columbus Fire Fighters Union Hall 379 W Broad St, Columbus, OH 43215 Note: For flights, Workshop starts at Noon ET on 19/July/2017 and finishes at Noon ET on 20/July/2017 Drury Inn & Suites: 88 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-221-7008 ttos://www.drurvhotels.com/locations/columbus-ob/drurv-inn-and-suites-columbus-convention: center Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Red Roof Plus Columbus Downtown Convention Center 111 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-224-6539 ittps://www.redroof.com/property/Columbus/OH/43215/Hotels-close-to-Greater-columbus- Convention-Center-US-23-1-670/RRI262/ Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.4 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Sheraton Columbus Hotel at Capital Square 75 East State Street, Columbus, OH, 43215 Phone: 1-614-365-4500 http://www.sheratoncolumbuscapitolsquare.com/ Approximate Rate: $170 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Central downtown area Hampton Inn and Suites Columbus Downtown 501 North High Street, Columbus, OH 43215 Phone: 1-614-559-2000 htto://hamptoninns.bilton.com/en/hotels/ohio/hampton-inn-and-suites-columbus-downtown- CMHHSHK/index.htmi?WT.mc. Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Page 1 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Courtyard Columbus Downtown 35 West Spring Street, Columbus, Ohio 43215 Phone: 1-614-228-3200 4d19-a255-54ba596febe2 Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Downtown west area; walkable Doubletree Suites by Hilton Columbus Downtown 50 South Front St, Columbus, Ohio, 43215-4145 Phone: 1-614-228-4600 CMHSBOT/index.htmi Approximate Rate: $200 Distance (in miles) from Hotel to Columbus Union Hall: 0.5 Notes: Closest hotel to meeting site; very short walk Residence Inn Columbus Downtown 36 East Gay Street, Columbus, Ohio 43215-3108 Phone: 1-614-222-2610 ec3-4d19-a255-54ba596febe2 Approximate Rate: $230 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Renaissance Columbus Downtown 50 North Third Street, Columbus, Ohio 43215 Phone: 1-614-228-5050 ttp://www.marriott.com/hotels/travel/cmhbr-renaissance-columbus-downtown-hotel/ Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.0 Notes: Central downtown area Hilton Columbus Downtown 401 North High Street, Columbus, OH 43215 Phone: 1-614-384-8600 Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.1 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars; New facility and nice. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) PROJECT CONTACTS Last Updated: 22 May 2017 Project Technical Panel Phone: 614-774-7446 David Bernzweig, Columbus Fire Department (OH) Email: Safety@local67.com Phone: 780-496-3801 Ken Block, Edmonton Fire/Rescue & Metro Chiefs Representative Email: ken.block@edmonton.ca Phone: 804-971-7983 Ken Brown, VA State Firefighter's Association & NVFC (Alt to B. McQueen) Email; kbrownret@aol.com Phone: 510-839-5111 Cell: 213-321-9393 Roger Curtis, ECMS Curtis & Sons (CA) Email: rcurtis@incurtis.com Phone: Paul Curtis, ECMS Curtis & Sons (CA) (Alt to Roger Curtis) Email: pcurtis@incurtis.com Phone: 253-277-4131 Cell: 503-314-4832 Steve Lakey, Northwest Safety Clean (WA) Email: Steve@northwestsafetyclean.com Phone: 304-406-7479 Mark Lambert, WV Fire Academy & NAFTD (WV) Email: mlambe13@mail.wvu.edu Phone: 617-828-3978 Ed McCarthy, Boston Fire Department (MA) Email: Edward.mccarthy@boston.goy Phone: 315-736-7479 Cell: 315-552-8245 Brian McQueen, FASNY & National Volunteer Fire Council (NY) Email: fasnydirector@gmail.com Phone: 602-534-2396 Mark Miller, Phoenix Fire Dept. (AZ) Email: mark.a.miller@phoenix.gov Phone: 919-524-1569 Bryan Ormond, NCSU (NC) Email: rbormond@ncsu.edu Phone: Russ Osgood, Firefighter Cancer Support Network (NH) (Alt to Keith Tyson) Email: rosgood@fcsn.net Phone: Larry Petrick, IAFF (DC) Email: LPetrick@iaff.org Phone: 617-549-9850 Jim Riley, Boston Fire Department (MA) (Alt to E. McCarthy) Email: james.riley@boston.gov Phone: 757-385-2892 Molly Riley, Virginia Beach Fire Dept. (VA) Email: mriley@vbgov.com Phone: 718-999-2922 Thomas Smith, FDNY (NY) Email: Thomas.Smith@fdny.nyc.gov Phone: 214-774-2213 Cell: 940-300-5718 Tim Tomlinson, Gear Cleaning Solutions (TX) Email: tim@gearcleaningsolutions.com Phone: Robert Tutterow, NFPA Fire Service Section (NC) Email: rdtutterow@gmail.com Phone: 786-351-3276 Keith Tyson, Firefighter Cancer Support Network (FL) Email: KTyson@FCSN.net Phone: 951-807-1914 Dick Weise, LA County Fire Dept. (CA) Email: weiselacofd@yahoo.com Phone: 949-291-0637 Ken Wiles, LA County Fire Dept. (CA) (Alt to Dick Weiss) Email: Ken.Wiles@fire.lacounty.gov Phone: 512-974-0286 Chris Youngblood, Austin Fire Dept. (TX) Email: Christopher.Youngblood@austintexas.gov 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Phase 1 Project Contacts Phone: 330-723-0000, x365 Steve Allison, Fire-Dex (OH) Email: steveallison@firedex.com Phone: 800-401-4780 Jack Binder, Edmar Chemical Company (OH) Email: jackbinder@edmarchem.com Phone: 920-570-0824 Bill Brooks, Alliance Corp. (WI) Email: ill.Brooks@AllianceL.com Phone: Charlie Dunn, TenCate Protective Fabrics Email: c.dunn@tencate.com Phone: 617-984-7325 Chris Farrell, NFPA & Staff Liaison for NFPA 1851 (MA) Email: cfarrell@nfpa.org Phone: 800-232-8323 Rob Freese, Globe Manufacturing (NH) Email: robf@globefiresuits.com Phone: Pat Freeman, Globe Manufacturing (NH) (Alternate to Rob Freese) Email: patf@globefiresuits.com Phone: 704-554-3313 Diane Hess, PBI Performance Products (NC) Email: Diane.Hess@PBIProducts.com Phone: 937-415-2932 Karen Lehtonen, LionFirst Responder Products (OH) Email: klehtonen@lionprotects.com Phone: 484-433-4072 Dan Silvestri, 9-1-1 Safety (PA) Email: Dan@911se.com Liaison Contacts Phone: Pierre Carlotti, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: lierre.carlotti@interieur.gouv.fr Phone: Eric Guillaume, Efectis & Liaison for ISO TC92/SC3 (France) Email: eric.guillaume@EFECTIS.COM Phone: Bill Haskell, NIOSH NPPTL (MA) Email: czi8@cdc.gov Phone: James Hoar, Boston Fire Department (MA) Email: james.hoar@boston.gov Phone: 631-242-0621 Steve King, Chair NFPA 1851 (NY) Email: tikitai@aol.com Phone: +33(0)1.55.76.26.18 Fanny Rieunier, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: fanny.rieunier@interieur.gouv.fr Phone: 612-247-6429 Marni Schmid, Fortunes Collide & Secretariat NFPA 1851 (MI) Email: marni@fortunes-collide.com Page 2 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Core Research Team Phone: 607-758-6537 Cell: 607-423-5617 Jason Allen, Intertek (NY) Email: jason.allen@intertek.com Phone: 304-285-6076 Daniel Farcas, NIOSH HELD (WV) Email: yfe2@cdc.gov Phone: Crystal Forester, NIOSH NPPTL (WV) Email: ckf7@cdc.gov Phone: 617-984-7284 Cell: 617-659-1159 Casey Grant, Fire Protection Research Foundation (MA) Email: cgrant@nfpa.org Phone: Lee Greenawald, NIOSH NPPTL (WV) Email: ilv1@cdc.gov Phone: Bill Lindsley, NIOSH HELD (WV) Email: wlindsley@cdc.gov Phone: Stephen Martin, NIOSH DRDS (WV) Email: stm9@cdc.gov Phone: John Noti, NIOSH HELD (WV) Email: ivr2@cdc.gov Phone: Deborah Sbarra, NIOSH NPPTL (WV) Email: drc3@cdc.gov Phone: 512-288-8272 cell: 512-623-9558 Jeff Stull, International Personal Protection (TX) Email: intiperpro@aol.com Phone: 304-285-5858 cell: 681-209-2571 Jay Tarley, NIOSH NPPTL (WV) Email: ist9@cdc.gov Additional Research Team Contacts Phone: 304-285-5884 Francoise Blachere, NIOSH HELD (WV) Email: czv3@cdc.gov Phone: Renee Dotson, NIOSH HELD (WV) Email: ced9@cdc.gov Phone: James Harris, NIOSH NPPTL (WV) Email: irh6@cdc.gov Phone: Ryan Lebouf, NIOSH DRDS (WV) Email: igu6@cdc.gov Phone: 617-984-7281 Eric Peterson, Fire Protection Research Foundation (MA) Email: epeterson@nfpa.org Phone: John Powers, NIOSH (WV) Email: jop5@cdc.gov Phone: 412-386-4621 Cell: 412-463-9561 Heather Reed, NIOSH NPPTL (PA) Email: yvt5@cdc.gov Page 3 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) (for more information see www.nfpa.org/PPECleaning) PROJECT SUMMARY Last updated: 5 February 2016 Background: Fire fighter exposure to personal protective equipment (PPE) that is dirty, soiled, and contaminated is an increasing concern for long-term fire fighter health. This exposure to persistent harmful contaminants in PPE is an extremely serious problem both on the fireground to highly toxic substances including a variety of carcinogens, and more insidiously to an increasing range of infectious pathogens that are encountered in patient care and different emergency operations. Fire fighter PPE becomes contaminated during these exposures and there are no industry standards that conclusively and reliably show that clothing is being adequately cleaned. While general cleaning procedures have been established in NFPA 1851, Standard on Selection, Care, and Maintenance of Protective Ensembles for Structural Fire Fighting and Proximity Fire Fighting, there are no procedures or requirements to demonstrate whether current cleaning practices, including those specified in NFPA 1851, will remove contaminants from fire fighter protective clothing. This project is intended to establish clear and definitive guidance to the fire service for applying cleaning and decontamination procedures that effectively remove both chemical and biological contaminants. Research Goal and Objectives, and Conceptual Approach: The overall goal of this project is to improve fire fighter safety and health by reducing continuing exposure to harmful contaminants in unclean or inadequately cleaned PPE. The objectives to achieve this goal are twofold: (1) To characterize fireground and emergency scene contamination leading to these exposures and develop the methodology for the consistent measurement of cleaning effectiveness; and (2) determine implementable cleaning, decontamination, and disinfection strategies that effectively reduce fire fighter exposures to persistent contaminants. The approach taken by this project is illustrated in Figure 1: Project Conceptual Approach. - Ensure Identify Devise Validate lab - - chemical and methods to methods - at biologicat conteminate againet field ses target clothing in contaminants laboratory exposures acceptance Project Direction Figure 1: Project Conceptual Approach 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :ttps://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Phases and Tasks: This project involves the following four key phases of activity: 1) Identification of Contaminants: Confirm identification and ability to characterize persistent chemical and biological contaminants in fire fighter PPE through target substances and microorganisms. 2) Establishment of Soil and Chemical Contamination/Decontamination Procedures: Develop and validate specific procedures that determine the effectiveness of laundering and other cleaning methods in removing specific soils and chemical contaminants. 3) Establishment of Biological Contamination/Disinfection or Sanitization Procedures: Develop and validate specific procedures that determine the effectiveness of laundering or disinfection/sanitization processes that remove/deactivate biologically-based contaminants. 4) Creation of Overall Fire Service Guidance: Prepare clear and definitive information for the fire service industry (fire fighters, fire departments, clothing manufacturers, material suppliers, cleaning/care organizations, and cleaning agent or equipment manufacturers) on appropriate approaches for properly cleaning fire fighter protective clothing and equipment. The specific tasks of this project are based on these four phases of the project, and these are illustrated in Figure 2: Project Tasks. PHASE 2 PHASEZ Task 2.4 Task 2.5 Task 1.1 Task 2.1 Validate testsat Refine test Appoint Technical Select cleaning selected ISPS methodology Review Panel methods/agents (chemical) (chemical) PHASE $ Task 4.1 Task 1.2 Task 2.2 Write qualification Review Prigr Put together test plan methods studies/literature (chemical) Task 2.3 Task 4.2 Task 1.3 PHASE 3 Perform laboratory Establish cleaning Setup analytical chemical Task 3.3 acceptance criteria capabilities decontaminant Put together test plan testing (biological) Task 4.3 Task 1.4 Perform Task 3.4 Prepare public inputs for NFPA 1851 demonstration tests Task 3.1 Perform laboratory Task 3.6 Select study biological Refine test microorganisms decontaminant methodology Task 1.5 testing (biological) Task 4.4 Refine biological Prepare industry decontamination Task 3.2 Task 3.5 guidance document scope Select biological Validate testsat cleaning methods selected ISPs (biological) Task 1.6 Task 4,5 Establish cleanliness Prepare project final metrics report Figure 2: Project Tasks Implementation and Schedule: This three year project is due to be completed no later than " August 2018, and is funded through an AFG Fire Prevention & Safety Grant from the U.S. Department of Homeland Security / Federal Emergency Management Agency. The Research Foundation will lead a unique research team partnership composed of the FPRF, National Institute for Occupational Safety and Health (NIOSH), International Personal Protection (IPP), and Intertek. The research team, along with several Independent Service Providers (ISPs), will work with the fire service partners and others to validate and optimize fire fighter PPE cleaning validation methods. For more information see www.nfpa.org/PPECleaning. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION Fire Fighter Cancer Cohort Study Full Title: The Firefighter Multicenter Cancer Cohort Study: Framework Development and Testing PROJECT SUMMARY Last Updated: 20 September 2016 Background: Cancer is a leading cause of fire service morbidity and mortality. Firefighter exposure to carcinogens occurs through skin contamination and through inhalation when respiratory protection is not worn when combustion products are present such as during overhaul, standby, and operation of apparatus, as well as through off-gassing of equipment and exposures in the fire station. However, we currently do not understand which exposures are responsible for cancer in firefighters, the mechanisms by which firefighter exposures cause cancer, nor the most effective means of reducing exposures. Since cancer has a long latency period, biomarkers are also needed that can measure the toxicological effects of carcinogen exposure well before the development of cancer, when interventions to prevent disease could be effective. Development of a large (>10,000 firefighter) multicenter firefighter cancer prospective cohort study will address these needs, but the framework for such a study needs to be first developed and tested among a smaller initial set of fire service partners. Implementation and Schedule: This research project is led by University of Arizona with collaborative support from multiple other research partners, including the University of Miami, National Institute for Occupational Safety and Health; National Fallen Firefighter Foundation, Fire Protection Research Foundation, and others. Initial funding for this project is through a 3-year DHS/FEMA Assistance to Fire Fighter (AFG) Fire Grant, with the intention to identify and obtain additional funding for the duration of the 30 year effort. The project start date is August 2016. The Principal Investigator for this project is: Jefferey L. Burgess, MD, MS, MPH, University of Arizona, email: iburgess@emailarizona.edu. Project Goal and Aims: The goal of the initial 3-year effort of this overall project is to develop and test a framework for establishing a long-term fire fighter multicenter prospective cohort study focused on carcinogenic exposures and effects. The specific aims are to: 1) Establish an oversight and planning board to provide study oversight, foster communication among fire organizations and help develop a long-term funding plan; 2) Create and test a cohort study data coordinating center and harmonized survey data protocols; 3) Develop and validate a firefighter carcinogen exposure matrix and data collection system; and 4) Create a biomarker assessment center and evaluate the association between cumulative firefighter exposures and epigenetic effects. For more information, contact: Casey Grant, Fire Protection Research Foundation 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7284 Fax: +1.617.984.7010 Email: cgrant@nfpa.org Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Methodology: This study will harmonize and build on recent and developing firefighter cancer prevention studies in Arizona, Florida and Massachusetts, adding volunteer fire departments. An oversight and planning board will be established by the Fire Protection Research Foundation (FPRF) in association with the National Fallen Firefighter Foundation (NFFF) Fire Service Occupational Cancer Alliance (FSOCA) to provide oversight of the study through collaboration among fire service organizations, academia, and government agencies, and develop a long-term funding and sustainability plan. A data coordination center team will design, develop and evaluate a framework for a multicenter prospective cohort study of firefighters and cancer risk, including standardized participant survey data collection tools and analysis protocols sufficient to address the short- and long-term study objectives as well as linkage with long-term outcome data including cancer development. An exposure assessment center team will develop a carcinogen exposure matrix and data collection system to provide improved occupational exposure data for comparison with epigenetic outcomes and eventual cancer outcomes. Carcinogen exposures associated with specific fire types will be evaluated across fire departments through industrial hygiene monitoring and analysis of urine for absorbed contaminants, supplementing existing FEMA-funded and other studies of firefighter exposures and allowing for participating fire departments to design interventions to reduce current exposures. Expansion of the National Fire Operations Reporting System (NFORS) will be explored as one option to uniformly collect incident and exposure data. Blood and buccal cells will be collected during annual medical surveillance evaluations, including both new recruits and incumbent firefighters. Pilot studies of epigenetic markers of cancer effect and cancer risk will be analyzed comparing municipal firefighters with high chronic exposures, volunteer firefighters with low chronic exposures, and non- firefighter friends of the municipal firefighters (serving as controls). Project Deliverables: The anticipated outcomes from this 3-year effort is to establish and test the framework necessary for the subsequent development of a large multicenter cohort study of cancer in the fire service. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226

