1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

DRUG SAFETY AND RISK MANAGEMENT

ADVISORY COMMITTEE (DSaRM)

COMMITTEE MEETING

Wednesday, May 5, 2004

8:18 a.m.

CDER Advisory Committee Conference Room.

5630 Fishers Lane

Rockville, Maryland

2

P A R T I C I P A N T S

DSaRM Committee Members:

Peter A. Gross, M.D., Chair

Shalini Jain, PA-C, M.B.A., Executive Secretary

Michael R. Cohen, R.Ph., M.S., D.Sc.

Stephanie Y. Crawford, Ph.D., M.P.H.

Curt D. Furberg, M.D., Ph.D.

Jacqueline S. Gardner, Ph.D. M.P.H.

Arthur A. Levin, M.P.H.

Henri R. Manasse, Jr., Ph.D.

Robyn S. Shapiro, J.D.

Annette Stemhagen, Dr.PH

Brian L. Strom, M.D., M.P.H.

GI Advisory Committee Members:

Alexander H. Krist, M.D.

Maria H. Sjogren, M.D.

Consultant:

Leslie Hendeles, Pharm.D.

FDA Participants:

Carol Holquist, R.Ph.

Marci Lee, Pharm.D.

Paul Seligman, M.D., M.P.H. \[a.m. and p.m.\]

Vibhakar Shah, Ph.D.

Eugene Sullivan, M.D.

Mark Avigan, M.D., C.M.

Julie Beitz, M.D.

Robert Justice, M.D., M.S.

Ann Marie Trentacosti, M.D.

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C O N T E N T S

AGENDA ITEM PAGE

Call to Order and Opening Remarks, Introduction of

Committee - Peter Gross, M.D., Chair, DSaRM 5

Conflict of Interest Statement - Shalini Jain,

PA-C, M.B.A., Executive Secretary, DSaRM 8

Opening Remarks - Paul Seligman, M.D., M.P.H.,

Director, Office of Pharmacoepidemiology &

Statistical Science (OPSS) and Acting Director,

Office of Drug Safety (ODS) 11

FDA Presentations

\- Permeability of LDPE Vials: A Clinical

Perspective - Eugene Sullivan, M.D., Deputy

Director, Division of Pulmonary Drug Products. 13

\- Medication Errors and Low-Density Polyethylene

(LDPE) Plastic Vials - Marci Lee, Pharm.D.,

Safety Evaluator, Division of Medication Errors

and Technical Support 23

\- LDPE Vials for Inhalation Drug Products: A

Chemistry, Manufacturing, and Controls (CMC)

Perspective - Vibhakar Shah, Ph.D., Chemist,

Division of New Drug Chemistry II 36

Questions from Committee 55

Industry Presentations

\- Container Labeling Options using rommelag Blow-

Fill-Seal Technology - Mohammad Sadeghi, V.P.,

Research/Development, Holopack International

Corp. 65

\- Labeling of LDPE Containers: Options for

Improving Identification for Prevention of

Medication Errors - Rick Schindewolf, V.P. & GM,

Biotechnology & Sterile Life Sciences, and

Patrick Poisson, Director of Technical Services,

Biotechnology & Sterile Life Sciences, Cardinal

Health 90

\- American Association of Respiratory Therapy

Care - Karen Stewart, M.S., R.R.T. 93

Questions from Committee 94

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C O N T E N T S (Continued)

Open Public Hearing 106

Introduction of LDPE Issues

Paul Seligman, M.D., M.P.H. 118

Committee Discussion 118

Committee Discussion (Continued) 182

Opening Remarks and Reintroduction of Advisory

Committee - Peter Gross, M.D., Chair 182

Conflict of Interest Statement - Shalini Jain,

PA-C., M.B.A. 185

Introduction of Lotronex Issue - Paul Seligman,

M.D., M.P.H. 187

Open Public Hearing 189

Sponsor Presentation

Risk Management Program for Lotronex - Craig Metz,

Ph.D., V.P., U.S. Regulatory Affairs,

GlaxoSmithKline 206

FDA Presentation

Lotronex Update - Robert Justice, M.D., M.S.,

Director, Division of Gastrointestinal and

Coagulation Drug Products 241

Questions from Committee 248

Adjourn 298

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1 P R O C E E D I N G S

2 DR. GROSS: Good morning. I\'m Peter

3 Gross. I\'m Chair of the Drug Safety and Risk

4 Management Committee, and starting with the person

5 at my left with that famous laugh, Brian Strom,

6 would you please introduce yourself?

7 DR. STROM: Thank you. I\'m Brian Strom

8 from the University of Pennsylvania.

9 MS. JAIN: You know what? Before we go

10 on, Brian, Peter and the rest of the committee as

11 well as the division wanted to say a warm thank-you

12 for serving on our committee. You\'ve been a great

13 asset for a year and a half, and we realize that

14 you\'re going to continue as consultant, and we just

15 wanted to say thanks.

16 DR. STROM: It\'s been a real pleasure, and

17 it was a hard decision to let the rotation happen.

18 I\'ve enjoyed it, but given other commitments back

19 home\--but it\'s been fun.

20 MS. JAIN: Thank you.

21 DR. GROSS: You\'ve been great, Brian. We

22 will continue to take advantage of your skills.

6

1 DR. MANASSE: My name is Henri Manasse.

2 I\'m chief executive officer and executive vice

3 president of the American Society of Health-System

4 Pharmacists, a membership organization that

5 represents about 32,000 pharmacists practicing in

6 hospitals and organized health systems.

7 MS. SHAPIRO: Robyn Shapiro. I\'m a

8 professor and director of the Center for the Study

9 of Bioethics at the Medical College of Wisconsin.

10 DR. STEMHAGEN: I\'m Annette Stemhagen.

11 I\'m Vice President of Strategic Development at

12 Covance, a contract research organization, and I

13 serve as an industry representative to this

14 committee.

15 DR. GARDNER: Jacqueline Gardner,

16 University of Washington, Department of Pharmacy.

17 MR. LEVIN: Art Levin, Center for Medical

18 Consumers, and I serve as the consumer

19 representative.

20 DR. FURBERG: Curt Furberg, professor of

21 public health sciences at the Wake Forest

22 University.

7

1 DR. HENDELES: I\'m Leslie Hendeles. I\'m a

2 clinical pharmacist at the University of Florida,

3 and I\'ve done research on the bronchospastic

4 effects of preservatives in nebulizer solutions.

5 DR. CRAWFORD: Good morning. Stephanie

6 Crawford, associate professor, College of Pharmacy,

7 University of Illinois at Chicago.

8 DR. COHEN: Mike Cohen, Institute for Safe

9 Medication Practices.

10 DR. SELIGMAN: Paul Seligman, Director,

11 Office of Pharmacoepidemiology and Statistical

12 Science, Center for Drug Evaluation and Research,

13 FDA.

14 DR. SULLVAN: My name is Gene Sullivan.

15 I\'m the Deputy Director of the Division of

16 Pulmonary and Allergy Drug Products here at FDA.

17 MS. HOLQUIST: I\'m Carol Holquist. I\'m

18 the Director of the Division of Medication Errors

19 and Technical Support in the Office of Drug Safety,

20 Center for Drug Evaluation and Research.

21 DR. LEE: Marci Lee, a pharmacist and

22 safety evaluator in the Division of Medication

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1 Errors and Technical Support.

2 MS. JAIN: Thank you, everyone. My name

3 is Shalini Jain. I\'m the Executive Secretary for

4 the Drug Safety and Risk Management Advisory

5 Committee. I\'ll now read the conflict of interest

6 statement for the meeting today. The meeting issue

7 is low-density polyethylene vials.

8 The following announcement addresses the

9 issue of conflict of interest with respect to this

10 meeting and is made a part of the record to

11 preclude even the appearance of such at this

12 meeting.

13 Based on the agenda, it has been

14 determined that the topics of today\'s meeting are

15 issues of broad applicability, and there are no

16 products being approved at this meeting. Unlike

17 issues before a committee in which a particular

18 product is discussed, issues of broader

19 applicability involve many industrial sponsors and

20 academic institutions.

21 All special government employees have been

22 screened for their financial interests as they may

9

1 apply to the general topics at hand. To determine

2 if any conflict of interest existed, the agency has

3 reviewed the agenda and all relevant financial

4 interests reported by the meeting participants.

5 The Food and Drug Administration has granted

6 general matters waivers to the special government

7 employees participating in this meeting who require

8 a waiver under Title 18, United States Code,

9 Section 208.

10 A copy of the waiver statements may be

11 obtained by submitting a written request to the

12 agency\'s Freedom of Information Office, Room 12A-30

13 of the Parklawn Building.

14 Because general topics impact so many

15 entities, it is not prudent to recite all potential

16 conflicts of interest as they apply to each member,

17 consultants, and guest speaker.

18 FDA acknowledges that there may be

19 potential conflicts of interest, but because of the

20 general nature of the discussion before the

21 committee, these potential conflicts are mitigated.

22 With respect to FDA\'s invited industry

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1 representative, we would like to disclose that Dr.

2 Annette Stemhagen is participating in this meeting

3 as an industry representative, acting on behalf of

4 regulated industry. Dr. Stemhagen is employed by

5 Covance Periapproval Services, Incorporated.

6 In addition, we would like to note that

7 Karen Stewart, FDA\'s invited guest speaker, is

8 participating as a representative of the

9 respiratory therapists in the United States through

10 the American Association for Respiratory Care. She

11 has no financial interest in or professional

12 relationship with any of the products or firms that

13 could be affected by the committee\'s discussions.