what is the subtitle for research foundation?

hlcn0226

hlcn0226_p0, hlcn0226_p1, hlcn0226_p2, hlcn0226_p3, hlcn0226_p4, hlcn0226_p5, hlcn0226_p6, hlcn0226_p7, hlcn0226_p8, hlcn0226_p9, hlcn0226_p10, hlcn0226_p11

research for the NFPA mission, Research for the NFPA Mission

129 From: Jürgen Troitzsch To: Osimitz Thomas; Dr. Blais Matthew; Prof. Rein Guillermo; Dr. Hayes Wallace; Dourson. Michael (doursomi); Kacew Sam; Dr. Wise Kimberly Subject: Fwd: Project on FF PPE Cleaning Validation Date: Monday, June 12, 2017 1:11:46 PM Attachments: PROU PANEL - PPE Cleaning (33) pdf PROJ SUMMARY - PPE Cleaning (7) pot FLYER FF Contam Control Workshop (6) odf HOTELS - Contam Control Wrkshp on 2017Jul19.pd PROJS JMMARY- FE Cancer Cohort Study (4) odf Dear All, I came across this project, which may be of interest in the frame of our fire fighters cancer activities. Kind regards/Viele Grüße Jürgen Dr. Jürgen Troitzsch Fire and Environment Protection Service FEPS Via Patrizia 32 CH-6612 Ascona, Switzerland Mobile: +41 79 289 17 16 Phone: +41 91 791 14 22 Email: itroitzsch@troitzsch.com Web: www.troitzsch.com De : Grant, Casey Envoyé : lundi 22 mai 2017 17:58 À : Safety@local67.com; kenblock@edmonton.ca. tis.com; mlambetamallN u.edu; dwardmecarthyebostengoy ark.a.miller@ehoen ix.gov; james.riley@bosta nagov; mrilev@ybgov.com Thomas Smith@fdnv.nyc.gov; ;timügearcleaningsolutions.s om KTvson@FCSN.net; Ken.Wiles @fire.jacounty.gov Farrell, Christopher cobtlogiobefiresuits.com; pattogiobefiresults.com; Diane.Hess@ Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 130 PBIProducts.com; Kebtonen@lionprotedscon leur.gouv.fr; GUILLAUME Eric <eric guillaume@EFECTIS.COM ;ilames.hoar@boston.gov; mamiefortunes-collide.com Cc : lasonallendintertekeor vfe2@cdc.gov; ckf7@codc.gov wlindslev@ cdc.gov; stmp@adc.edu ivr2@cdc.gov; drc3@cdc.gov; ; istendice OY; Objet : Project on FF PPE Cleaning Validation To: Panel, Research Team and Liaisons for Project on "Fire Fighter PPE Cleaning Validation" It has been some time since we last spoke, and I have the following three items to be addressed: 1) A lot has been happening with our project and we want to hold a 90 minute conference call in early August 2017 to bring everyone up-to-date. I've created a scheduling poll to determine the optimum date/time Please respond before Noon ET on Wednesday 31/May/2017 so that we can get this on our calendars. I've attached the Project Roster and Project Summary in case anyone needs a refresher for this project addressing "how clean is clean". Thanks. 2) I've been asked to participate in a webinar tomorrow (23/Mav/2017) from noon ET to 1:30 pm ET on "Factors Relating to Cancer and Contamination in the US Fire Service". I've been assigned a portion of this webinar (among two other speakers) to address on-going research and I'm planning to address our project among several other on-going efforts. The link is on the NFPA home page at: FYI.. 3) Some of you are already aware of the Workshop in Columbus, Ohio on 19- 20/Julv/2017, and if not I want to call it to your attention. This is for the separate one year AFG project on "Campaign for Fire Service Contamination Control". Attached is a Flyer that provides additional details, and also attached is a list of hotels in the area to assist with travel. The workshop will be held from Noon to Noon on 19-20/July and we still have room if you would like to attend. In addition, the separate project (i.e., a third related project) on "Fire Fighter Cancer Cohort Study" will hold a separate planning meeting on the afternoon of 20/July from 1 pm to 5 pm (Project Summary is attached). All are welcome to attend this as well. If you are a fire service panel member we can cover your travel, and I can send follow-up instructions to you separately. For anyone interested in attending the Columbus meetings on 19-20/July, please let us know by email to cgrant@nfoa.org and Thanks.. Casey C. Grant, P.E. Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION "CAMPAIGN FOR FIRE SERVICE CONTAMINATION CONTROL" WORKSHOP Location: Columbus Fire Fighters Union Hall, 379 W Broad St, Columbus, OH 43215 Workshop Dates: 19-20 July 2017 (Last Updated: 21 April 2017; subject to update) Background: Exposure to chemical and biological contaminants on the fire ground is an increasing concern for long-term fire fighter health. Cancer and other diseases resulting from chronic exposures has become a leading concern for the fire service. This is presumed to be associated with fireground exposures relating to protection/hygiene practices and persistent harmful contamination found in fire fighter equipment, apparatus carrying that equipment, and stations where the equipment resides. Workshop Goal and Objectives: The goal of this Workshop is to identify concepts and materials that are or can be useful to control the spread of harmful fire ground contaminants, ultimately in support of improved fire fighter long-term health. The following objectives support this goal (and reflect anticipated deliverables): Identify, review and recommend baseline materials (existing and proposed) addressing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and prioritize gaps that are barriers to enhancing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and review key characteristics for effective promotion and communication. Clarify target audiences for outreach and consider stakeholder research prior to developing a comprehensive communications plan to improve outcome. Prioritize messages for year one. Agenda: Wed; 19/July 1:00 pm Day One: Welcome and Call to Order Casey Grant, FPRF 1:15 pm Overview of Baseline Materials and Review of Gaps Jeff Stull, IPP 2:00 pm Review of Outreach Peg, Paul, PPA 2:30 pm Case Study: Best Practice Information Beth Gallup, KFD 3:00 pm PM Break 3:15 pm Casey Study: Standards Revisions Dave Bernzweig, CFD 3:45 pm Case Study: Equipment & Facilities Paul Erickson, LEWA 4:15 pm Breakout Groups Workshop Attendees 5:00 pm Adjourn for Day One (& Evening Networking Reception) Thur; 20/July 8:30 am Day Two: Group Review of Baseline Materials Jeff Stull, IPP 8:45 am Breakout Groups Continue Workshop Attendees 9:45 am AM Break 10:00 am Breakout Group Report Workshop Attendees 11:00 am Plenary Discussion Workshop Attendees 11:30 am Workshop Wrap-up & Summary Observations Casey Grant, FPRF 12:00 pm Adjournment Registration: Workshop attendance is limited to the first 50 attendees, and others will be placed the on a waiting list. To request attendance or for more information, please contact epeterson@nfpa.org. After the Workshop a report will be available. This Workshop is funded through an AFG Fire Prevention & Safety Grant from U.S.DHS/FEMA. 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 WORKSHOP ON FIRE SERVICE CONTAMINATION CONTROL 19-20 July 2017 (Noon to Noon ET) Columbus Fire Fighters Union Hall 379 W Broad St, Columbus, OH 43215 Note: For flights, Workshop starts at Noon ET on 19/July/2017 and finishes at Noon ET on 20/July/2017 Drury Inn & Suites: 88 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-221-7008 ttos://www.drurvhotels.com/locations/columbus-ob/drurv-inn-and-suites-columbus-convention: center Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Red Roof Plus Columbus Downtown Convention Center 111 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-224-6539 ittps://www.redroof.com/property/Columbus/OH/43215/Hotels-close-to-Greater-columbus- Convention-Center-US-23-1-670/RRI262/ Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.4 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Sheraton Columbus Hotel at Capital Square 75 East State Street, Columbus, OH, 43215 Phone: 1-614-365-4500 http://www.sheratoncolumbuscapitolsquare.com/ Approximate Rate: $170 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Central downtown area Hampton Inn and Suites Columbus Downtown 501 North High Street, Columbus, OH 43215 Phone: 1-614-559-2000 htto://hamptoninns.bilton.com/en/hotels/ohio/hampton-inn-and-suites-columbus-downtown- CMHHSHK/index.htmi?WT.mc. Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Page 1 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Courtyard Columbus Downtown 35 West Spring Street, Columbus, Ohio 43215 Phone: 1-614-228-3200 4d19-a255-54ba596febe2 Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Downtown west area; walkable Doubletree Suites by Hilton Columbus Downtown 50 South Front St, Columbus, Ohio, 43215-4145 Phone: 1-614-228-4600 CMHSBOT/index.htmi Approximate Rate: $200 Distance (in miles) from Hotel to Columbus Union Hall: 0.5 Notes: Closest hotel to meeting site; very short walk Residence Inn Columbus Downtown 36 East Gay Street, Columbus, Ohio 43215-3108 Phone: 1-614-222-2610 ec3-4d19-a255-54ba596febe2 Approximate Rate: $230 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Renaissance Columbus Downtown 50 North Third Street, Columbus, Ohio 43215 Phone: 1-614-228-5050 ttp://www.marriott.com/hotels/travel/cmhbr-renaissance-columbus-downtown-hotel/ Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.0 Notes: Central downtown area Hilton Columbus Downtown 401 North High Street, Columbus, OH 43215 Phone: 1-614-384-8600 Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.1 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars; New facility and nice. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) PROJECT CONTACTS Last Updated: 22 May 2017 Project Technical Panel Phone: 614-774-7446 David Bernzweig, Columbus Fire Department (OH) Email: Safety@local67.com Phone: 780-496-3801 Ken Block, Edmonton Fire/Rescue & Metro Chiefs Representative Email: ken.block@edmonton.ca Phone: 804-971-7983 Ken Brown, VA State Firefighter's Association & NVFC (Alt to B. McQueen) Email; kbrownret@aol.com Phone: 510-839-5111 Cell: 213-321-9393 Roger Curtis, ECMS Curtis & Sons (CA) Email: rcurtis@incurtis.com Phone: Paul Curtis, ECMS Curtis & Sons (CA) (Alt to Roger Curtis) Email: pcurtis@incurtis.com Phone: 253-277-4131 Cell: 503-314-4832 Steve Lakey, Northwest Safety Clean (WA) Email: Steve@northwestsafetyclean.com Phone: 304-406-7479 Mark Lambert, WV Fire Academy & NAFTD (WV) Email: mlambe13@mail.wvu.edu Phone: 617-828-3978 Ed McCarthy, Boston Fire Department (MA) Email: Edward.mccarthy@boston.goy Phone: 315-736-7479 Cell: 315-552-8245 Brian McQueen, FASNY & National Volunteer Fire Council (NY) Email: fasnydirector@gmail.com Phone: 602-534-2396 Mark Miller, Phoenix Fire Dept. (AZ) Email: mark.a.miller@phoenix.gov Phone: 919-524-1569 Bryan Ormond, NCSU (NC) Email: rbormond@ncsu.edu Phone: Russ Osgood, Firefighter Cancer Support Network (NH) (Alt to Keith Tyson) Email: rosgood@fcsn.net Phone: Larry Petrick, IAFF (DC) Email: LPetrick@iaff.org Phone: 617-549-9850 Jim Riley, Boston Fire Department (MA) (Alt to E. McCarthy) Email: james.riley@boston.gov Phone: 757-385-2892 Molly Riley, Virginia Beach Fire Dept. (VA) Email: mriley@vbgov.com Phone: 718-999-2922 Thomas Smith, FDNY (NY) Email: Thomas.Smith@fdny.nyc.gov Phone: 214-774-2213 Cell: 940-300-5718 Tim Tomlinson, Gear Cleaning Solutions (TX) Email: tim@gearcleaningsolutions.com Phone: Robert Tutterow, NFPA Fire Service Section (NC) Email: rdtutterow@gmail.com Phone: 786-351-3276 Keith Tyson, Firefighter Cancer Support Network (FL) Email: KTyson@FCSN.net Phone: 951-807-1914 Dick Weise, LA County Fire Dept. (CA) Email: weiselacofd@yahoo.com Phone: 949-291-0637 Ken Wiles, LA County Fire Dept. (CA) (Alt to Dick Weiss) Email: Ken.Wiles@fire.lacounty.gov Phone: 512-974-0286 Chris Youngblood, Austin Fire Dept. (TX) Email: Christopher.Youngblood@austintexas.gov 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Phase 1 Project Contacts Phone: 330-723-0000, x365 Steve Allison, Fire-Dex (OH) Email: steveallison@firedex.com Phone: 800-401-4780 Jack Binder, Edmar Chemical Company (OH) Email: jackbinder@edmarchem.com Phone: 920-570-0824 Bill Brooks, Alliance Corp. (WI) Email: ill.Brooks@AllianceL.com Phone: Charlie Dunn, TenCate Protective Fabrics Email: c.dunn@tencate.com Phone: 617-984-7325 Chris Farrell, NFPA & Staff Liaison for NFPA 1851 (MA) Email: cfarrell@nfpa.org Phone: 800-232-8323 Rob Freese, Globe Manufacturing (NH) Email: robf@globefiresuits.com Phone: Pat Freeman, Globe Manufacturing (NH) (Alternate to Rob Freese) Email: patf@globefiresuits.com Phone: 704-554-3313 Diane Hess, PBI Performance Products (NC) Email: Diane.Hess@PBIProducts.com Phone: 937-415-2932 Karen Lehtonen, LionFirst Responder Products (OH) Email: klehtonen@lionprotects.com Phone: 484-433-4072 Dan Silvestri, 9-1-1 Safety (PA) Email: Dan@911se.com Liaison Contacts Phone: Pierre Carlotti, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: lierre.carlotti@interieur.gouv.fr Phone: Eric Guillaume, Efectis & Liaison for ISO TC92/SC3 (France) Email: eric.guillaume@EFECTIS.COM Phone: Bill Haskell, NIOSH NPPTL (MA) Email: czi8@cdc.gov Phone: James Hoar, Boston Fire Department (MA) Email: james.hoar@boston.gov Phone: 631-242-0621 Steve King, Chair NFPA 1851 (NY) Email: tikitai@aol.com Phone: +33(0)1.55.76.26.18 Fanny Rieunier, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: fanny.rieunier@interieur.gouv.fr Phone: 612-247-6429 Marni Schmid, Fortunes Collide & Secretariat NFPA 1851 (MI) Email: marni@fortunes-collide.com Page 2 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Core Research Team Phone: 607-758-6537 Cell: 607-423-5617 Jason Allen, Intertek (NY) Email: jason.allen@intertek.com Phone: 304-285-6076 Daniel Farcas, NIOSH HELD (WV) Email: yfe2@cdc.gov Phone: Crystal Forester, NIOSH NPPTL (WV) Email: ckf7@cdc.gov Phone: 617-984-7284 Cell: 617-659-1159 Casey Grant, Fire Protection Research Foundation (MA) Email: cgrant@nfpa.org Phone: Lee Greenawald, NIOSH NPPTL (WV) Email: ilv1@cdc.gov Phone: Bill Lindsley, NIOSH HELD (WV) Email: wlindsley@cdc.gov Phone: Stephen Martin, NIOSH DRDS (WV) Email: stm9@cdc.gov Phone: John Noti, NIOSH HELD (WV) Email: ivr2@cdc.gov Phone: Deborah Sbarra, NIOSH NPPTL (WV) Email: drc3@cdc.gov Phone: 512-288-8272 cell: 512-623-9558 Jeff Stull, International Personal Protection (TX) Email: intiperpro@aol.com Phone: 304-285-5858 cell: 681-209-2571 Jay Tarley, NIOSH NPPTL (WV) Email: ist9@cdc.gov Additional Research Team Contacts Phone: 304-285-5884 Francoise Blachere, NIOSH HELD (WV) Email: czv3@cdc.gov Phone: Renee Dotson, NIOSH HELD (WV) Email: ced9@cdc.gov Phone: James Harris, NIOSH NPPTL (WV) Email: irh6@cdc.gov Phone: Ryan Lebouf, NIOSH DRDS (WV) Email: igu6@cdc.gov Phone: 617-984-7281 Eric Peterson, Fire Protection Research Foundation (MA) Email: epeterson@nfpa.org Phone: John Powers, NIOSH (WV) Email: jop5@cdc.gov Phone: 412-386-4621 Cell: 412-463-9561 Heather Reed, NIOSH NPPTL (PA) Email: yvt5@cdc.gov Page 3 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) (for more information see www.nfpa.org/PPECleaning) PROJECT SUMMARY Last updated: 5 February 2016 Background: Fire fighter exposure to personal protective equipment (PPE) that is dirty, soiled, and contaminated is an increasing concern for long-term fire fighter health. This exposure to persistent harmful contaminants in PPE is an extremely serious problem both on the fireground to highly toxic substances including a variety of carcinogens, and more insidiously to an increasing range of infectious pathogens that are encountered in patient care and different emergency operations. Fire fighter PPE becomes contaminated during these exposures and there are no industry standards that conclusively and reliably show that clothing is being adequately cleaned. While general cleaning procedures have been established in NFPA 1851, Standard on Selection, Care, and Maintenance of Protective Ensembles for Structural Fire Fighting and Proximity Fire Fighting, there are no procedures or requirements to demonstrate whether current cleaning practices, including those specified in NFPA 1851, will remove contaminants from fire fighter protective clothing. This project is intended to establish clear and definitive guidance to the fire service for applying cleaning and decontamination procedures that effectively remove both chemical and biological contaminants. Research Goal and Objectives, and Conceptual Approach: The overall goal of this project is to improve fire fighter safety and health by reducing continuing exposure to harmful contaminants in unclean or inadequately cleaned PPE. The objectives to achieve this goal are twofold: (1) To characterize fireground and emergency scene contamination leading to these exposures and develop the methodology for the consistent measurement of cleaning effectiveness; and (2) determine implementable cleaning, decontamination, and disinfection strategies that effectively reduce fire fighter exposures to persistent contaminants. The approach taken by this project is illustrated in Figure 1: Project Conceptual Approach. - Ensure Identify Devise Validate lab - - chemical and methods to methods - at biologicat conteminate againet field ses target clothing in contaminants laboratory exposures acceptance Project Direction Figure 1: Project Conceptual Approach 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :ttps://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Phases and Tasks: This project involves the following four key phases of activity: 1) Identification of Contaminants: Confirm identification and ability to characterize persistent chemical and biological contaminants in fire fighter PPE through target substances and microorganisms. 2) Establishment of Soil and Chemical Contamination/Decontamination Procedures: Develop and validate specific procedures that determine the effectiveness of laundering and other cleaning methods in removing specific soils and chemical contaminants. 3) Establishment of Biological Contamination/Disinfection or Sanitization Procedures: Develop and validate specific procedures that determine the effectiveness of laundering or disinfection/sanitization processes that remove/deactivate biologically-based contaminants. 4) Creation of Overall Fire Service Guidance: Prepare clear and definitive information for the fire service industry (fire fighters, fire departments, clothing manufacturers, material suppliers, cleaning/care organizations, and cleaning agent or equipment manufacturers) on appropriate approaches for properly cleaning fire fighter protective clothing and equipment. The specific tasks of this project are based on these four phases of the project, and these are illustrated in Figure 2: Project Tasks. PHASE 2 PHASEZ Task 2.4 Task 2.5 Task 1.1 Task 2.1 Validate testsat Refine test Appoint Technical Select cleaning selected ISPS methodology Review Panel methods/agents (chemical) (chemical) PHASE $ Task 4.1 Task 1.2 Task 2.2 Write qualification Review Prigr Put together test plan methods studies/literature (chemical) Task 2.3 Task 4.2 Task 1.3 PHASE 3 Perform laboratory Establish cleaning Setup analytical chemical Task 3.3 acceptance criteria capabilities decontaminant Put together test plan testing (biological) Task 4.3 Task 1.4 Perform Task 3.4 Prepare public inputs for NFPA 1851 demonstration tests Task 3.1 Perform laboratory Task 3.6 Select study biological Refine test microorganisms decontaminant methodology Task 1.5 testing (biological) Task 4.4 Refine biological Prepare industry decontamination Task 3.2 Task 3.5 guidance document scope Select biological Validate testsat cleaning methods selected ISPs (biological) Task 1.6 Task 4,5 Establish cleanliness Prepare project final metrics report Figure 2: Project Tasks Implementation and Schedule: This three year project is due to be completed no later than " August 2018, and is funded through an AFG Fire Prevention & Safety Grant from the U.S. Department of Homeland Security / Federal Emergency Management Agency. The Research Foundation will lead a unique research team partnership composed of the FPRF, National Institute for Occupational Safety and Health (NIOSH), International Personal Protection (IPP), and Intertek. The research team, along with several Independent Service Providers (ISPs), will work with the fire service partners and others to validate and optimize fire fighter PPE cleaning validation methods. For more information see www.nfpa.org/PPECleaning. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION Fire Fighter Cancer Cohort Study Full Title: The Firefighter Multicenter Cancer Cohort Study: Framework Development and Testing PROJECT SUMMARY Last Updated: 20 September 2016 Background: Cancer is a leading cause of fire service morbidity and mortality. Firefighter exposure to carcinogens occurs through skin contamination and through inhalation when respiratory protection is not worn when combustion products are present such as during overhaul, standby, and operation of apparatus, as well as through off-gassing of equipment and exposures in the fire station. However, we currently do not understand which exposures are responsible for cancer in firefighters, the mechanisms by which firefighter exposures cause cancer, nor the most effective means of reducing exposures. Since cancer has a long latency period, biomarkers are also needed that can measure the toxicological effects of carcinogen exposure well before the development of cancer, when interventions to prevent disease could be effective. Development of a large (>10,000 firefighter) multicenter firefighter cancer prospective cohort study will address these needs, but the framework for such a study needs to be first developed and tested among a smaller initial set of fire service partners. Implementation and Schedule: This research project is led by University of Arizona with collaborative support from multiple other research partners, including the University of Miami, National Institute for Occupational Safety and Health; National Fallen Firefighter Foundation, Fire Protection Research Foundation, and others. Initial funding for this project is through a 3-year DHS/FEMA Assistance to Fire Fighter (AFG) Fire Grant, with the intention to identify and obtain additional funding for the duration of the 30 year effort. The project start date is August 2016. The Principal Investigator for this project is: Jefferey L. Burgess, MD, MS, MPH, University of Arizona, email: iburgess@emailarizona.edu. Project Goal and Aims: The goal of the initial 3-year effort of this overall project is to develop and test a framework for establishing a long-term fire fighter multicenter prospective cohort study focused on carcinogenic exposures and effects. The specific aims are to: 1) Establish an oversight and planning board to provide study oversight, foster communication among fire organizations and help develop a long-term funding plan; 2) Create and test a cohort study data coordinating center and harmonized survey data protocols; 3) Develop and validate a firefighter carcinogen exposure matrix and data collection system; and 4) Create a biomarker assessment center and evaluate the association between cumulative firefighter exposures and epigenetic effects. For more information, contact: Casey Grant, Fire Protection Research Foundation 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7284 Fax: +1.617.984.7010 Email: cgrant@nfpa.org Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Methodology: This study will harmonize and build on recent and developing firefighter cancer prevention studies in Arizona, Florida and Massachusetts, adding volunteer fire departments. An oversight and planning board will be established by the Fire Protection Research Foundation (FPRF) in association with the National Fallen Firefighter Foundation (NFFF) Fire Service Occupational Cancer Alliance (FSOCA) to provide oversight of the study through collaboration among fire service organizations, academia, and government agencies, and develop a long-term funding and sustainability plan. A data coordination center team will design, develop and evaluate a framework for a multicenter prospective cohort study of firefighters and cancer risk, including standardized participant survey data collection tools and analysis protocols sufficient to address the short- and long-term study objectives as well as linkage with long-term outcome data including cancer development. An exposure assessment center team will develop a carcinogen exposure matrix and data collection system to provide improved occupational exposure data for comparison with epigenetic outcomes and eventual cancer outcomes. Carcinogen exposures associated with specific fire types will be evaluated across fire departments through industrial hygiene monitoring and analysis of urine for absorbed contaminants, supplementing existing FEMA-funded and other studies of firefighter exposures and allowing for participating fire departments to design interventions to reduce current exposures. Expansion of the National Fire Operations Reporting System (NFORS) will be explored as one option to uniformly collect incident and exposure data. Blood and buccal cells will be collected during annual medical surveillance evaluations, including both new recruits and incumbent firefighters. Pilot studies of epigenetic markers of cancer effect and cancer risk will be analyzed comparing municipal firefighters with high chronic exposures, volunteer firefighters with low chronic exposures, and non- firefighter friends of the municipal firefighters (serving as controls). Project Deliverables: The anticipated outcomes from this 3-year effort is to establish and test the framework necessary for the subsequent development of a large multicenter cohort study of cancer in the fire service. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226