14 With respect to the three invited industry

15 guest speakers, we would like to disclose that

16 Mohammad Sadeghi is employed by Holopack

17 International, Richard Schindewolf is employed by

18 Cardinal Health and is vice president and general

19 manager of Biotechnology and Sterile Life Sciences.

20 Patrick Poisson is employed by Cardinal Health, and

21 he serves as Director of Technical Services at the

22 Biotechnology and Sterile Life Sciences division.

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1 In the event that the discussions involve

2 any other products or firms not already on the

3 agenda for which FDA participants have a financial

4 interest, the participants\' involvement and their

5 exclusion will be noted for the record.

6 With respect to all other participants, we

7 ask in the interest of fairness that they address

8 any current or previous financial involvement with

9 any firm whose product they may wish to comment

10 upon.

11 Thank you.

x DR. SELIGMAN: Good morning. On behalf of

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13 the Center for Drug Evaluation and Research, it is

14 my pleasure to welcome members of the Drug Safety

15 and Risk Management Advisory Committee and members

16 of the public to today\'s meeting. As always, we

17 greatly appreciate the time and efforts devoted by

18 the committee members and all participants in

19 providing advice to the FDA on important public

20 health issues.

21 We have two topics on the agenda for

22 discussion today\--the first related to the

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1 prevention of medication errors and the second

2 providing an update on a risk management program

3 that was considered by this committee two years ago

4 and was implemented in 2002.

5 The first topic will focus primarily on

6 minimizing the incidence of medication errors with

7 drug products packages in low-density polyethylene,

8 or LDPE, containers. The package is intended to

9 preserve drug product purity and quality. However,

10 current techniques used to label the product create

11 problems related to legibility of the product name

12 and strength. Additionally, various products are

13 packaged in containers that look similar. We\'ve

14 found that these difficult-to-read labels and

15 look-alike containers have contributed to

16 medication errors involving the administration of

17 wrong dosage strength or wrong drug product to the

18 patient.

19 Today, we would like to discuss what other

20 solutions or alternative packaging designs exist

21 that could improve the legibility of the label,

22 prevent ingress of chemical contaminants, and in

13

1 the process reduce or eliminate medication errors.

2 Then later this afternoon, we will receive an

3 update on the Lotronex risk management program.

4 With that brief introduction, I look

5 forward to our discussions today and, again, I also

6 want to personally thank Dr. Strom for his service

7 on this committee.

8 With that, I guess we may proceed with the

9 first speaker. Dr. Gross?

10 DR. GROSS: Dr. Sullivan will be the first

11 speaker on the Permeability of LDPE Vials: A

12 Clinical Perspective.

13 DR. SULLIVAN: Good morning. As I

14 mentioned, my name is Gene Sullivan. By training

15 I\'m a pulmonologist, and I\'m the Deputy Director of

16 the Division of Pulmonary and Allergy Drug Products

17 in the Center for Drug Evaluation and Research here

18 at FDA.

19 This morning, I\'m going to spend about 15

20 minutes or so providing some background for the

21 discussions today. I\'ll be conveying some clinical

22 observations regarding issues raised by the use of

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1 LDPE vials in the packaging of inhalation drug

2 products, particularly as it relates to the

3 permeability of the vials.

4 This slide provides an overview of my

5 presentation. I\'ll begin with some introductory

6 remarks which will put my presentation into the

7 context of today\'s discussions and will serve to

8 introduce the remainder of the talk. Next I will

9 discuss the inhalation drug products that are

10 involved, providing some examples and a brief

11 description of the nature of these drugs.

12 Following this, I will discuss the patient

13 populations for which these drugs are used,

14 emphasizing aspects of these populations that put

15 them at risk for adverse effects of chemical

16 contaminants. Then I will discuss the potential

17 sources of chemical contaminants, their potential

18 adverse effects, and the difficulties that exist in

19 terms of adequately monitoring for them. Finally,

20 I will summarize the issue and current state of

21 affairs in order to set the stage for the remainder

22 of today\'s discussion regarding minimizing the

15

1 potential for medication errors.

2 The topic for discussion for today\'s

3 Advisory Committee meeting is how best to minimize

4 the potential for medication errors associated with

5 LDPE containers, particularly given the clinical

6 concerns related to their permeability and the

7 resulting move away from the paper labels that have

8 previously been used to identify the products. My

9 presentation is intended to review the nature of

10 these clinical concerns in order to provide

11 background for the remainder of the discussions

12 today.

13 This slide summarizes the clinical

14 concerns that I mentioned. Many inhalation drug

15 products are packaged in LDPE containers. LDPE is

16 a material that is permeable to volatile chemicals,

17 and there are numerous volatile chemicals that

18 exist in the immediate packaging environment.

19 Volatile chemicals that find their way into

20 inhalation solutions may have a number of adverse

21 effects on the airways, and because these adverse

22 effects may be poorly tolerated by patients,

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1 efforts should be made to minimize the potential

2 for contamination of inhalation drug products.

3 Such efforts have included minimizing the content

4 of volatile chemicals in the immediate packaging

5 environment.

6 For instance, the practice of using paper

7 labels, which are applied directly to the LDPE

8 containers and which contain numerous volatile

9 chemicals, is not recommended. However, as you

10 will see in subsequent presentations, the use of

11 alternative labeling approaches has raised the

12 issue of medication errors.

13 Now, I also want to point out that my

14 presentation is focused on the clinical concerns

15 related to chemical contamination of these

16 products. In the next presentation, Dr. Shah will

17 also talk about product quality concerns. For

18 instance, ingress of volatile chemicals might

19 adversely affect the stability of the active drug

20 substance in a particular drug product.

21 This slide provides some examples of

22 inhalation drug products that are packaged in LDPE

17

1 containers. They include bronchodilators, such as

2 Albuterol, Ipatropium, Metaproterenol, and

3 Levalbuterol; also a mass cell stabilizer, cromolyn

4 sodium; an inhaled steroid, Budesonide; and an

5 antibiotic, Tobramycin.

6 These products are inhalation solutions,

7 or sometimes suspensions, that are intended for

8 oral inhalation using a nebulizer. One thing to

9 keep in mind is that the manufacturing processes

10 and materials for inhalation products are very

11 carefully controlled in order to maintain a very

12 high standard of product purity. That is, a

13 significant amount of attention is paid to the

14 manufacturing processes and the materials used so

15 that the content of contaminants is minimized.

16 This would include contaminants that arise during

17 the manufacturing processes, so-called process of

18 synthetic impurities; contaminants that arise due

19 to degradation of components of the formulation; or

20 the subject of today\'s concern, contaminants that

21 enter the formulation from the packaging materials,

22 so-called leachables.

18

1 These drugs may be used in a regular

2 dosing schedule or may be used as an as-needed

3 basis, and the bronchodilator products in

4 particular are common used in the inpatient and

5 acute-care settings, including emergency

6 departments and intensive care units.

7 These inhalation products are used by

8 patients with a variety of pulmonary disorders,

9 most commonly patients with asthma, COPD\--which is

10 chronic obstructive pulmonary disease, a category

11 of lung disease comprised of chronic bronchitis and

12 emphysema\--and cystic fibrosis. Although these

13 diseases are distinct, in general they are

14 characterized by fixed or variable obstruction to

15 airflow and a variety of patterns of histologic

16 abnormalities, including various patterns of airway

17 inflammation. In addition, asthma in particular is

18 associated with an underlying propensity for

19 allergic responses. And most of the diseases are

20 associated with a sensitivity to nonspecific

21 irritants which result in acute bronchospasm, a

22 feature known as airway hyperresponsiveness.

19

1 To focus specifically on asthmatics for a

2 moment, asthmatics may react adversely to both

3 nonspecific chemical irritants and to allergens to

4 which they have developed specific immunity.

5 Irritant reactions are characterized by symptoms of

6 wheezing and shortness of breath. It is well known

7 that patients with severe asthma may react to very

8 low levels of exposure to irritants. Clinically,

9 this is often related to perfumes, cleaning agents,

10 or smoke in the environment. In fact, we commonly

11 make use of this feature of asthma to help

12 establish the diagnosis using methacholine

13 challenge testing. In the methacholine challenge

14 test, patients with suspect asthma are exposed to

15 successively higher concentrations of this irritant

16 in order to elicit bronchospasm.

17 In addition to the nonspecific irritant

18 reactions, asthmatics may also develop bronchospasm

19 from inhaled allergens. This allergic reaction is

20 associated with both an acute early-phase broncho-

21 constriction and a delayed late-phase response

22 characterized by airway inflammation and airflow

20

1 limitation.

2 So what are the potential sources of

3 contaminants in inhalation drug products packaged

4 in LDPE? In general, these are from volatile

5 chemicals found in the labels and secondary bulk

6 packaging. These chemicals may be found in the

7 various glues, inks, and lacquers that are used.

8 One thing to point out is that the specific

9 chemical nature of these inks, glues, et cetera,

10 may, in fact, change after approval due to changes

11 in the sources of these packaging materials.

12 The FDA conducted an analytical survey of

13 approved inhalation solutions marketed in LDPE

14 containers and found that 29 of the 37 samples

15 tested positive for various volatile chemicals that

16 were presumed to have originated in the packaging

17 materials. Dr. Shah will describe this analysis in

18 much more detail in his presentation later this

19 morning.

20 Chemical contaminants in inhalation drug

21 products may be associated with a variety of

22 adverse effects, including irritant and immunologic

21

1 effects, leading to acute bronchospasm and airway

2 inflammation and hyperresponsiveness, other toxicologic

3 injury, or even potentially carcinogenicity.