what is the phone number for david bernzweig under the list of "project technical panel"?

hlcn0226

hlcn0226_p0, hlcn0226_p1, hlcn0226_p2, hlcn0226_p3, hlcn0226_p4, hlcn0226_p5, hlcn0226_p6, hlcn0226_p7, hlcn0226_p8, hlcn0226_p9, hlcn0226_p10, hlcn0226_p11

614-774-7446

129 From: Jürgen Troitzsch To: Osimitz Thomas; Dr. Blais Matthew; Prof. Rein Guillermo; Dr. Hayes Wallace; Dourson. Michael (doursomi); Kacew Sam; Dr. Wise Kimberly Subject: Fwd: Project on FF PPE Cleaning Validation Date: Monday, June 12, 2017 1:11:46 PM Attachments: PROU PANEL - PPE Cleaning (33) pdf PROJ SUMMARY - PPE Cleaning (7) pot FLYER FF Contam Control Workshop (6) odf HOTELS - Contam Control Wrkshp on 2017Jul19.pd PROJS JMMARY- FE Cancer Cohort Study (4) odf Dear All, I came across this project, which may be of interest in the frame of our fire fighters cancer activities. Kind regards/Viele Grüße Jürgen Dr. Jürgen Troitzsch Fire and Environment Protection Service FEPS Via Patrizia 32 CH-6612 Ascona, Switzerland Mobile: +41 79 289 17 16 Phone: +41 91 791 14 22 Email: itroitzsch@troitzsch.com Web: www.troitzsch.com De : Grant, Casey Envoyé : lundi 22 mai 2017 17:58 À : Safety@local67.com; kenblock@edmonton.ca. tis.com; mlambetamallN u.edu; dwardmecarthyebostengoy ark.a.miller@ehoen ix.gov; james.riley@bosta nagov; mrilev@ybgov.com Thomas Smith@fdnv.nyc.gov; ;timügearcleaningsolutions.s om KTvson@FCSN.net; Ken.Wiles @fire.jacounty.gov Farrell, Christopher cobtlogiobefiresuits.com; pattogiobefiresults.com; Diane.Hess@ Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 130 PBIProducts.com; Kebtonen@lionprotedscon leur.gouv.fr; GUILLAUME Eric <eric guillaume@EFECTIS.COM ;ilames.hoar@boston.gov; mamiefortunes-collide.com Cc : lasonallendintertekeor vfe2@cdc.gov; ckf7@codc.gov wlindslev@ cdc.gov; stmp@adc.edu ivr2@cdc.gov; drc3@cdc.gov; ; istendice OY; Objet : Project on FF PPE Cleaning Validation To: Panel, Research Team and Liaisons for Project on "Fire Fighter PPE Cleaning Validation" It has been some time since we last spoke, and I have the following three items to be addressed: 1) A lot has been happening with our project and we want to hold a 90 minute conference call in early August 2017 to bring everyone up-to-date. I've created a scheduling poll to determine the optimum date/time Please respond before Noon ET on Wednesday 31/May/2017 so that we can get this on our calendars. I've attached the Project Roster and Project Summary in case anyone needs a refresher for this project addressing "how clean is clean". Thanks. 2) I've been asked to participate in a webinar tomorrow (23/Mav/2017) from noon ET to 1:30 pm ET on "Factors Relating to Cancer and Contamination in the US Fire Service". I've been assigned a portion of this webinar (among two other speakers) to address on-going research and I'm planning to address our project among several other on-going efforts. The link is on the NFPA home page at: FYI.. 3) Some of you are already aware of the Workshop in Columbus, Ohio on 19- 20/Julv/2017, and if not I want to call it to your attention. This is for the separate one year AFG project on "Campaign for Fire Service Contamination Control". Attached is a Flyer that provides additional details, and also attached is a list of hotels in the area to assist with travel. The workshop will be held from Noon to Noon on 19-20/July and we still have room if you would like to attend. In addition, the separate project (i.e., a third related project) on "Fire Fighter Cancer Cohort Study" will hold a separate planning meeting on the afternoon of 20/July from 1 pm to 5 pm (Project Summary is attached). All are welcome to attend this as well. If you are a fire service panel member we can cover your travel, and I can send follow-up instructions to you separately. For anyone interested in attending the Columbus meetings on 19-20/July, please let us know by email to cgrant@nfoa.org and Thanks.. Casey C. Grant, P.E. Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION "CAMPAIGN FOR FIRE SERVICE CONTAMINATION CONTROL" WORKSHOP Location: Columbus Fire Fighters Union Hall, 379 W Broad St, Columbus, OH 43215 Workshop Dates: 19-20 July 2017 (Last Updated: 21 April 2017; subject to update) Background: Exposure to chemical and biological contaminants on the fire ground is an increasing concern for long-term fire fighter health. Cancer and other diseases resulting from chronic exposures has become a leading concern for the fire service. This is presumed to be associated with fireground exposures relating to protection/hygiene practices and persistent harmful contamination found in fire fighter equipment, apparatus carrying that equipment, and stations where the equipment resides. Workshop Goal and Objectives: The goal of this Workshop is to identify concepts and materials that are or can be useful to control the spread of harmful fire ground contaminants, ultimately in support of improved fire fighter long-term health. The following objectives support this goal (and reflect anticipated deliverables): Identify, review and recommend baseline materials (existing and proposed) addressing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and prioritize gaps that are barriers to enhancing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and review key characteristics for effective promotion and communication. Clarify target audiences for outreach and consider stakeholder research prior to developing a comprehensive communications plan to improve outcome. Prioritize messages for year one. Agenda: Wed; 19/July 1:00 pm Day One: Welcome and Call to Order Casey Grant, FPRF 1:15 pm Overview of Baseline Materials and Review of Gaps Jeff Stull, IPP 2:00 pm Review of Outreach Peg, Paul, PPA 2:30 pm Case Study: Best Practice Information Beth Gallup, KFD 3:00 pm PM Break 3:15 pm Casey Study: Standards Revisions Dave Bernzweig, CFD 3:45 pm Case Study: Equipment & Facilities Paul Erickson, LEWA 4:15 pm Breakout Groups Workshop Attendees 5:00 pm Adjourn for Day One (& Evening Networking Reception) Thur; 20/July 8:30 am Day Two: Group Review of Baseline Materials Jeff Stull, IPP 8:45 am Breakout Groups Continue Workshop Attendees 9:45 am AM Break 10:00 am Breakout Group Report Workshop Attendees 11:00 am Plenary Discussion Workshop Attendees 11:30 am Workshop Wrap-up & Summary Observations Casey Grant, FPRF 12:00 pm Adjournment Registration: Workshop attendance is limited to the first 50 attendees, and others will be placed the on a waiting list. To request attendance or for more information, please contact epeterson@nfpa.org. After the Workshop a report will be available. This Workshop is funded through an AFG Fire Prevention & Safety Grant from U.S.DHS/FEMA. 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 WORKSHOP ON FIRE SERVICE CONTAMINATION CONTROL 19-20 July 2017 (Noon to Noon ET) Columbus Fire Fighters Union Hall 379 W Broad St, Columbus, OH 43215 Note: For flights, Workshop starts at Noon ET on 19/July/2017 and finishes at Noon ET on 20/July/2017 Drury Inn & Suites: 88 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-221-7008 ttos://www.drurvhotels.com/locations/columbus-ob/drurv-inn-and-suites-columbus-convention: center Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Red Roof Plus Columbus Downtown Convention Center 111 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-224-6539 ittps://www.redroof.com/property/Columbus/OH/43215/Hotels-close-to-Greater-columbus- Convention-Center-US-23-1-670/RRI262/ Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.4 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Sheraton Columbus Hotel at Capital Square 75 East State Street, Columbus, OH, 43215 Phone: 1-614-365-4500 http://www.sheratoncolumbuscapitolsquare.com/ Approximate Rate: $170 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Central downtown area Hampton Inn and Suites Columbus Downtown 501 North High Street, Columbus, OH 43215 Phone: 1-614-559-2000 htto://hamptoninns.bilton.com/en/hotels/ohio/hampton-inn-and-suites-columbus-downtown- CMHHSHK/index.htmi?WT.mc. Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Page 1 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Courtyard Columbus Downtown 35 West Spring Street, Columbus, Ohio 43215 Phone: 1-614-228-3200 4d19-a255-54ba596febe2 Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Downtown west area; walkable Doubletree Suites by Hilton Columbus Downtown 50 South Front St, Columbus, Ohio, 43215-4145 Phone: 1-614-228-4600 CMHSBOT/index.htmi Approximate Rate: $200 Distance (in miles) from Hotel to Columbus Union Hall: 0.5 Notes: Closest hotel to meeting site; very short walk Residence Inn Columbus Downtown 36 East Gay Street, Columbus, Ohio 43215-3108 Phone: 1-614-222-2610 ec3-4d19-a255-54ba596febe2 Approximate Rate: $230 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Renaissance Columbus Downtown 50 North Third Street, Columbus, Ohio 43215 Phone: 1-614-228-5050 ttp://www.marriott.com/hotels/travel/cmhbr-renaissance-columbus-downtown-hotel/ Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.0 Notes: Central downtown area Hilton Columbus Downtown 401 North High Street, Columbus, OH 43215 Phone: 1-614-384-8600 Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.1 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars; New facility and nice. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) PROJECT CONTACTS Last Updated: 22 May 2017 Project Technical Panel Phone: 614-774-7446 David Bernzweig, Columbus Fire Department (OH) Email: Safety@local67.com Phone: 780-496-3801 Ken Block, Edmonton Fire/Rescue & Metro Chiefs Representative Email: ken.block@edmonton.ca Phone: 804-971-7983 Ken Brown, VA State Firefighter's Association & NVFC (Alt to B. McQueen) Email; kbrownret@aol.com Phone: 510-839-5111 Cell: 213-321-9393 Roger Curtis, ECMS Curtis & Sons (CA) Email: rcurtis@incurtis.com Phone: Paul Curtis, ECMS Curtis & Sons (CA) (Alt to Roger Curtis) Email: pcurtis@incurtis.com Phone: 253-277-4131 Cell: 503-314-4832 Steve Lakey, Northwest Safety Clean (WA) Email: Steve@northwestsafetyclean.com Phone: 304-406-7479 Mark Lambert, WV Fire Academy & NAFTD (WV) Email: mlambe13@mail.wvu.edu Phone: 617-828-3978 Ed McCarthy, Boston Fire Department (MA) Email: Edward.mccarthy@boston.goy Phone: 315-736-7479 Cell: 315-552-8245 Brian McQueen, FASNY & National Volunteer Fire Council (NY) Email: fasnydirector@gmail.com Phone: 602-534-2396 Mark Miller, Phoenix Fire Dept. (AZ) Email: mark.a.miller@phoenix.gov Phone: 919-524-1569 Bryan Ormond, NCSU (NC) Email: rbormond@ncsu.edu Phone: Russ Osgood, Firefighter Cancer Support Network (NH) (Alt to Keith Tyson) Email: rosgood@fcsn.net Phone: Larry Petrick, IAFF (DC) Email: LPetrick@iaff.org Phone: 617-549-9850 Jim Riley, Boston Fire Department (MA) (Alt to E. McCarthy) Email: james.riley@boston.gov Phone: 757-385-2892 Molly Riley, Virginia Beach Fire Dept. (VA) Email: mriley@vbgov.com Phone: 718-999-2922 Thomas Smith, FDNY (NY) Email: Thomas.Smith@fdny.nyc.gov Phone: 214-774-2213 Cell: 940-300-5718 Tim Tomlinson, Gear Cleaning Solutions (TX) Email: tim@gearcleaningsolutions.com Phone: Robert Tutterow, NFPA Fire Service Section (NC) Email: rdtutterow@gmail.com Phone: 786-351-3276 Keith Tyson, Firefighter Cancer Support Network (FL) Email: KTyson@FCSN.net Phone: 951-807-1914 Dick Weise, LA County Fire Dept. (CA) Email: weiselacofd@yahoo.com Phone: 949-291-0637 Ken Wiles, LA County Fire Dept. (CA) (Alt to Dick Weiss) Email: Ken.Wiles@fire.lacounty.gov Phone: 512-974-0286 Chris Youngblood, Austin Fire Dept. (TX) Email: Christopher.Youngblood@austintexas.gov 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Phase 1 Project Contacts Phone: 330-723-0000, x365 Steve Allison, Fire-Dex (OH) Email: steveallison@firedex.com Phone: 800-401-4780 Jack Binder, Edmar Chemical Company (OH) Email: jackbinder@edmarchem.com Phone: 920-570-0824 Bill Brooks, Alliance Corp. (WI) Email: ill.Brooks@AllianceL.com Phone: Charlie Dunn, TenCate Protective Fabrics Email: c.dunn@tencate.com Phone: 617-984-7325 Chris Farrell, NFPA & Staff Liaison for NFPA 1851 (MA) Email: cfarrell@nfpa.org Phone: 800-232-8323 Rob Freese, Globe Manufacturing (NH) Email: robf@globefiresuits.com Phone: Pat Freeman, Globe Manufacturing (NH) (Alternate to Rob Freese) Email: patf@globefiresuits.com Phone: 704-554-3313 Diane Hess, PBI Performance Products (NC) Email: Diane.Hess@PBIProducts.com Phone: 937-415-2932 Karen Lehtonen, LionFirst Responder Products (OH) Email: klehtonen@lionprotects.com Phone: 484-433-4072 Dan Silvestri, 9-1-1 Safety (PA) Email: Dan@911se.com Liaison Contacts Phone: Pierre Carlotti, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: lierre.carlotti@interieur.gouv.fr Phone: Eric Guillaume, Efectis & Liaison for ISO TC92/SC3 (France) Email: eric.guillaume@EFECTIS.COM Phone: Bill