4 In terms of monitoring for adverse effects

5 that might be attributed to chemical contaminants

6 in these products, it is important to note that

7 appropriate attribution may be very difficult

8 because the expected adverse effects\--bronchospasm

9 and airway hyperresponsiveness\--mimic the symptoms

10 for which the drugs are being used. This is a very

11 difficult circumstance and makes it quite likely

12 that adverse effects would not be recognized and

13 reported. For instance, modest bronchospasm

14 related to chemical contaminants might lead to

15 reduced efficacy of the drug, but this would likely

16 not be identified. Even if the adverse effect were

17 more significant, the findings would likely be

18 attributed to refractory underlying disease.

19 So, to summarize, many inhalation drug

20 products are packaged in low-density polyethylene

21 containers. This material is permeable to volatile

22 chemicals. Numerous volatile chemicals exist in

22

1 the immediate packaging environment.

2 Various volatile chemicals have, in fact,

3 been identified in these products. These volatile

4 chemicals may have irritant as well as other

5 toxicologic effects. And because these effects may

6 be particularly poorly tolerated by patients,

7 efforts should be made to minimize the potential

8 for contamination of inhalation drug products.

9 It was this line of reasoning that in part

10 led to the development of the Draft Guidance

11 entitled \"Inhalation Drug Products Packaged in

12 Semipermeable Container Closure Systems.\" Among

13 other things, the Draft Guidance recommends that

14 measures be taken to limit chemical contamination

15 of these products. One such measure would be the

16 use of alternative approaches to paper labels, such

17 as direct embossing or debossing of the containers.

18 However, as will be discussed in

19 subsequent presentations, the move away from paper

20 labels has introduced a new concern, that of

21 medication errors due to difficult-to-read and

22 look-alike packaging. The issue of how best to

23

1 minimize the potential for medication errors will

2 be the topic for today\'s discussion.

3 DR. GROSS: Thank you, Dr. Sullivan.

4 The next speaker will be Shah.

5 MS. JAIN: He is not here.

6 DR. GROSS: Okay. Later for Dr. Shah.

7 Dr. Marci Lee will now talk about

8 medication errors and low-density polyethylene

9 plastic vials.

10 DR. LEE: Good morning. My name is Marci

11 Lee. I am a pharmacist and safety evaluator in the

12 Division of Medication Errors and Technical Support

13 in the Office of Drug Safety.

14 The purpose of this presentation is to

15 describe medication error reports and feedback from

16 patients and practitioners involving products

17 packaged in LDPE containers. I will focus on some

18 factors we identified that may contribute to

19 confusion and errors with these products. Finally,

20 I will describe packaging and labeling approaches

21 for your consideration.

22 Our error analysis included in your

24

1 background package was from 87 relevant reports.

2 These came from patients, caregivers, and

3 practitioners, such as respiratory therapists and

4 pharmacists, who reported to the programs listed.

5 These reports were received between January 1993

6 and August 2002. Many reports involved difficulty

7 reading embossed product containers. Some reports

8 were actual errors where the wrong medication or

9 the wrong dosage strengths were dispensed.

10 Although some of these were detected before the

11 medication was administered to the patient, some

12 were not. The outcomes of these reports ranged

13 from no harm to difficulty breathing, which can be

14 life-threatening. The remainder of the reports

15 described the potential for confusion and errors

16 with these products. Subsequently, as of April

17 2004, 51 additional relevant medication error

18 reports were identified for a total of 138 reports.

19 In addition to our analysis, FDA received

20 correspondence from ISMP, USP, and Senator Harkin

21 regarding the safe use of products packaged in LDPE

22 containers.

25

1 Several themes emerged from the narratives

2 of the medication error reports as factors that can

3 contribute to errors. They include

4 difficult-to-read containers, look-alike packaging,

5 and routine handling of LDPE by patients and health

6 care practitioners.

7 Some of the slides for this portion of the

8 presentation will include direct quotes from the

9 error reporters. The first contributing factor to

10 consider is the difficult-to-read labeling.

11 Concern was expressed in a medication error report

12 because it is difficult to see the name of the drug

13 and its ingredients. Another person noted that if

14 the lot and expiration date are on opposite sides

15 of the same area of plastic, it is even more

16 difficult to read. In addition, practitioners

17 described how the vials needed to be angled in the

18 light to read them. For some, the text is

19 difficult or impossible to read.

20 In addition to difficult-to-read

21 containers, another concern from the medication

22 error perspective is the issue of look-alike

26

1 packaging. Often there is very little on the

2 container itself to help people distinguish these

3 products.

4 This photo accompanied one medication

5 error report. It highlights the potential for

6 confusion from look-alike vials from just a few of

7 the products available in these containers. Almost

8 all of these vials contain a different drug

9 product. The paper labels and the unique round

10 vial shape help to differentiate three of the vials

11 from the rest. However, these two can be difficult

12 to read.

13 In addition, this problem spans various

14 drug classes and routes of administration. This

15 complicates the picture for practitioners and

16 creates the opportunity for errors to occur among

17 inhalation, injection, ophthalmic, and oral

18 products.

19 In this case, heparin is an injectable

20 medication. This photo was included with the

21 report of potential for confusion between heparin

22 and Tobramycin due to look-alike containers.

27

1 Pharmacies may store a variety of these products,

2 and the potential for confusion will likely

3 increase as we see more products other than

4 inhalation solutions packaged in the LDPE

5 containers. This increases the likelihood for

6 administration of the wrong drug product by the

7 wrong route of administration.

8 Another example of an injectable drug

9 product with similar packaging is Naropin. These

10 ampules are specially design to fit both Luer lock

11 and Luer slip syringes. Although this feature may

12 minimize the likelihood for confusion with the

13 other LDPE containers, there is still potential for

14 confusion between the dosage strengths within the

15 Naropin product line. This vial includes black

16 type on a clear background. Again, for some this

17 may be difficult to read.

18 Timoptic OCUDOSE is an example of an

19 ophthalmic solution packaged in an LDPE container.

20 This image shows that the tip of the container has

21 been extended to allow for a label. However, there

22 may be potential for contamination despite the

28

1 placement of this label.

2 Gastrocom is an example of a product for

3 oral administration that is packaged in an LDPE

4 container. This image illustrates the instructions

5 for use.

6 In summary, there are least four different

7 routes of administration for products packaged in

8 LDPE containers. Again, this complicates the

9 picture for practitioners and creates the

10 opportunity for errors to occur among inhalation,

11 injection, ophthalmic, and oral drug products.

12 We have discussed several issues that

13 contribute to medication errors with LDPE

14 containers. We have seen examples of containers

15 that are difficult to read and difficult to

16 distinguish from one another. We have noted that

17 the look-alike contains look-alike containers are

18 not from a single drug product category or

19 associated with a single route of administration.

20 Now we will explore how routine handling of LDPE

21 containers by patients and practitioners can

22 contribute to errors.

29

1 The foil overwrap serves to protect the

2 containers from light and the environment. It is

3 recommended that the containers are stored in the

4 foil overwrap until time of use. However, the

5 reality is that the foil overwraps are commonly

6 discarded. Once discarded, the clearly labeled

7 portion of the packaging is often eliminated.

8 One reason noted in our analysis for the

9 overwrap to be removed is an effort to fit the

10 products into a medication cart. The foil overwrap

11 and carton for many inhalation solutions use color

12 to differentiate the dosage strength. Most foil

13 overwraps contain multiple unit dose LDPE vials.

14 For example, the foil overwrap for Xopenex contains

15 12 vials.

16 Carol, if you\'ll pass the sample?

17 This image includes the 12 vials which are

18 contents of a single foil pouch of Xopenex. All of

19 the vials in this image are the same dosage

20 strength. However, Xopenex is available in three

21 different dosage strengths. The vials for all

22 three strengths look alike when they are removed

30

1 from the foil. Although the foil helps to

2 differentiate them, it is possible that these vials

3 may not remain in the foil pouch until their time

4 of use. These individual LDPE containers can be

5 stored in a variety of places once removed from the

6 foil overwrap.

7 It is a common practice for LDPE

8 containers to be stored in the pockets or pouches

9 of the practitioners who administer these

10 medications. In summary, while it is possible for

11 various products to have clearly marked foil

12 overwraps, as long as the containers themselves are

13 poorly marked there is still potential for

14 confusion.

15 Once the container leaves the foil

16 overwraps, it no longer matters how well labeled

17 the foil pouch is. This is a concern, regardless

18 of the number of vials contained in the foil

19 overwrap. However, a single container in the foil

20 pouch may minimize the likelihood for the vial to

21 become separated from the overwrap.

22 At this point we would like to stimulate

31

1 ideas for discussion about how to address the

2 issues that have been raised so far. The remainder

3 of this presentation will include a series of

4 photos. These images will highlight various

5 packaging and labeling approaches to consider.

6 Remember to keep in mind who will be using the

7 products and how they will be used. Our goal is to

8 identify packaging that will resolve our concerns

9 but not introduce any new problems for those who

10 manufacture or use the products.

11 The paper label approach allows for use of

12 color to distinguish look-alike vials. For some,

13 these may difficult to read due to the small font

14 size of the text. The reports in our analysis

15 demonstrated that some people may identify these

16 medications by the color of their label alone.

17 Based on the earlier presentation, we learned of

18 the potential safety and product quality concerns

19 with this approach for inhalation solutions.

20 Although this packaging no longer appears

21 to be used for Timoptic, this image illustrates

22 another approach with paper labels. The paper

32

1 label is applied to the tip of the container. The

2 packaging allows for use of color to differentiate

3 the containers and dosage strengths. However, it

4 may not address the potential for ingress.

5 Again, consider the size of the label and

6 the potential font size issues which may make the

7 text difficult to read.

8 We have a sample of this also going

9 around.

10 Here is an approach that extends the tip

11 of the container to allow for the text to be

12 embossed in the flange instead of the body of the

13 vial. This approach allows for more space for

14 printed text; however, if both sides are embossed,

15 they tend to interfere with the readability of the

16 text.

17 In contrast, this approach includes an

18 embossed container without an extended flange. In

19 addition, the container is topped with the letter

20 V-shaped tip. In this case, V is for Ventolin.

21 This approach allows for use of the unique vial

22 shape and possibly texture to help differentiate

33

1 the product.

2 Another approach used to differentiate the

3 various products in LDPE vials is the use of the

4 embossed letters A, I, and R at the tip of the

5 container. In addition to a visual cue, the vial

6 makes use of texture to distinguish the products.

7 A is for Albuterol, I is for Ipatropium, and so on.

8 Again, for some this is difficult to read.

9 One approach that has contributed to

10 medication errors with acetylcysteine is the use of

11 a glass vial. The packaging has led to medication

12 errors where practitioners inject the product

13 instead of administering the drug via inhalation

14 because the vials look similar to those that

15 contain an injectable product. According to the

16 May 30, 2001, ISMP newsletter article, these error

17 occur despite warnings on the label that state \"Not

18 for injection\" or \"For inhalation.\" In addition,

19 they have a target area on the rubber stopper

20 similar to the injectable products.

21 Another approach used to distinguish these

22 products includes the use of a uniquely shaped

34

1 container. Although these round vials distinguish

2 Pulmicort from other drug products, it is difficult

3 to differentiate between the two dosage strengths

4 of Pulmicort once they are removed from the foil.

5 The image on the right illustrates what the

6 containers look like once the foil overwrap is

7 removed.

8 Some products, such as sodium chloride

9 inhalation solution, utilize a tinted vial as a

10 means of differentiation. This approach allows for

11 the use of color to help differentiate the

12 containers from other products. However, this

13 particular packaging has not been evaluated by CDER

14 at FDA. These vials also include embossed text.

15 Another approach is the shrink wrap

16 approach which allows for the combination of

17 embossed information on the end of the vial and the

18 use of black print on a clear background. Again,

19 for some this may be difficult to read. The

20 printed portion of this label clings to the vials

21 without adhesives, eliminating one potential source

22 of packaging contamination. However, there are

35

1 still sources of volatile chemicals with the shrink

2 wrap approach.

3 There\'s also a sample of this going

4 around. The individual foil overwrap approach was

5 described in the Draft Guidance that Dr. Sullivan

6 referred to in his presentation. This method will

7 protect the drug product from contamination from

8 the environment and minimize the opportunity for

9 contamination from the packaging itself.

10 Each foil overwrap contains a single vial.

11 This is thought to increase the likelihood of the

12 pouch staying with the container and minimize the

13 risk for errors. The overwrap allows for the use

14 of color and other means of differentiation to help

15 distinguish these products.

16 At this time we are seeking other ideas

17 and approaches to consider. What other materials

18 could we use? What has been done for other

19 products? What will meet the needs of those using

20 the products in both the inpatient and outpatient

21 setting? How should FDA evaluate any proposed

22 changes?

36

1 Also ask yourself, Will it prevent

2 contamination from secondary packaging in the

3 environment? Will it be difficult to read? Will

4 it look like other containers? Will it create new

5 problems? Will it be difficult to use? And,

6 finally, should inhalation products be handled

7 separately from products with other routes of

8 administration? We look forward to hearing your

9 ideas and suggestions.

10 DR. GROSS: Okay. To round out the

11 presentations, Dr. Shah will talk about the

12 perspective for chemistry, manufacturing, and

13 controls.

14 DR. SHAH: Good morning. My name is

15 Vibhakar Shah, and I\'m a chemist in the Office of

16 New Drug Chemistry for Pulmonary and Allergy Drug

17 Products. Before I start, I would like to

18 apologize for my delay. I was stuck in traffic for

19 almost one and a half hours. Let me tell you, it\'s

20 not a pleasant experience. But, in any case,

21 that\'s life. And I\'m sure when we move to White

22 Oak it\'s going to get worse.

37

1 \[Laughter.\]

2 DR. SHAH: You were supposed to hear this

3 talk before Marci\'s talk, but, anyway, here it

4 goes.

5 You already heard from Dr. Sullivan the

6 clinical concerns arising due to the permeability

7 of LDPE vials, especially when used with paper

8 labels for inhalation drug products, and also you

9 heard some of the medication errors which are

10 caused because of legibility issues with the paper

11 labels. And I\'m going to talk about in the next 20

12 minutes regarding the problems and issues with

13 product quality concerns arising due to the use of

14 LDPE containers, with or without paper labels and

15 with or without overwrap, for these drug products.

16 In the context of today\'s discussion, my

17 presentation will also focus on how best to

18 minimize the potential medication errors given the

19 quality concerns associated with these container

20 closures.

21 With that, this slide gives you the

22 outline of my talk. I\'m going to start with a

38

1 brief introduction to the type of inhalation drug

2 products that are packaged in LDPE containers, and

3 after that I\'ll be overviewing the current

4 container-closure systems that are used. Following

5 that, I would like to discuss the results of an

6 analytical survey conducted by the agency for

7 several inhalation drug products under the Drug

8 Product Quality Surveillance Program. This survey

9 particularly identified the clinical concerns as

10 well as the quality concerns arising from the drug

11 product contamination by packaging components

12 because of the permeability of LDPE.

13 Following that, I would like to discuss

14 some of the quality concerns arising with the use

15 of LDPE vials, with or without paper label and foil

16 overwrap. I will discuss the agency\'s current

17 approaches to control and minimize the product

18 contamination from packaging components and discuss

19 current recommendations for packaging of inhalation

20 drug products as provided in the Draft Guidance.

21 And I will end my presentation with summarizing the

22 quality concerns, what I have discussed so far.

39

1 This slide lists the inhalation dosage

2 forms administered by oral inhalation, and these

3 drug products include inhalation solutions,

4 suspensions, spray, inhalation aerosol, and

5 inhalation powder. However, for today\'s

6 discussion, the remainder of the talk will focus on

7 inhalation solutions and suspensions as they are

8 the only two dosage forms that are packaged in LDPE

9 containers.

10 This slide you have already seen in Dr.

11 Sullivan\'s presentation. It just shows the type of

12 drug products which are packaged into LDPE

13 containers.

14 Currently, inhalation solutions and

15 suspensions are packaged in LDPE vials, and there

16 are three components, basically: LDPE vials, vial

17 labels, and foil overwrap pouch. Not all the

18 inhalation solutions and suspensions may have foil

19 overwrap pouch or adhesive paper label. But in any

20 case, the unit-dose vial\--that is, the LDPE

21 vial\--is made up of low-density polyethylene by

22 blow-fill-seal or form-fill-seal process. The

40

1 labeling information on a vial is conveyed either

2 by a self-adhesive printed paper label or by

3 embossing or debossing the labeling information on

4 the LDPE vial itself during the fabrication of the

5 vial.

6 Foil overwrap acts as a protective

7 secondary package and may contain anywhere from one

8 to 12 vials per pouch. The labeling information

9 may be conveyed by a self-adhesive paper label on

10 the foil overwrap, or the foil overwrap may be

11 printed. Furthermore, different colors for foil

12 pouches may be used to differentiate the multiple

13 strengths of the drug product.

14 Now, let me go over the container-closure

15 components of the LDPE vial, paper label, and

16 foil-laminate. I\'ll start the LDPE vial.

17 The unit-dose vial, which is made up of

18 low-density polyethylene, is chemically a

19 polyethylene homo-polymer resin. The polyethylene

20 resin is made by polymerization process and may

21 contain several chemical additives in addition to

22 the reactant polymer. They include chain transfer

41

1 agent, chain initiator, antioxidant, so on and so

2 forth.

3 Furthermore, it is available in different

4 grades for different applications. That indicates

5 that the composition of the LDPE may change

6 depending upon how it is being used. There are

7 many manufacturers and suppliers of this LDPE.

T1B This slide lists some of the 8

9 characteristics and properties offered by LDPE or

10 LDPE vials which probably makes it a material of

11 choice for packaging of inhalation solution and

12 suspensions from a manufacturer\'s point of view.

13 These include: they are flexible and malleable;

14 stress crack, impact, and tear resistant; they are

15 considered chemically inert at room temperature; or

16 it may be used at elevated temperature for extended

17 periods of time; or it can be sterilized. They are

18 used on high-speed production lines and,

19 aesthetically, they can be clear to translucent in

20 appearance.

21 However, it is permeable to volatile

22 chemicals and gases, and because of this

42

1 permeability, there are several quality concerns

2 which I\'ll be discussing later in my talk.

3 The next I would like to talk about is the

4 paper label, the components of a self-adhesive

5 paper label and how it may contribute to the

6 quality concerns of inhalation solutions and

7 suspensions.

8 Typically, a paper label consists of a

9 base paper, adhesive, inks, pigments and dyes,

10 varnishes, over-lacquer, et cetera, and depending

11 upon the application, the base paper may contain or

12 may be treated with all or many of the chemicals

13 that I have listed here.

14 Adhesive is the layer which comes in

15 immediate contact with the LDPE vial when it is use

16 with self-adhesive paper labels. This slide lists

17 typical chemical composition of an adhesive. This

18 is not an all-inclusive list. There are many more

19 proprietary chemicals used in the formulation of

20 these adhesives. Depending upon the physical

21 chemical properties of these chemicals, that is to

22 say, volatility, they may permeate through the LDPE

43

1 vial into the drug product.

2 I have listed here some of the

3 over-lacquer components. Over-lacquer is an

4 evaporative(?) coating which is typically comprised

5 of chemicals such as plasticizers, resins, (?)

6 solvents, diluents, surfactants, and many more.