Haskell, NIOSH NPPTL (MA) Email: czi8@cdc.gov Phone: James Hoar, Boston Fire Department (MA) Email: james.hoar@boston.gov Phone: 631-242-0621 Steve King, Chair NFPA 1851 (NY) Email: tikitai@aol.com Phone: +33(0)1.55.76.26.18 Fanny Rieunier, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: fanny.rieunier@interieur.gouv.fr Phone: 612-247-6429 Marni Schmid, Fortunes Collide & Secretariat NFPA 1851 (MI) Email: marni@fortunes-collide.com Page 2 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Core Research Team Phone: 607-758-6537 Cell: 607-423-5617 Jason Allen, Intertek (NY) Email: jason.allen@intertek.com Phone: 304-285-6076 Daniel Farcas, NIOSH HELD (WV) Email: yfe2@cdc.gov Phone: Crystal Forester, NIOSH NPPTL (WV) Email: ckf7@cdc.gov Phone: 617-984-7284 Cell: 617-659-1159 Casey Grant, Fire Protection Research Foundation (MA) Email: cgrant@nfpa.org Phone: Lee Greenawald, NIOSH NPPTL (WV) Email: ilv1@cdc.gov Phone: Bill Lindsley, NIOSH HELD (WV) Email: wlindsley@cdc.gov Phone: Stephen Martin, NIOSH DRDS (WV) Email: stm9@cdc.gov Phone: John Noti, NIOSH HELD (WV) Email: ivr2@cdc.gov Phone: Deborah Sbarra, NIOSH NPPTL (WV) Email: drc3@cdc.gov Phone: 512-288-8272 cell: 512-623-9558 Jeff Stull, International Personal Protection (TX) Email: intiperpro@aol.com Phone: 304-285-5858 cell: 681-209-2571 Jay Tarley, NIOSH NPPTL (WV) Email: ist9@cdc.gov Additional Research Team Contacts Phone: 304-285-5884 Francoise Blachere, NIOSH HELD (WV) Email: czv3@cdc.gov Phone: Renee Dotson, NIOSH HELD (WV) Email: ced9@cdc.gov Phone: James Harris, NIOSH NPPTL (WV) Email: irh6@cdc.gov Phone: Ryan Lebouf, NIOSH DRDS (WV) Email: igu6@cdc.gov Phone: 617-984-7281 Eric Peterson, Fire Protection Research Foundation (MA) Email: epeterson@nfpa.org Phone: John Powers, NIOSH (WV) Email: jop5@cdc.gov Phone: 412-386-4621 Cell: 412-463-9561 Heather Reed, NIOSH NPPTL (PA) Email: yvt5@cdc.gov Page 3 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) (for more information see www.nfpa.org/PPECleaning) PROJECT SUMMARY Last updated: 5 February 2016 Background: Fire fighter exposure to personal protective equipment (PPE) that is dirty, soiled, and contaminated is an increasing concern for long-term fire fighter health. This exposure to persistent harmful contaminants in PPE is an extremely serious problem both on the fireground to highly toxic substances including a variety of carcinogens, and more insidiously to an increasing range of infectious pathogens that are encountered in patient care and different emergency operations. Fire fighter PPE becomes contaminated during these exposures and there are no industry standards that conclusively and reliably show that clothing is being adequately cleaned. While general cleaning procedures have been established in NFPA 1851, Standard on Selection, Care, and Maintenance of Protective Ensembles for Structural Fire Fighting and Proximity Fire Fighting, there are no procedures or requirements to demonstrate whether current cleaning practices, including those specified in NFPA 1851, will remove contaminants from fire fighter protective clothing. This project is intended to establish clear and definitive guidance to the fire service for applying cleaning and decontamination procedures that effectively remove both chemical and biological contaminants. Research Goal and Objectives, and Conceptual Approach: The overall goal of this project is to improve fire fighter safety and health by reducing continuing exposure to harmful contaminants in unclean or inadequately cleaned PPE. The objectives to achieve this goal are twofold: (1) To characterize fireground and emergency scene contamination leading to these exposures and develop the methodology for the consistent measurement of cleaning effectiveness; and (2) determine implementable cleaning, decontamination, and disinfection strategies that effectively reduce fire fighter exposures to persistent contaminants. The approach taken by this project is illustrated in Figure 1: Project Conceptual Approach. - Ensure Identify Devise Validate lab - - chemical and methods to methods - at biologicat conteminate againet field ses target clothing in contaminants laboratory exposures acceptance Project Direction Figure 1: Project Conceptual Approach 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :ttps://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Phases and Tasks: This project involves the following four key phases of activity: 1) Identification of Contaminants: Confirm identification and ability to characterize persistent chemical and biological contaminants in fire fighter PPE through target substances and microorganisms. 2) Establishment of Soil and Chemical Contamination/Decontamination Procedures: Develop and validate specific procedures that determine the effectiveness of laundering and other cleaning methods in removing specific soils and chemical contaminants. 3) Establishment of Biological Contamination/Disinfection or Sanitization Procedures: Develop and validate specific procedures that determine the effectiveness of laundering or disinfection/sanitization processes that remove/deactivate biologically-based contaminants. 4) Creation of Overall Fire Service Guidance: Prepare clear and definitive information for the fire service industry (fire fighters, fire departments, clothing manufacturers, material suppliers, cleaning/care organizations, and cleaning agent or equipment manufacturers) on appropriate approaches for properly cleaning fire fighter protective clothing and equipment. The specific tasks of this project are based on these four phases of the project, and these are illustrated in Figure 2: Project Tasks. PHASE 2 PHASEZ Task 2.4 Task 2.5 Task 1.1 Task 2.1 Validate testsat Refine test Appoint Technical Select cleaning selected ISPS methodology Review Panel methods/agents (chemical) (chemical) PHASE $ Task 4.1 Task 1.2 Task 2.2 Write qualification Review Prigr Put together test plan methods studies/literature (chemical) Task 2.3 Task 4.2 Task 1.3 PHASE 3 Perform laboratory Establish cleaning Setup analytical chemical Task 3.3 acceptance criteria capabilities decontaminant Put together test plan testing (biological) Task 4.3 Task 1.4 Perform Task 3.4 Prepare public inputs for NFPA 1851 demonstration tests Task 3.1 Perform laboratory Task 3.6 Select study biological Refine test microorganisms decontaminant methodology Task 1.5 testing (biological) Task 4.4 Refine biological Prepare industry decontamination Task 3.2 Task 3.5 guidance document scope Select biological Validate testsat cleaning methods selected ISPs (biological) Task 1.6 Task 4,5 Establish cleanliness Prepare project final metrics report Figure 2: Project Tasks Implementation and Schedule: This three year project is due to be completed no later than " August 2018, and is funded through an AFG Fire Prevention & Safety Grant from the U.S. Department of Homeland Security / Federal Emergency Management Agency. The Research Foundation will lead a unique research team partnership composed of the FPRF, National Institute for Occupational Safety and Health (NIOSH), International Personal Protection (IPP), and Intertek. The research team, along with several Independent Service Providers (ISPs), will work with the fire service partners and others to validate and optimize fire fighter PPE cleaning validation methods. For more information see www.nfpa.org/PPECleaning. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION Fire Fighter Cancer Cohort Study Full Title: The Firefighter Multicenter Cancer Cohort Study: Framework Development and Testing PROJECT SUMMARY Last Updated: 20 September 2016 Background: Cancer is a leading cause of fire service morbidity and mortality. Firefighter exposure to carcinogens occurs through skin contamination and through inhalation when respiratory protection is not worn when combustion products are present such as during overhaul, standby, and operation of apparatus, as well as through off-gassing of equipment and exposures in the fire station. However, we currently do not understand which exposures are responsible for cancer in firefighters, the mechanisms by which firefighter exposures cause cancer, nor the most effective means of reducing exposures. Since cancer has a long latency period, biomarkers are also needed that can measure the toxicological effects of carcinogen exposure well before the development of cancer, when interventions to prevent disease could be effective. Development of a large (>10,000 firefighter) multicenter firefighter cancer prospective cohort study will address these needs, but the framework for such a study needs to be first developed and tested among a smaller initial set of fire service partners. Implementation and Schedule: This research project is led by University of Arizona with collaborative support from multiple other research partners, including the University of Miami, National Institute for Occupational Safety and Health; National Fallen Firefighter Foundation, Fire Protection Research Foundation, and others. Initial funding for this project is through a 3-year DHS/FEMA Assistance to Fire Fighter (AFG) Fire Grant, with the intention to identify and obtain additional funding for the duration of the 30 year effort. The project start date is August 2016. The Principal Investigator for this project is: Jefferey L. Burgess, MD, MS, MPH, University of Arizona, email: iburgess@emailarizona.edu. Project Goal and Aims: The goal of the initial 3-year effort of this overall project is to develop and test a framework for establishing a long-term fire fighter multicenter prospective cohort study focused on carcinogenic exposures and effects. The specific aims are to: 1) Establish an oversight and planning board to provide study oversight, foster communication among fire organizations and help develop a long-term funding plan; 2) Create and test a cohort study data coordinating center and harmonized survey data protocols; 3) Develop and validate a firefighter carcinogen exposure matrix and data collection system; and 4) Create a biomarker assessment center and evaluate the association between cumulative firefighter exposures and epigenetic effects. For more information, contact: Casey Grant, Fire Protection Research Foundation 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7284 Fax: +1.617.984.7010 Email: cgrant@nfpa.org Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Methodology: This study will harmonize and build on recent and developing firefighter cancer prevention studies in Arizona, Florida and Massachusetts, adding volunteer fire departments. An oversight and planning board will be established by the Fire Protection Research Foundation (FPRF) in association with the National Fallen Firefighter Foundation (NFFF) Fire Service Occupational Cancer Alliance (FSOCA) to provide oversight of the study through collaboration among fire service organizations, academia, and government agencies, and develop a long-term funding and sustainability plan. A data coordination center team will design, develop and evaluate a framework for a multicenter prospective cohort study of firefighters and cancer risk, including standardized participant survey data collection tools and analysis protocols sufficient to address the short- and long-term study objectives as well as linkage with long-term outcome data including cancer development. An exposure assessment center team will develop a carcinogen exposure matrix and data collection system to provide improved occupational exposure data for comparison with epigenetic outcomes and eventual cancer outcomes. Carcinogen exposures associated with specific fire types will be evaluated across fire departments through industrial hygiene monitoring and analysis of urine for absorbed contaminants, supplementing existing FEMA-funded and other studies of firefighter exposures and allowing for participating fire departments to design interventions to reduce current exposures. Expansion of the National Fire Operations Reporting System (NFORS) will be explored as one option to uniformly collect incident and exposure data. Blood and buccal cells will be collected during annual medical surveillance evaluations, including both new recruits and incumbent firefighters. Pilot studies of epigenetic markers of cancer effect and cancer risk will be analyzed comparing municipal firefighters with high chronic exposures, volunteer firefighters with low chronic exposures, and non- firefighter friends of the municipal firefighters (serving as controls). Project Deliverables: The anticipated outcomes from this 3-year effort is to establish and test the framework necessary for the subsequent development of a large multicenter cohort study of cancer in the fire service. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226