7 Some of these chemicals are proprietary in nature.

8 Over-lacquer, or varnish, may be used for a

9 transparent glassy appearance of the label, also a

10 stabilizer for the print work and art work, or it

11 can be used as a protective barrier to the moisture

12 and overall to extend the longevity of the label.

13 Again, in this case also, depending upon the

14 physical chemical properties of some of these

15 chemicals and their constituents, also the

16 concentration and storage conditions, these

17 chemicals may have a potential to permeate through

18 the LDPE vials into the drug product.

19 These are typical ink components. One may

20 think that ink might be just a single-component

21 formulation. However, if you look at it, there is

22 more than one chemical included into the ink

44

1 formulation. And, again, these are also propriety

2 formulations.

3 These ink formulations may be (?)-based

4 or organic solvent-based, and depending upon the

5 brand of solvents which are used in the

6 formulation, they may have a potential to permeate

7 through the LDPE vials into the drug product.

8 The last I would like to talk about is the

9 foil-laminate. Primarily, foil-laminate is used as

10 a protective secondary packaging for the drug

11 formulations that may be sensitive to light and

12 react to gases such as oxygen.

13 Typically, foil-laminate is a flexible

14 packaging composed of multiple layers of various

15 types of plastic films which are fused together

16 either by heat or pressure-sensitive adhesives

17 applied to one or both sides of an aluminum foil.

18 In this cartoon, aluminum foil is represented by

19 layer D, and as you can see, the whole foil

20 overwrap surrounds the drug product vial on an

21 automated packaging line.

22 The thickness of aluminum foil, which is

45

1 D, and the number of pinholes per unit area are

2 crucial for ensuring the consistent barrier to

3 permeability. Furthermore, each of the composite

4 layers may contain volatility chemicals, organic

5 solvents, as they are used in adhesives, which may

6 permeate through a LDPE vial into the drug product,

7 especially the adhesive layer that is closer to the

8 drug product. In this case, that is shown by G.

9 So the composition of these are very critical. One

10 has to really have a knowledge of its composition

11 before they can be selected for the foil overwrap.

12 Alternate approaches to adhesive can be considered,

13 such as fusion of the multiple layers of

14 foil-laminate by heat-set process.

15 In addition to the clinical concerns

16 discussed by Dr. Sullivan, the permeability of LDPE

17 raises several quality concerns, and these are

18 listed on this slide, mainly the drug product

19 contamination through ingress of volatile chemicals

20 which may be originating from the environment that

21 may be irritant or toxic to the respiratory tract

22 and may sensitize individuals; drug product

46

1 degradation because of the reactive gases and light

2 that permeate through the LDPE vial and cause

3 degradation of the drug product; and change in

4 product concentration because of the water

5 evaporation through the LDPE vials. This in turn

6 can accelerate the drug product degradation because

7 of the concentration of the drug product.

8 Now, let me share with you the results of

9 an analytical survey of approved NDA and ANDA

10 inhalation solutions marketed in LDPE vials without

11 protective overwrap. The basis for this survey was

12 a large-scale voluntary recall of inhalation

13 solution by a firm due to contamination of the drug

14 product with 1-phenoxypropanol. This is a known

15 component present in the packaging components.

16 This recall was conducted with FDA\'s knowledge and

17 followed by a health hazard evaluation. It was

18 later found out that the source of this chemical

19 was the varnish or over-lacquer that was used for a

20 shelf carton.

21 Alarmed by this incident, the agency was

22 concerned that there may be other inhalation drug

47

1 products with such contamination from packaging

2 components. As a result, it was decided to conduct

3 a product quality survey of some of the marketed

4 inhalation solutions.

5 This was initiated by the Office of

6 Generic Drugs in consultation with the Division of

7 Pulmonary and Allergy Drug Products and in

8 coordination with the Office of Compliance, Office

9 of Regulatory Affairs, field offices, and Pacific

10 Regional Laboratory. Seven ANDAs and one NDA for

11 inhalation solutions covering five different drug

12 substances were selected.

13 There were 38 samples representing 37 lots

14 of various drug products in LDPE vials without a

15 protective overwrap foil pouch. The samples were

16 screened for potential volatile chemicals which are

17 known to be present in the packaging components,

18 such as vanillin, 2-phenoxyethanol, and

19 1-phenoxy-2-propanol by sensitive analytical

20 techniques such as GCMS and HPLC methods. Let me

21 share the results of this survey.

22 Twenty-nine out of 38 samples tested

48

1 positive for chemical contamination originating

2 from packaging components. Five known chemical

3 contaminants, as listed below, were detected

4 originating from packaging, such as benzophenone,

5 polyethylene glycol, 2-(2-butoxyethoxy)ethanol,

6 2-(2-ethoxyethoxy) ethanol acetate, and

7 2-hydroxy-2-methylpropriophenone.

8 A health hazard evaluation was conducted

9 at the levels these components were detected in

10 these drug products. However, it was indicated

11 that the levels of these components did not raise

12 sufficient safety concern in the intended

13 population to warrant a recall of these drug

14 products. Nonetheless, the following issues were

15 of concern:

16 It was indicated that potential for these

17 chemicals to cause bronchospasm at levels detected

18 is unknown, especially in patients with respiratory

19 diseases.

20 It was also indicated that concentration

21 of these chemicals might be grater at the end of

22 expiry than what was detected at the time they were

49

1 tested.

2 It also showed that permeation through

3 LDPE vial is a real phenomenon.

4 It was also concluded that additional

5 chemicals may be present, but may not get detected

6 because the analytical techniques which were used

7 may not be suitable, not knowing what components

8 might be present into those solutions.

9 And, also, future changes in the materials

10 used in labeling and packaging may result in

11 contamination with different chemicals.

12 So, in a nutshell, product contamination

13 can occur because of the formulation component

14 degradation or by leaching of chemical constituents

15 from packaging components, such as resin components

16 I have listed, paper label components, foil

17 overwrap components, cartons, and environment.

18 These are the typical extractable or

19 leachable components which have been found in the

20 drug product from packaging components. Some of

21 them are irganox 129, 2, 2, 6-trimethyloctane,

22 which is coming from resin components. Some of the

50

1 paper label components that we have seen is benzoic

2 acid, ethyl phthalate, benzophenone, danocur 1173,

3 cyclic phthalates. From the foil overwrap, we have

4 seen methacrylic acid, 2-phenoxyethanol, and some

5 of the organic solvents such as acetone,

6 2-butanone, ethylacetate, propylacetate, heptane,

7 and toluene. And from cartons, methacrylic acid

8 and 1-phenoxy-2-propanol.

9 So this raises a significant quality

10 concern, and there are several other factors.

11 These are the factors. Because of the proprietary

12 nature of components and composition of this

13 packaging material, we may not know what is present

14 in the solution. The composition of these

15 components which are present in the packaging may

16 change without the knowledge of applicant and the

17 agency. And you cannot detect if you don\'t know

18 what you are looking for. As a result, there is no

19 one analytical procedure to detect unknown chemical

20 contaminants. And there is incomplete

21 toxicological data or information available for

22 many of these identified chemical contaminants.

51

1 And as the environmental conditions change, that

2 may introduce new contaminants.

3 So what are the potential approaches the

4 agency has taken to minimize and control the

5 contamination from packaging components to the

6 extent possible? Our approach has been and we have

7 recommended that characterize or identify all

8 possible extractables and establish a profile for

9 each packaging component, for resin, vial, paper

10 label, foil-laminate overwrap.

11 What I mean by extractable is extractable

12 is a chemical compound, which can be volatile or

13 non-volatile, that gets extracted from a packaging

14 component in a suitable solvent by utilizing

15 optimum extraction conditions, such as time and

16 temperature.

17 Extractable profile for a given packaging

18 component typically can be a chromatogram

19 representing all possible extractables.

20 After that, establish a correlation

21 between extractable and its leachable potential,

22 and what I mean by leachable is leachable is any

52

1 chemical compound that leaches into the drug

2 product formulation either from a packaging

3 component or a local environment on storage through

4 expiry of the drug product. An extractable can be

5 a leachable.

6 And to ensure batch-to-batch consistency

7 of the drug product, appropriate specification for

8 a leachable is established based on its

9 qualification and observed levels in the drug

10 product on storage.

11 As a result, the next approach is we asked

12 them to set meaningful acceptance criteria for a

13 given extractable in corresponding incoming

14 packaging components based on its qualification

15 level and actual observed data. Once that is

16 accomplished, meaningful acceptance criteria for a

17 given leachable based on actual observed data in

18 the drug product also be established.

19 These are the recommendations we have

20 provided in the Draft Guidance. We have

21 recommended that adequate knowledge of composition

22 and physico-chemical properties of packaging

53

1 components is essential for appropriate selection

2 of these components. We discourage paper label

3 directly on the LDPE vial and encourage alternative

4 approaches, including embossing or debossing, in

5 lieu of the paper label on the LDPE vial because of

6 the reasons I discussed, because of the product

7 contamination. This can be accomplished by

8 extended bottom flanges to unit-dose vial that can

9 carry essential vial labeling information and can

10 retain the product identity.

11 We have also recommended use of protective

12 overwrap foil pouch for the LDPE unit-dose vial.

13 This in turn can minimize the ingress and leaching

14 of chemical contaminants from the local environment

15 provided that the components that have been

16 selected for the fabrication of the overwrap foil

17 pouch are appropriately selected.

18 The self-adhesive paper label on a foil

19 pouch or pre-printed foil pouch is also

20 recommended, and different color schemes to

21 differentiate multiple strengths of the drug

22 product is also recommended. This in turn can

54

1 prevent ingress or leaching of chemical

2 contaminants from paper labels and may improve the

3 legibility issues.

4 The last recommendation we have in our

5 Draft Guidance is to limit the number of unit-dose

6 vials per pouch, ideally to one LDPE vial per foil

7 pouch. This can minimize the risk of medication

8 error by patients and health care professionals,

9 and it can prevent unnecessary exposure to local

10 environment when compared to packaging of

11 multi-unit-dose vials in a foil pouch.

12 So, in summary, so far I have presented to

13 you that volatile chemicals present in the

14 packaging components and local environment have a

15 great potential to permeate through LDPE vials into

16 drug product formulation on storage. The agency\'s

17 analytical survey and other supportive data have

18 confirmed ingress and leaching of such volatile

19 chemicals into the drug product formulations.

20 Ingress or leaching of such chemicals into

21 drug product formulation poses a safety concern for

22 patients with respiratory illnesses, such as asthma

55

1 and COPD. Embossing or debossing of LDPE vial in

2 lieu of paper label is recognized to have

3 legibility issue. However, paper labels, although

4 perceived to address legibility issue, overall may

5 not be the optimum solution because of the safety

6 concerns associated with potential leaching and

7 ingress of paper label components in the drug

8 product through LDPE vial.

9 The agency\'s current recommendations as

10 stated in the Draft Guidance may serve as a first

11 step in the right direction to address the issues

12 that are being discussed today. And the agency is

13 seeking other viable approaches to address these

14 issues to promote safe product use without

15 compromising the integrity of the drug product.

16 With that, I will conclude my talk, and

17 thank you for your attention.

18 DR. GROSS: Thank you very much, Dr. Shah,

19 and I want to thank the first three speakers who

20 presented a very clear review of the problem.

21 We are now open for discussion. Perhaps

22 I\'ll start off with a couple questions.

56

1 We talk about low-density polyethylene.

2 Does high-density polyethylene reduce transmission,

3 number one? Number two, would increasing the

4 thickness of the container reduce transmission?

5 And, number three, have other plastics been

6 considered? I\'m not a chemist so I don\'t know, but

7 polypropylene, polystyrene? And are any of those

8 possibilities?

9 DR. SHAH: So far, traditionally, LDPE is

10 the choice of material by the manufacturer because

11 of some of the properties it can offer. And I

12 guess one can increase the thickness of the LDPE

13 vial or may use a different polymer. However, one

14 has to keep in mind that by nature, when you do the

15 fabrication of the vials, it may have some kind of

16 a permeability. But that depends on the degree of

17 permeability. LDPE offers one side of the

18 spectrum, or other polymers may offer a different

19 type of permeability. But one has to conduct some

20 of the studies to show that it does not permeate.

21 DR. GROSS: Michael?

22 DR. COHEN: Dr. Lee mentioned shrink wrap

57

1 at one point, and then added that there might still

2 be some concern about, you know, the volatility, I

3 guess, of the inks in the shrink wrap itself. It

4 does not come in contact with the actual LDPE

5 plastic, though, so I\'m trying to figure out why

6 that would be a concern. Do you think it\'s still

7 possible for that to leach in?

8 DR. SHAH: Yes, let me answer that.

9 Shrink wrap, again, it\'s a plastic and it suffers

10 through the same thing. It comes in direct contact

11 with the LDPE vial. So depending upon the chemical

12 components of the ink and how it is being used, in

13 a shelf carton or anything, it still will have the

14 same unit problems that I discussed.

15 DR. COHEN: Can I ask a follow-up?

16 DR. GROSS: Yes, go ahead, Michael.

17 DR. COHEN: Have you done testing\--

18 DR. SHAH: No, we\--I mean, we have not

19 even received\--or we have not approved a drug

20 product with the shrink wrap. There is no example

21 of that, at least to CDER. Maybe in other

22 divisions, another agency, but we haven\'t received

58

1 any.

2 DR. GROSS: Jackie, next question?

3 DR. GARDNER: I understand the problem of

4 potentially masking the effect of contamination by

5 the condition, but I was surprised to see only 87

6 reports of medication errors that you\'re working

7 from. And given the excellent presentation and the

8 potential for confusion, I\'m surprised that there

9 were so few because it looks like it would happen a

10 lot. I wondered if we could have some perspective

11 on why there would be so few, and maybe Mike can

12 help with that.

13 And then the second thing is I wondered

14 whether any of the potential suggested

15 recommendations or the different packaging types

16 have been tested in any way that we could

17 reasonably expect that they might reduce the

18 potential for error if they were implemented,

19 whether the foil wrap or any of these things have

20 been tested among the people who would be using

21 them.

22 DR. GROSS: Next question, Leslie?

59

1 Does anybody have an answer? Marci?

2 DR. LEE: Thank you. As to the number of

3 reports being few, since the review was done, there

4 have been additional reports submitted to the

5 agency for a total, I think I said, of 138 reports,

6 which may still sound like a small number, but

7 considering the problem is probably very underreported. We

8 also had some reports that were

9 describing errors that had to do with restocking.

10 For example, a transport team\'s pouch was supposed

11 to contain three Albuterol and three Ipatropium

12 vials, and at this one given time it contained one

13 vial of one drug and five of the other. So, you

14 know, in the report the narrative says, \"We suspect

15 that at least one patient has been affected by this

16 problem.\"

17 The same thing can happen in an inpatient

18 setting where the drugs are getting intermixed in a

19 bin. So it\'s really an unknown, the actual impact

20 of the problem.

21 DR. GROSS: Leslie?

22 DR. HENDELES: I\'d like to just respond to

60

1 Jackie\'s comment. Mixing these medicines up is

2 very unlikely to be associated with a visible toxic

3 reaction, so that might be\--if anything, the

4 adverse consequences is a lack of therapeutic

5 effect when you\'re treating a disease that\'s

6 involving acute bronchospasm. So the clinician

7 can\'t distinguish between lack of drug effect from

8 worsening of the disease.

9 But the question I had was: Is there any

10 evidence that these contaminants in any way

11 interact with the active drugs to either decrease

12 their stability or to in some way inactivate them?

13 DR. SHAH: They may not inactivate, but

14 they will increase the degradation of the products.

15 They may react with the active, and then you will

16 form an adduct. But you are not going to, you

17 know, inactivate the drug product.

18 DR. SULLIVAN: The other thing t keep in

19 mind is that the list of potential contaminants is

20 innumerable. So what may be true of one chemical

21 may not be true of the others.

22 DR. GROSS: Curt Furberg?

61

1 DR. FURBERG: I\'d like to expand on that

2 question. What are the health effects of these

3 contaminants? Are they all toxants? And if we

4 don\'t know that these contaminants have adverse

5 health effects, is this a big issue?

6 DR. SULLIVAN: Well, I think the unknown

7 is part of the problem, and being a clinician at

8 the agency, we\'ve been tasked with addressing the

9 specific risk of specific chemicals that have been

10 found in assays done, particularly\--it was

11 discussed in the analytical survey and so forth.

12 So we get asked this question: What\'s the

13 toxicologic potential of this chemical? And we

14 don\'t know most of the time. There haven\'t been

15 toxicologic studies done. We don\'t know the

16 carcinogenic potential. We don\'t know the extent

17 to which it acts as an irritant or has other toxic

18 effects. And then we have to judge, okay, what\'s

19 the risk out there, and it\'s very difficult.

20 DR. FURBERG: Yes, but shouldn\'t you add

21 that to your recommendation that we find out?

22 DR. SULLIVAN: Well, I think that\'s part

62

1 of why we\'re saying it\'s best to just try to limit

2 potential exposure, because you can\'t list all of

3 these chemicals. For instance, the one that was

4 mentioned was found in a drug product, and it was

5 traced back to the fact that the actual carton that

6 these vials were contained in, the manufacturer of

7 that carton, who isn\'t the drug manufacturer,

8 changed the glue or lacquer in that carton. And so

9 a chemical that we wouldn\'t have previously been

10 aware of made its way into the drug.

11 DR. SHAH: Again, the agency does not

12 control the cartons. We will control to a point

13 and look into the things. The carton is something

14 very\--and as a result, I think our approach has

15 been\--or we recommend the use of overwrap pouch.

16 That can also limit to a certain extent. I mean,

17 there is no 100-percent guarantee that it may not

18 permeate or the glues which are used in the

19 foil-laminate itself may get into the drug product.

20 But one needs to study these things

21 before, you know, providing to the agency.

22 DR. GROSS: Okay. Henri, and then we\'ll

63

1 hold questions after that until later.

2 DR. MANASSE: I have a couple of

3 questions. One is: Do we see the impact of the

4 degradation on all of the active ingredients, that

5 is, for the Albuterol and the Tobramycin and the

6 cromolyn? Is that pretty much standard across all

7 of the ingredients that these volatile substances

8 do have a degrading impact?

9 The other question I had is: What

10 experiences can we gain from either the food and/or

11 the cosmetic industry? Are there experiences there

12 since so much of this packaging is also with

13 low-density polyethylene containers?

14 And my last question relates to the

15 potential application of the bar code to packages

16 vis-a-vis the incoming rule. To what extent will

17 symbology printing either exacerbate or lessen this

18 particular issue?

19 DR. SHAH: I kind of lost you. What was

20 the first question?

21 DR. MANASSE: The first question, Is the

22 infusion, leaching of the contaminants equally

64

1 impactful on all the active ingredients in these

2 products?

3 DR. SHAH: I think some of these will stay

4 as a degradation product. They may not impact the

5 active ingredient, but it will be just a product

6 contamination.

7 Now, itself, how it will affect the

8 particular patient population, that is\--as Dr.

9 Sullivan said, we don\'t know the potential of that.

10 So it may not probably reduce the concentration of

11 the active into the drug product. However, that

12 uncertainty regarding the safety is a concern.