what is the email id for bryan ormand under the list of 'project technical panel'?

hlcn0226

hlcn0226_p0, hlcn0226_p1, hlcn0226_p2, hlcn0226_p3, hlcn0226_p4, hlcn0226_p5, hlcn0226_p6, hlcn0226_p7, hlcn0226_p8, hlcn0226_p9, hlcn0226_p10, hlcn0226_p11

rbormond@ncsu.edu

129 From: Jürgen Troitzsch To: Osimitz Thomas; Dr. Blais Matthew; Prof. Rein Guillermo; Dr. Hayes Wallace; Dourson. Michael (doursomi); Kacew Sam; Dr. Wise Kimberly Subject: Fwd: Project on FF PPE Cleaning Validation Date: Monday, June 12, 2017 1:11:46 PM Attachments: PROU PANEL - PPE Cleaning (33) pdf PROJ SUMMARY - PPE Cleaning (7) pot FLYER FF Contam Control Workshop (6) odf HOTELS - Contam Control Wrkshp on 2017Jul19.pd PROJS JMMARY- FE Cancer Cohort Study (4) odf Dear All, I came across this project, which may be of interest in the frame of our fire fighters cancer activities. Kind regards/Viele Grüße Jürgen Dr. Jürgen Troitzsch Fire and Environment Protection Service FEPS Via Patrizia 32 CH-6612 Ascona, Switzerland Mobile: +41 79 289 17 16 Phone: +41 91 791 14 22 Email: itroitzsch@troitzsch.com Web: www.troitzsch.com De : Grant, Casey Envoyé : lundi 22 mai 2017 17:58 À : Safety@local67.com; kenblock@edmonton.ca. tis.com; mlambetamallN u.edu; dwardmecarthyebostengoy ark.a.miller@ehoen ix.gov; james.riley@bosta nagov; mrilev@ybgov.com Thomas Smith@fdnv.nyc.gov; ;timügearcleaningsolutions.s om KTvson@FCSN.net; Ken.Wiles @fire.jacounty.gov Farrell, Christopher cobtlogiobefiresuits.com; pattogiobefiresults.com; Diane.Hess@ Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 130 PBIProducts.com; Kebtonen@lionprotedscon leur.gouv.fr; GUILLAUME Eric <eric guillaume@EFECTIS.COM ;ilames.hoar@boston.gov; mamiefortunes-collide.com Cc : lasonallendintertekeor vfe2@cdc.gov; ckf7@codc.gov wlindslev@ cdc.gov; stmp@adc.edu ivr2@cdc.gov; drc3@cdc.gov; ; istendice OY; Objet : Project on FF PPE Cleaning Validation To: Panel, Research Team and Liaisons for Project on "Fire Fighter PPE Cleaning Validation" It has been some time since we last spoke, and I have the following three items to be addressed: 1) A lot has been happening with our project and we want to hold a 90 minute conference call in early August 2017 to bring everyone up-to-date. I've created a scheduling poll to determine the optimum date/time Please respond before Noon ET on Wednesday 31/May/2017 so that we can get this on our calendars. I've attached the Project Roster and Project Summary in case anyone needs a refresher for this project addressing "how clean is clean". Thanks. 2) I've been asked to participate in a webinar tomorrow (23/Mav/2017) from noon ET to 1:30 pm ET on "Factors Relating to Cancer and Contamination in the US Fire Service". I've been assigned a portion of this webinar (among two other speakers) to address on-going research and I'm planning to address our project among several other on-going efforts. The link is on the NFPA home page at: FYI.. 3) Some of you are already aware of the Workshop in Columbus, Ohio on 19- 20/Julv/2017, and if not I want to call it to your attention. This is for the separate one year AFG project on "Campaign for Fire Service Contamination Control". Attached is a Flyer that provides additional details, and also attached is a list of hotels in the area to assist with travel. The workshop will be held from Noon to Noon on 19-20/July and we still have room if you would like to attend. In addition, the separate project (i.e., a third related project) on "Fire Fighter Cancer Cohort Study" will hold a separate planning meeting on the afternoon of 20/July from 1 pm to 5 pm (Project Summary is attached). All are welcome to attend this as well. If you are a fire service panel member we can cover your travel, and I can send follow-up instructions to you separately. For anyone interested in attending the Columbus meetings on 19-20/July, please let us know by email to cgrant@nfoa.org and Thanks.. Casey C. Grant, P.E. Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION "CAMPAIGN FOR FIRE SERVICE CONTAMINATION CONTROL" WORKSHOP Location: Columbus Fire Fighters Union Hall, 379 W Broad St, Columbus, OH 43215 Workshop Dates: 19-20 July 2017 (Last Updated: 21 April 2017; subject to update) Background: Exposure to chemical and biological contaminants on the fire ground is an increasing concern for long-term fire fighter health. Cancer and other diseases resulting from chronic exposures has become a leading concern for the fire service. This is presumed to be associated with fireground exposures relating to protection/hygiene practices and persistent harmful contamination found in fire fighter equipment, apparatus carrying that equipment, and stations where the equipment resides. Workshop Goal and Objectives: The goal of this Workshop is to identify concepts and materials that are or can be useful to control the spread of harmful fire ground contaminants, ultimately in support of improved fire fighter long-term health. The following objectives support this goal (and reflect anticipated deliverables): Identify, review and recommend baseline materials (existing and proposed) addressing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and prioritize gaps that are barriers to enhancing best practices, standards, research, equipment, facilities, and other areas of focus. Identify and review key characteristics for effective promotion and communication. Clarify target audiences for outreach and consider stakeholder research prior to developing a comprehensive communications plan to improve outcome. Prioritize messages for year one. Agenda: Wed; 19/July 1:00 pm Day One: Welcome and Call to Order Casey Grant, FPRF 1:15 pm Overview of Baseline Materials and Review of Gaps Jeff Stull, IPP 2:00 pm Review of Outreach Peg, Paul, PPA 2:30 pm Case Study: Best Practice Information Beth Gallup, KFD 3:00 pm PM Break 3:15 pm Casey Study: Standards Revisions Dave Bernzweig, CFD 3:45 pm Case Study: Equipment & Facilities Paul Erickson, LEWA 4:15 pm Breakout Groups Workshop Attendees 5:00 pm Adjourn for Day One (& Evening Networking Reception) Thur; 20/July 8:30 am Day Two: Group Review of Baseline Materials Jeff Stull, IPP 8:45 am Breakout Groups Continue Workshop Attendees 9:45 am AM Break 10:00 am Breakout Group Report Workshop Attendees 11:00 am Plenary Discussion Workshop Attendees 11:30 am Workshop Wrap-up & Summary Observations Casey Grant, FPRF 12:00 pm Adjournment Registration: Workshop attendance is limited to the first 50 attendees, and others will be placed the on a waiting list. To request attendance or for more information, please contact epeterson@nfpa.org. After the Workshop a report will be available. This Workshop is funded through an AFG Fire Prevention & Safety Grant from U.S.DHS/FEMA. 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 WORKSHOP ON FIRE SERVICE CONTAMINATION CONTROL 19-20 July 2017 (Noon to Noon ET) Columbus Fire Fighters Union Hall 379 W Broad St, Columbus, OH 43215 Note: For flights, Workshop starts at Noon ET on 19/July/2017 and finishes at Noon ET on 20/July/2017 Drury Inn & Suites: 88 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-221-7008 ttos://www.drurvhotels.com/locations/columbus-ob/drurv-inn-and-suites-columbus-convention: center Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Red Roof Plus Columbus Downtown Convention Center 111 East Nationwide Blvd, Columbus, OH 43215 Phone: 1-614-224-6539 ittps://www.redroof.com/property/Columbus/OH/43215/Hotels-close-to-Greater-columbus- Convention-Center-US-23-1-670/RRI262/ Approximate Rate: $130 Distance (in miles) from Hotel to Columbus Union Hall: 1.4 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Sheraton Columbus Hotel at Capital Square 75 East State Street, Columbus, OH, 43215 Phone: 1-614-365-4500 http://www.sheratoncolumbuscapitolsquare.com/ Approximate Rate: $170 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Central downtown area Hampton Inn and Suites Columbus Downtown 501 North High Street, Columbus, OH 43215 Phone: 1-614-559-2000 htto://hamptoninns.bilton.com/en/hotels/ohio/hampton-inn-and-suites-columbus-downtown- CMHHSHK/index.htmi?WT.mc. Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 1.3 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars. Page 1 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Courtyard Columbus Downtown 35 West Spring Street, Columbus, Ohio 43215 Phone: 1-614-228-3200 4d19-a255-54ba596febe2 Approximate Rate: $175 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Notes: Downtown west area; walkable Doubletree Suites by Hilton Columbus Downtown 50 South Front St, Columbus, Ohio, 43215-4145 Phone: 1-614-228-4600 CMHSBOT/index.htmi Approximate Rate: $200 Distance (in miles) from Hotel to Columbus Union Hall: 0.5 Notes: Closest hotel to meeting site; very short walk Residence Inn Columbus Downtown 36 East Gay Street, Columbus, Ohio 43215-3108 Phone: 1-614-222-2610 ec3-4d19-a255-54ba596febe2 Approximate Rate: $230 Distance (in miles) from Hotel to Columbus Union Hall: 0.8 Renaissance Columbus Downtown 50 North Third Street, Columbus, Ohio 43215 Phone: 1-614-228-5050 ttp://www.marriott.com/hotels/travel/cmhbr-renaissance-columbus-downtown-hotel/ Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.0 Notes: Central downtown area Hilton Columbus Downtown 401 North High Street, Columbus, OH 43215 Phone: 1-614-384-8600 Approximate Rate: $240 Distance (in miles) from Hotel to Columbus Union Hall: 1.1 Notes: North area; not too far away; walkable, but you may want to Uber over; in a good part of downtown with lots of shops, restaurants, and bars; New facility and nice. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) PROJECT CONTACTS Last Updated: 22 May 2017 Project Technical Panel Phone: 614-774-7446 David Bernzweig, Columbus Fire Department (OH) Email: Safety@local67.com Phone: 780-496-3801 Ken Block, Edmonton Fire/Rescue & Metro Chiefs Representative Email: ken.block@edmonton.ca Phone: 804-971-7983 Ken Brown, VA State Firefighter's Association & NVFC (Alt to B. McQueen) Email; kbrownret@aol.com Phone: 510-839-5111 Cell: 213-321-9393 Roger Curtis, ECMS Curtis & Sons (CA) Email: rcurtis@incurtis.com Phone: Paul Curtis, ECMS Curtis & Sons (CA) (Alt to Roger Curtis) Email: pcurtis@incurtis.com Phone: 253-277-4131 Cell: 503-314-4832 Steve Lakey, Northwest Safety Clean (WA) Email: Steve@northwestsafetyclean.com Phone: 304-406-7479 Mark Lambert, WV Fire Academy & NAFTD (WV) Email: mlambe13@mail.wvu.edu Phone: 617-828-3978 Ed McCarthy, Boston Fire Department (MA) Email: Edward.mccarthy@boston.goy Phone: 315-736-7479 Cell: 315-552-8245 Brian McQueen, FASNY & National Volunteer Fire Council (NY) Email: fasnydirector@gmail.com Phone: 602-534-2396 Mark Miller, Phoenix Fire Dept. (AZ) Email: mark.a.miller@phoenix.gov Phone: 919-524-1569 Bryan Ormond, NCSU (NC) Email: rbormond@ncsu.edu Phone: Russ Osgood, Firefighter Cancer Support Network (NH) (Alt to Keith Tyson) Email: rosgood@fcsn.net Phone: Larry Petrick, IAFF (DC) Email: LPetrick@iaff.org Phone: 617-549-9850 Jim Riley, Boston Fire Department (MA) (Alt to E. McCarthy) Email: james.riley@boston.gov Phone: 757-385-2892 Molly Riley, Virginia Beach Fire Dept. (VA) Email: mriley@vbgov.com Phone: 718-999-2922 Thomas Smith, FDNY (NY) Email: Thomas.Smith@fdny.nyc.gov Phone: 214-774-2213 Cell: 940-300-5718 Tim Tomlinson, Gear Cleaning Solutions (TX) Email: tim@gearcleaningsolutions.com Phone: Robert Tutterow, NFPA Fire Service Section (NC) Email: rdtutterow@gmail.com Phone: 786-351-3276 Keith Tyson, Firefighter Cancer Support Network (FL) Email: KTyson@FCSN.net Phone: 951-807-1914 Dick Weise, LA County Fire Dept. (CA) Email: weiselacofd@yahoo.com Phone: 949-291-0637 Ken Wiles, LA County Fire Dept. (CA) (Alt to Dick Weiss) Email: Ken.Wiles@fire.lacounty.gov Phone: 512-974-0286 Chris Youngblood, Austin Fire Dept. (TX) Email: Christopher.Youngblood@austintexas.gov 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Phase 1 Project Contacts Phone: 330-723-0000, x365 Steve Allison, Fire-Dex (OH) Email: steveallison@firedex.com Phone: 800-401-4780 Jack Binder, Edmar Chemical Company (OH) Email: jackbinder@edmarchem.com Phone: 920-570-0824 Bill Brooks, Alliance Corp. (WI) Email: ill.Brooks@AllianceL.com Phone: Charlie Dunn, TenCate Protective Fabrics Email: c.dunn@tencate.com Phone: 617-984-7325 Chris Farrell, NFPA & Staff Liaison for NFPA 1851 (MA) Email: cfarrell@nfpa.org Phone: 800-232-8323 Rob Freese, Globe Manufacturing (NH) Email: robf@globefiresuits.com Phone: Pat Freeman, Globe Manufacturing (NH) (Alternate to Rob Freese) Email: patf@globefiresuits.com Phone: 704-554-3313 Diane Hess, PBI Performance Products (NC) Email: Diane.Hess@PBIProducts.com Phone: 937-415-2932 Karen Lehtonen, LionFirst Responder Products (OH) Email: klehtonen@lionprotects.com Phone: 484-433-4072 Dan Silvestri, 9-1-1 Safety (PA) Email: Dan@911se.com Liaison Contacts Phone: Pierre Carlotti, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: lierre.carlotti@interieur.gouv.fr Phone: Eric Guillaume, Efectis & Liaison for ISO TC92/SC3 (France) Email: eric.guillaume@EFECTIS.COM Phone: Bill Haskell, NIOSH NPPTL (MA) Email: czi8@cdc.gov Phone: James Hoar, Boston Fire Department (MA) Email: james.hoar@boston.gov Phone: 631-242-0621 Steve King, Chair NFPA 1851 (NY) Email: tikitai@aol.com Phone: +33(0)1.55.76.26.18 Fanny Rieunier, Ministry of Interior & Liaison for ISO TC92/SC3 (France) Email: fanny.rieunier@interieur.gouv.fr Phone: 612-247-6429 Marni Schmid, Fortunes Collide & Secretariat NFPA 1851 (MI) Email: marni@fortunes-collide.com Page 2 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Core Research Team Phone: 607-758-6537 Cell: 607-423-5617 Jason Allen, Intertek (NY) Email: jason.allen@intertek.com Phone: 304-285-6076 Daniel Farcas, NIOSH HELD (WV) Email: yfe2@cdc.gov Phone: Crystal Forester, NIOSH NPPTL (WV) Email: ckf7@cdc.gov Phone: 617-984-7284 Cell: 617-659-1159 Casey Grant, Fire Protection Research Foundation (MA) Email: cgrant@nfpa.org Phone: Lee Greenawald, NIOSH NPPTL (WV) Email: ilv1@cdc.gov Phone: Bill Lindsley, NIOSH HELD (WV) Email: wlindsley@cdc.gov Phone: Stephen Martin, NIOSH DRDS (WV) Email: stm9@cdc.gov Phone: John Noti, NIOSH HELD (WV) Email: ivr2@cdc.gov Phone: Deborah Sbarra, NIOSH NPPTL (WV) Email: drc3@cdc.gov Phone: 512-288-8272 cell: 512-623-9558 Jeff Stull, International Personal Protection (TX) Email: intiperpro@aol.com Phone: 304-285-5858 cell: 681-209-2571 Jay Tarley, NIOSH NPPTL (WV) Email: ist9@cdc.gov Additional Research Team Contacts Phone: 304-285-5884 Francoise Blachere, NIOSH HELD (WV) Email: czv3@cdc.gov Phone: Renee Dotson, NIOSH HELD (WV) Email: ced9@cdc.gov Phone: James Harris, NIOSH NPPTL (WV) Email: irh6@cdc.gov Phone: Ryan Lebouf, NIOSH DRDS (WV) Email: igu6@cdc.gov Phone: 617-984-7281 Eric Peterson, Fire Protection Research Foundation (MA) Email: epeterson@nfpa.org Phone: John Powers, NIOSH (WV) Email: jop5@cdc.gov Phone: 412-386-4621 Cell: 412-463-9561 Heather Reed, NIOSH NPPTL (PA) Email: yvt5@cdc.gov Page 3 of 3 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION PPE Cleaning Validation Validation of Cleaning Procedures for Fire Fighter Personal Protective Equipment (PPE) (for more information see www.nfpa.org/PPECleaning) PROJECT SUMMARY Last updated: 5 February 2016 Background: Fire fighter exposure to personal protective equipment (PPE) that is dirty, soiled, and contaminated is an increasing concern for long-term fire fighter health. This exposure to persistent harmful contaminants in PPE is an extremely serious problem both on the fireground to highly toxic substances including a variety of carcinogens, and more insidiously to an increasing range of infectious pathogens that are encountered in patient care and different emergency operations. Fire fighter PPE becomes contaminated during these exposures and there are no industry standards that conclusively and reliably show that clothing is being adequately cleaned. While general cleaning procedures have been established in NFPA 1851, Standard on Selection, Care, and Maintenance of Protective Ensembles for Structural Fire Fighting and Proximity Fire Fighting, there are no procedures or requirements to demonstrate whether current cleaning practices, including those specified in NFPA 1851, will remove contaminants from fire fighter protective clothing. This project is intended to establish clear and definitive guidance to the fire service for applying cleaning and decontamination procedures that effectively remove both chemical and biological contaminants. Research Goal and Objectives, and Conceptual Approach: The overall goal of this project is to improve fire fighter safety and health by reducing continuing exposure to harmful contaminants in unclean or inadequately cleaned PPE. The objectives to achieve this goal are twofold: (1) To characterize fireground and emergency scene contamination leading to these exposures and develop the methodology for the consistent measurement of cleaning effectiveness; and (2) determine implementable cleaning, decontamination, and disinfection strategies that effectively reduce fire fighter exposures to persistent contaminants. The approach taken by this project is illustrated in Figure 1: Project Conceptual Approach. - Ensure Identify Devise Validate lab - - chemical and methods to methods - at biologicat conteminate againet field ses target clothing in contaminants laboratory exposures acceptance Project Direction Figure 1: Project Conceptual Approach 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7281 Fax: +1.617.984.7010 Email: Foundation@NFPA.org www.NFPA.org/Foundation Source: :ttps://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Phases and Tasks: This project involves the following four key phases of activity: 1) Identification of Contaminants: Confirm identification and ability to characterize persistent chemical and biological contaminants in fire fighter PPE through target substances and microorganisms. 2) Establishment of Soil and Chemical Contamination/Decontamination Procedures: Develop and validate specific procedures that determine the effectiveness of laundering and other cleaning methods in removing specific soils and chemical contaminants. 3) Establishment of Biological Contamination/Disinfection or Sanitization Procedures: Develop and validate specific procedures that determine the effectiveness of laundering or disinfection/sanitization processes that remove/deactivate biologically-based contaminants. 4) Creation of Overall Fire Service Guidance: Prepare clear and definitive information for the fire service industry (fire fighters, fire departments, clothing manufacturers, material suppliers, cleaning/care organizations, and cleaning agent or equipment manufacturers) on appropriate approaches for properly cleaning fire fighter protective clothing and equipment. The specific tasks of this project are based on these four phases of the project, and these are illustrated in Figure 2: Project Tasks. PHASE 2 PHASEZ Task 2.4 Task 2.5 Task 1.1 Task 2.1 Validate testsat Refine test Appoint Technical Select cleaning selected ISPS methodology Review Panel methods/agents (chemical) (chemical) PHASE $ Task 4.1 Task 1.2 Task 2.2 Write qualification Review Prigr Put together test plan methods studies/literature (chemical) Task 2.3 Task 4.2 Task 1.3 PHASE 3 Perform laboratory Establish cleaning Setup analytical chemical Task 3.3 acceptance criteria capabilities decontaminant Put together test plan testing (biological) Task 4.3 Task 1.4 Perform Task 3.4 Prepare public inputs for NFPA 1851 demonstration tests Task 3.1 Perform laboratory Task 3.6 Select study biological Refine test microorganisms decontaminant methodology Task 1.5 testing (biological) Task 4.4 Refine biological Prepare industry decontamination Task 3.2 Task 3.5 guidance document scope Select biological Validate testsat cleaning methods selected ISPs (biological) Task 1.6 Task 4,5 Establish cleanliness Prepare project final metrics report Figure 2: Project Tasks Implementation and Schedule: This three year project is due to be completed no later than " August 2018, and is funded through an AFG Fire Prevention & Safety Grant from the U.S. Department of Homeland Security / Federal Emergency Management Agency. The Research Foundation will lead a unique research team partnership composed of the FPRF, National Institute for Occupational Safety and Health (NIOSH), International Personal Protection (IPP), and Intertek. The research team, along with several Independent Service Providers (ISPs), will work with the fire service partners and others to validate and optimize fire fighter PPE cleaning validation methods. For more information see www.nfpa.org/PPECleaning. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 RESEARCH FOUNDATION NFPA RESEARCH FOR THE NFPA MISSION Fire Fighter Cancer Cohort Study Full Title: The Firefighter Multicenter Cancer Cohort Study: Framework Development and Testing PROJECT SUMMARY Last Updated: 20 September 2016 Background: Cancer is a leading cause of fire service morbidity and mortality. Firefighter exposure to carcinogens occurs through skin contamination and through inhalation when respiratory protection is not worn when combustion products are present such as during overhaul, standby, and operation of apparatus, as well as through off-gassing of equipment and exposures in the fire station. However, we currently do not understand which exposures are responsible for cancer in firefighters, the mechanisms by which firefighter exposures cause cancer, nor the most effective means of reducing exposures. Since cancer has a long latency period, biomarkers are also needed that can measure the toxicological effects of carcinogen exposure well before the development of cancer, when interventions to prevent disease could be effective. Development of a large (>10,000 firefighter) multicenter firefighter cancer prospective cohort study will address these needs, but the framework for such a study needs to be first developed and tested among a smaller initial set of fire service partners. Implementation and Schedule: This research project is led by University of Arizona with collaborative support from multiple other research partners, including the University of Miami, National Institute for Occupational Safety and Health; National Fallen Firefighter Foundation, Fire Protection Research Foundation, and others. Initial funding for this project is through a 3-year DHS/FEMA Assistance to Fire Fighter (AFG) Fire Grant, with the intention to identify and obtain additional funding for the duration of the 30 year effort. The project start date is August 2016. The Principal Investigator for this project is: Jefferey L. Burgess, MD, MS, MPH, University of Arizona, email: iburgess@emailarizona.edu. Project Goal and Aims: The goal of the initial 3-year effort of this overall project is to develop and test a framework for establishing a long-term fire fighter multicenter prospective cohort study focused on carcinogenic exposures and effects. The specific aims are to: 1) Establish an oversight and planning board to provide study oversight, foster communication among fire organizations and help develop a long-term funding plan; 2) Create and test a cohort study data coordinating center and harmonized survey data protocols; 3) Develop and validate a firefighter carcinogen exposure matrix and data collection system; and 4) Create a biomarker assessment center and evaluate the association between cumulative firefighter exposures and epigenetic effects. For more information, contact: Casey Grant, Fire Protection Research Foundation 1 Batterymarch Park, Quincy, MA 02169-7471 Telephone: +1.617.984.7284 Fax: +1.617.984.7010 Email: cgrant@nfpa.org Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226 Project Methodology: This study will harmonize and build on recent and developing firefighter cancer prevention studies in Arizona, Florida and Massachusetts, adding volunteer fire departments. An oversight and planning board will be established by the Fire Protection Research Foundation (FPRF) in association with the National Fallen Firefighter Foundation (NFFF) Fire Service Occupational Cancer Alliance (FSOCA) to provide oversight of the study through collaboration among fire service organizations, academia, and government agencies, and develop a long-term funding and sustainability plan. A data coordination center team will design, develop and evaluate a framework for a multicenter prospective cohort study of firefighters and cancer risk, including standardized participant survey data collection tools and analysis protocols sufficient to address the short- and long-term study objectives as well as linkage with long-term outcome data including cancer development. An exposure assessment center team will develop a carcinogen exposure matrix and data collection system to provide improved occupational exposure data for comparison with epigenetic outcomes and eventual cancer outcomes. Carcinogen exposures associated with specific fire types will be evaluated across fire departments through industrial hygiene monitoring and analysis of urine for absorbed contaminants, supplementing existing FEMA-funded and other studies of firefighter exposures and allowing for participating fire departments to design interventions to reduce current exposures. Expansion of the National Fire Operations Reporting System (NFORS) will be explored as one option to uniformly collect incident and exposure data. Blood and buccal cells will be collected during annual medical surveillance evaluations, including both new recruits and incumbent firefighters. Pilot studies of epigenetic markers of cancer effect and cancer risk will be analyzed comparing municipal firefighters with high chronic exposures, volunteer firefighters with low chronic exposures, and non- firefighter friends of the municipal firefighters (serving as controls). Project Deliverables: The anticipated outcomes from this 3-year effort is to establish and test the framework necessary for the subsequent development of a large multicenter cohort study of cancer in the fire service. Page 2 of 2 Source: https://www.industrydocuments.ucsf.edu/docs/hlcn0226