13 The second question was?

14 DR. MANASSE: The second question relating

15 to experiences in the food and cosmetic industry

16 and what may be learned there.

17 DR. SHAH: Okay. I think by far the

18 most\--these packaging components are used also in

19 tablets and other solid oral dosage forms. There

20 the risk is less because you are taking it orally.

21 Here the problem is because of the patient

22 population, we are more concerned. And I don\'t

65

1 know what else can be learned from food and other

2 industries because there is\--I don\'t know that much

3 scrutiny is there. The only thing that is there is

4 whether they are adequate in terms of oral dosage

5 use. That\'s it.

6 Does that answer\--

7 DR. MANASSE: And my last question related

8 to the upcoming application of the bar coding rule

9 and the imprinting of symbologies to implement that

10 particular rule.

11 DR. LEE: Actually, LDPE vials was one of

12 the products that was exempt from that rule. It

13 won\'t be required down to the vial, but any outer

14 packaging it will be on.

15 DR. GROSS: Okay. We\'ll take a break now

16 and reconvene at 9:45.

17 \[Recess.\]

T2A DR. GROSS: The first speaker will be

18

19 Mohammad Sadeghi, who will talk about container

20 labeling options using rommelag blow-fill-seal

21 technology.

22 DR. SADEGHI: Good morning. I\'m Mohammad

66

1 Sadeghi with Holopack International. I\'m here to

2 talk about container labeling options using

3 blow-fill-seal technology, and most of all these

4 products you\'ve been hearing today about and

5 packaging and LDPE, low-density polyethylene,

6 they\'re all manufactured using blow-fill-seal

7 technology.

8 So what I\'m going to do is go over what

9 the blow-fill-seal process is, what container

10 labeling options you have, what are the pros and

11 cons on each, and some examples.

12 Blow-fill-seal technology is an integrated

13 aseptic technology for manufacturing aseptic

14 products. That\'s an example of a machine. The way

15 it works is you feed in raw pellet resins from one

16 end and the (?) solution from another, and the

17 machine will actually melt the pellet, created the

18 container, fill it aseptically, and seal it.

19 The process consists of four major steps.

20 As you see, the plastic is molten first and

21 extruded in a cylindrical shape, and the molds are

22 formed into the container, the needle comes in, and

67

1 there is the Class 100 in this (?) area, fills

2 the container, and it withdraws, and then the

3 container is sealed and ejected from the machine.

4 Now, labeling options that you can have

5 with this technology consist of embossing, paper

6 label on tab if you do not want to put it directly

7 on the container, or printing on the tabs.

8 Embossing consists of a mirror\--engraving

9 mold with a mirror image of the information. You

10 have small vacuum ports on the mold surface that

11 actually will do this, such into the softened

12 plastic into the engraving embossing, hence

13 embossing the container.

14 This is an example of what a mold cavity

15 looks like, and you see the surface inside the main

16 cavity where the engraving takes place.

17 This is a close-up of what it\'s like to

18 have as the imprint. What you see in the bottom

19 would be replaceable magazines that you can change

20 for lot number and expiration date.

21 Another option of embossing is hot stamp,

22 which in this case instead of molding it during the

68

1 production, as the container is ejected from the

2 BFS machine, it\'s actually put into a machine where

3 it actually is a hot stamp that would actually

4 emboss the container, again, and this is done on

5 the tabs and not directly on the body of the

6 container.

7 Paper labels on tabs, one of the reasons

8 this container was developed was to avoid direct

9 contact labels with\--paper labels with the actual

10 container body, and the secondary was the

11 small-volume containers that required information

12 and there was not enough surface area to put the

13 engraving on the container. They developed a tab.

14 Either it can be on the cap or as a tail, have the

15 embossed information.

16 You can use the same tab, actually,

17 instead of\--it\'s a solid surface, so you can use it

18 either to print or add paper to the label.

19 The pros and cons of each labeling option:

20 Embossing has been discussed here. The pros are

21 there is no maintenance of label inventories;

22 ensure 100-percent labeling of containers; labels

69

1 cannot be removed; and ensure each unit is

2 traceable and no leachables. The cons are, which

3 has been discussed also, it is difficult to read on

4 clear containers.

5 Paper label on tabs is\--paper label

6 obviously makes it clearer to read, and you can use

7 colors. It greatly reduces potential leaching into

8 the solution because it\'s not directly applied to

9 the container body. However, there is still

10 potential leaching of adhesive.

11 Direct printing on the tab, it\'s clearer

12 than embossing on the tab to be read; it eliminates

13 potential leaching from paper, adhesive, varnish

14 and stuff that goes with the paper label; and it

15 greatly reduces potential leaching into the

16 solution, again, because it\'s on the tab, on a

17 separate space on the container, not directly on

18 the container body; and, lastly, allows for bar

19 code printing on line as well. However, you still

20 have the ink, which potentially can leach into the

21 solution.

22 Now, examples of these various things,

70

1 there\'s a container with embossed labeling. The

2 containers can be also embossed and color-coded

3 because the same container can be used for

4 different concentrations of products, or you can

5 have color-coded and embossed to represent the same

6 product in different concentrations or doses.

7 You can apply the paper on the tab, both

8 removing the paper from direct exposure to the

9 solution, but also it is readable. Or having

10 direct printing on the tab for bar code

11 information.

12 Also, you have traditional paper on the

13 container, which is\...

14 Now, the other thing is the issue of\--one

15 of the things that comes to mind is the size of the

16 containers, is eliminating paper containers\--paper

17 labels from all outside containers or is it

18 dependent\--it is a size-dependent solution.

19 Obviously, if you have a liter container such as

20 viewed here and you have a paper label, is that

21 also going to be\--it\'s something that has to be

22 removed, and considered this is\--it should be in

71

1 relation to the size of the container. If it is a

2 three- (?) container, you have the same treatment

3 as one-liter container.

4 Another example of various container

5 sizes.

6 Thank you.

7 DR. GROSS: Okay. Now we\'ll hear from the

8 Cardinal Health team, Rick Schindewolf and Patrick

9 Poisson.

x MR. POISSON: Good morning. My name is

10

11 Patrick Poisson. I\'m the Director of Technical

12 Services at Cardinal Health Woodstock. With me

13 today is Mr. Rick Schindewolf, who\'s the general

14 manager of the Woodstock, Illinois, facility.

15 Just a little bit about our role in the

16 industry. Cardinal is a diversified health care

17 company with operations in distribution, manufacturing,

18 research, and management solutions. The

19 Cardinal Health Woodstock facility is a

20 blow-fill-seal facility that produces approximately

21 1 billion units annually. Our product portfolio

22 involves NDA, ANDA, 510(k), and USP Monograph

72

1 products.

2 Some of the advantages of why people

3 select low-density polyethylene in blow-fill-seal

4 is blow-fill-seal is recognized as an advanced

5 aseptic process. There\'s also an immense

6 flexibility in container design that allows various

7 applications of the container and its use. It\'s

8 also a very cost-effective approach to producing

9 pharmaceutical products.

10 Now, some of the limitations: As

11 previously mentioned, LDPE is a semipermeable

12 material. The technology also uses heat to form

13 the container, and there may be issues with

14 heat-sensitive products. And based on the focus of

15 this meeting today, there are obviously some

16 labeling issues as well.

17 Now, the general industry approach has

18 been to emboss and deboss the containers to display

19 the necessary information, which includes product

20 name, concentration, manufacturer, lot number, et

21 cetera. Typically, respiratory products are

22 packaged in a secondary overwrap in multiple units

73

1 or single units, and that provides the additional

2 protection necessary to prevent chemical

3 contamination.

4 This has already been touched upon, but

5 these are the main highlights of the Draft

6 Guidance, and I won\'t spend any time on this since

7 this has been discussed already.

8 Now, what are some of the advantages to

9 the embossing/debossing approach? It provides an

10 immediate tamper-evident identification of the

11 product. It eliminates the potential for

12 contamination from labels. And it provides ease of

13 label copy control.

14 Some of the limitations associated with

15 that: It can be difficult to read on clear

16 containers. It does not provide a very readily bar

17 code-readable print. And the vial size affects

18 legibility of the print that\'s embossed and

19 debossed. We cannot emboss or deboss down to a

20 very small font size that\'s readable that could

21 compete with a paper label.

22 Now, we believe there are some

74

1 possibilities for enhancing product identification

2 in the low-density polyethylene container, and

3 these are listed here: reduce the content

4 requirement to allow an increased text size;

5 addition of physical/tactile identifiers for

6 generic product groups; alternative label

7 approaches such as a sleeve label; color coding

8 unit-dose vials for generic product groups; and

9 individual secondary overwrap.

10 Increased text size. There\'s a limited

11 surface area on the container that is available for

12 embossing/debossing. Due to the technology, we

13 cannot emboss or deboss on the sides of the vial.

14 We can only emboss and deboss on the front. The

15 text size can be significantly increased; however,

16 we would have to remove some of the information

17 that\'s normally provided. This approach would not

18 change any of the materials involved in the

19 process, so there would be no impact on the current

20 product chemistry. This could also be implemented

21 fairly quickly, eight to ten weeks. And there

22 would be a one-time cost for the manufacturer to

75

1 buy the appropriate equipment.

2 This is a drawing of what that concept

3 would look like.

4 In addition to that, physical/tactile

5 identifiers could be added to the container. This

6 would provide an easily recognizable/legible symbol

7 on the container that would represent a product

8 type, for instance, A for Albuterol sulfate, I for

9 Ipatropium bromide, et cetera. This is already

10 currently being implemented on products

11 manufactured at Cardinal Health. This also does

12 not change any of the container materials or

13 process, so, again, no impact on the current

14 product chemistry. This also could be implemented

15 in eight to ten weeks, depending on the regulatory

16 approval of this label change, possibly as a CBE

17 30. Again, there would be a one-time minimal cost

18 to buy the necessary equipment to do such a change.