What is the fullform of TCE?

kqbn0226

kqbn0226_p13, kqbn0226_p14, kqbn0226_p15

Trichloroethylene

NAS (2014) & IRIS Process "Finding: IRIS-specific guidelines for consistent, coherent, and transparent assessment and communication of uncertainty remain incompletely developed. The inconsistent treatment of uncertainties remains a source of confusion and causes difficulty in characterizing and communicating uncertainty. Recommendation: Uncertainty analysis should be conducted systematically and coherently in IRIS assessments. To that end, EPA should develop IRIS-specific guidelines to frame uncertainty analysis and uncertainty communication. Moreover, uncertainty analysis should become an integral component of the IRIS process." [emphasis added] 12 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) ARA TCE Workgroup formed in the Fall of 2012 Open invitation: over 300 scientists from multiple international organizations, including government, industry, academia and NGOs, on 6 conference calls and one webinar. Trichloroethylene (TCE) Risk Assessment Guidance for Contaminated Sites (April 2013) Webcast: Practical Guidance for Contaminated Sites:TCE Risk Assessment Case Study (November 4, 2013) 13 Source: ttps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) Guidance for Contaminated Sites:Trichloroethylene Case Study. Gadagbui, et al., SOT, 53rd Annual Meeting & ToxExpo,23-27 March 2014, Phoenix,AZ. Development of a Non-cancer Hazard Range for Effective Risk Assessment and Risk Management of Contaminated Sites:A Case Study with TCE and Other Chemicals, Beyond Science & Decisions: Problem Formulation to Dose- Response Assessment,Workshop VIII, 21-22 May 2014, Austin, TX. 14 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226

How many scientists from multiple international organizations are invited?

kqbn0226

kqbn0226_p13, kqbn0226_p14, kqbn0226_p15

over 300 scientists

NAS (2014) & IRIS Process "Finding: IRIS-specific guidelines for consistent, coherent, and transparent assessment and communication of uncertainty remain incompletely developed. The inconsistent treatment of uncertainties remains a source of confusion and causes difficulty in characterizing and communicating uncertainty. Recommendation: Uncertainty analysis should be conducted systematically and coherently in IRIS assessments. To that end, EPA should develop IRIS-specific guidelines to frame uncertainty analysis and uncertainty communication. Moreover, uncertainty analysis should become an integral component of the IRIS process." [emphasis added] 12 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) ARA TCE Workgroup formed in the Fall of 2012 Open invitation: over 300 scientists from multiple international organizations, including government, industry, academia and NGOs, on 6 conference calls and one webinar. Trichloroethylene (TCE) Risk Assessment Guidance for Contaminated Sites (April 2013) Webcast: Practical Guidance for Contaminated Sites:TCE Risk Assessment Case Study (November 4, 2013) 13 Source: ttps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) Guidance for Contaminated Sites:Trichloroethylene Case Study. Gadagbui, et al., SOT, 53rd Annual Meeting & ToxExpo,23-27 March 2014, Phoenix,AZ. Development of a Non-cancer Hazard Range for Effective Risk Assessment and Risk Management of Contaminated Sites:A Case Study with TCE and Other Chemicals, Beyond Science & Decisions: Problem Formulation to Dose- Response Assessment,Workshop VIII, 21-22 May 2014, Austin, TX. 14 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226

When was ARA TCE Workgroup formed?

kqbn0226

kqbn0226_p13, kqbn0226_p14, kqbn0226_p15

ARA TCE Workgroup formed in the Fall of 2012, in the fall of 2012

NAS (2014) & IRIS Process "Finding: IRIS-specific guidelines for consistent, coherent, and transparent assessment and communication of uncertainty remain incompletely developed. The inconsistent treatment of uncertainties remains a source of confusion and causes difficulty in characterizing and communicating uncertainty. Recommendation: Uncertainty analysis should be conducted systematically and coherently in IRIS assessments. To that end, EPA should develop IRIS-specific guidelines to frame uncertainty analysis and uncertainty communication. Moreover, uncertainty analysis should become an integral component of the IRIS process." [emphasis added] 12 Source: https://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) ARA TCE Workgroup formed in the Fall of 2012 Open invitation: over 300 scientists from multiple international organizations, including government, industry, academia and NGOs, on 6 conference calls and one webinar. Trichloroethylene (TCE) Risk Assessment Guidance for Contaminated Sites (April 2013) Webcast: Practical Guidance for Contaminated Sites:TCE Risk Assessment Case Study (November 4, 2013) 13 Source: ttps://www.industrydocuments.ucsf.edu/docs/kqbn0226 Problem Response: Alliance for Risk Assessment (ARA) Guidance for Contaminated Sites:Trichloroethylene Case Study. Gadagbui, et al., SOT, 53rd Annual Meeting & ToxExpo,23-27 March 2014, Phoenix,AZ. Development of a Non-cancer Hazard Range for Effective Risk Assessment and Risk Management of Contaminated Sites:A Case Study with TCE and Other Chemicals, Beyond Science & Decisions: Problem Formulation to Dose- Response Assessment,Workshop VIII, 21-22 May 2014, Austin, TX. 14 Source: ittps://www.industrydocuments.ucsf.edu/docs/kqbn0226