19 This is a drawing of what that concept

20 could look like. And we have some samples which

21 we\'ll pass around for the committee to see. And

22 those can also be provided in clear plastic. And

76

1 here are some photos of the same vials.

2 This is a picture contrasted with one of

3 the current formats that is out on the market, so

4 you can see that there\'s a definite increase in the

5 identification of the products resulting from this

6 type of change.

7 The sleeve label concept would involve a

8 redesign of the extended tab to make that area

9 amenable for application of a non-paper label.

10 Cardinal has designed such a vial that has a patent

11 pending that would be capable of receiving a shrink

12 wrap sleeve.

13 This label provides a contrasted

14 background for enhanced legibility and also provide

15 a bar code-readable print. This would involve no

16 changes to the product contacting surfaces of the

17 container. The shrink of pressure sensitive label

18 would be applied to an appendage of the container,

19 not in direct contact with the product.

20 This would also involve an increased

21 manufacturing cost for equipment, labor, and

22 materials, and we believe it could be implemented

77

1 in 12 to 14 months following regulatory approval

2 with associated stability testing data.

3 This is a picture of what that concept

4 looks like, and we have some samples that we\'ll

5 pass around. This particular product was mentioned

6 in an earlier presentation as the catheter flush

7 saline and heparin.

8 Color coding. Products could be

9 color-coded to aid in identification. That would

10 be a similar approach to the AAO recommendations

11 for cap color for ophthalmic products. It provides

12 a contrasting background to aid the legibility. A

13 colored vial is easier to read. However, it could

14 impact the product chemistry with leachables and

15 extractables. There would be a slight increase in

16 manufacturing costs for raw materials. Again,

17 implementation time would be based on stability

18 data and regulatory approval of such a change.

19 This is a picture of what that concept

20 would look like.

21 Individual secondary overwrap, that has

22 been touched upon. It provides enhanced labeling

78

1 opportunities, bar code-readable print for a

2 single-dose vial. However, the overwrap can and

3 will be separated from that unit at some point in

4 time during its use, and we don\'t control that, so

5 we cannot predict when that will happen. So there

6 could be legibility/identification issues still at

7 the time of use. There\'s a significant

8 manufacturing cost increase with the raw materials,

9 equipment necessary, and labor. If that was done

10 with the current process, that change, the

11 implementation time would be 12 to 14 months

12 following regulatory approval of the packaging

13 change with associated stability data.

14 In summary, we believe there are

15 opportunities for improvement of the labeling of

16 low-density polyethylene containers. Each

17 alternative is a viable alternative, we believe,

18 and it should be assessed based on impact to the

19 product, speed of implementation, ease of

20 regulatory approval, and cost to the patient.

21 Thank you\--oh, sorry. Our recommendations

22 are to increase label information font size on

79

1 individual vials. Add a tactile symbol for generic

2 identification based on the following advantages:

3 quick approach, no impact on product chemistry or

4 stability, and no impact on patient cost. For

5 hospital-dispensed unit-dose vials, add a sleeve

6 label to accommodate bar coding.

7 Thank you.

8 DR. GROSS: Thank you very much.

9 Our next speaker is Karen Stewart of the

10 American Association of Respiratory Care.

x MS. STEWART: Good morning. Thank you for

11

12 giving me the opportunity to present today. I

13 think in your packets you have my written

14 statement, and I have a couple of slides here that

15 I want to share with you.

16 I\'ve been a registered respiratory

17 therapist since 1971, and I am here as the

18 spokesperson for the American Association for

19 Respiratory Care representing respiratory

20 therapists both nationwide and internationally.

21 Respiratory therapists, like all other

22 health care professionals, are very concerned about

80

1 medication errors. In recent years, since the

2 elimination of most paper labels on unit-dose vials

3 of medication, it has become increasingly difficult

4 to determine the content of the unit-dose vial.

5 I\'m going to share with you some pictures of what

6 the therapist typically has on their person as

7 they\'re making rounds.

8 Not only is the print on the vial

9 difficult to read, the size and the shape of the

10 vial contributes to this difficulty.

11 In 2001, the American Association for

12 Respiratory Care completed a human resource survey,

13 and at that time the average age of a respiratory

14 therapist was 44. This is another contributing

15 factor to the difficulty of reading the content of

16 the medication vial. While I may have just

17 emphasized that the current relative age of the

18 respiratory therapist and the difficulty the older

19 therapist experiences in reading the labels, I want

20 to clarify to you that deciphering respiratory care

21 medication labels is a problem that cuts across all

22 age groups of respiratory therapists. The problem

81

1 is how the medication is labeled or not labeled

2 appropriately.

3 The work flow of the respiratory therapist

4 I think is probably most important for you to

5 understand. The therapist typically includes

6 delivering medications and treatments to a number

7 of patients for a local geographic region in a

8 hospital. The patients that are assigned have a

9 very wide variety of medications that are being

10 delivered to them. Once the medication is checked

11 by the pharmacist for drug interactions, the

12 therapist typically carries medication with them as

13 they begin rounds. It would not be unusual for a

14 therapist to carry between 14 and 15 different

15 vials of medication. The medications must be under

16 control so that therapists either carry the

17 medication in a fanny pack or they carry the

18 medication in a locked draw on a cart they carry

19 with them.

20 In some institutions, medications are in a

21 Pyxsis system. In this situation, the medication

22 can either be placed in a single patient medication

82

1 labeled drawer or they come from stock supply. So,

2 again, multiple vials in a stock drawer.

3 I just wanted to give you a view of what\'s

4 in somebody\'s pocket typically.

5 Another concern that faces the respiratory

6 therapist is the lack of bar coding on the vial.

7 Many hospitals are moving toward the scanning of

8 medication bar codes. The driving force for this

9 use of technology is to identify the correct

10 patient, identify the correct medication, confirm

11 the correct dose of medication, confirm the correct

12 route of medication, and record the time of the

13 medication delivery.

14 I want to share with you a few comments

15 that I picked up from some respiratory therapists

16 in just the most recent weeks.

17 Staff have complained about the inability

18 to see clearly the medication information. For

19 this reason, we switched to a different product

20 that is individually wrapped in clearly labeled,

21 color-coded foil packaging. The current situation

22 with the raised-letter labeling is an accident

83

1 waiting to happen. I know you talked earlier about

2 underreporting. It\'s because we\'ve given the dose

3 and never know we gave the wrong one in some cases.

4 This is a second therapist: I complained

5 bitterly when the look-alike vials came out. We

6 did not leave them for any nurses to confuse. We

7 do not know of any medication errors beck of the

8 look-alikes. Doesn\'t mean it didn\'t happen. We

9 just don\'t know.

10 So, again, a little bit more emphasis on

11 the fact that we are seeing probably underreporting.

12 This is a third one: We have had problems

13 with the unit-doze Xopenex and Atrovent looking

14 alike and labeled in the same clear package. We

15 use Pyxsis and it\'s still a problem.

16 So even moving the medication into a more

17 controlled environment continues to be a problem

18 for the therapist who\'s on the floor.

19 This is a fourth therapist: One

20 encouraging thing that I have seen is differing

21 shapes and sizes on a very few of the medications.

84

1 Since the death of the multi-dose vial of

2 Albuterol, we have a supplier who sends us

3 unit-dose vials of Albuterol that have a very

4 distinctive teardrop shape and a much smaller size

5 for medication. I give that a Bravo. A similar

6 thing has happened with the octagonal unit-dose

7 vials of Pulmicort.

8 And I think if you look at the very end of

9 this, that small round is the Pulmicort. But this

10 is what\'s in the pocket of the therapist, and all

11 they have to read on most of those are just that

12 clear lettering.

13 I was at a program, I did a program in

14 Cincinnati last week, and I mentioned this in a

15 patient safety presentation that I did to

16 therapists. About 600 were there, and what was

17 interesting about it is several of them came up to

18 me afterward and said, Can you imagine what the

19 night shift therapist goes through trying to read

20 these?

21 Now, low light\--it\'s bad enough, you know,

22 with the age, but the low light.

85

1 There\'s a couple more comments from

2 therapists in there. I think that you\'ve probably

3 got those. You get the gist of what we\'re trying

4 to say. So on behalf of the American Association

5 of Respiratory Care, I really appreciate the

6 opportunity to share the association comments.

7 I have one more slide that I want to share

8 with you, and it\'s this one. What you\'re seeing

9 here are just the different medications. One of

10 those happens to be Tobramycin. One of them\--two

11 of them are bronchodilators. Two of them are

12 exactly the same medication in different doses.

13 Just to really emphasize what the packaging is

14 doing to the therapist at the bedside.

15 Thank you.

x DR. GROSS: Okay. Thank you very much.

16

17 We will not have the committee ask some questions

18 of the speakers, and you can ask questions of any

19 of the speakers that have presented this morning.

20 Leslie?

21 DR. HENDELES: I have two questions for

22 Karen. First, is there any Joint Commission

86

1 requirements in terms of how respiratory therapists

2 are supposed to handle medication?

3 MS. STEWART: There\'s been\--

4 DR. HENDELES: And I have a second

5 question, which is: Would respiratory therapists

6 mind carrying these single-unit dose vials wrapped

7 in foil in their pockets?

8 MS. STEWART: There are recommendations

9 around the delivery of medications from JCAHO, and

10 most of that is surrounding the control. It is

11 first the pharmacist\'s review of that medication to

12 see if there are any other interactions, and the

13 second being that that medication is always under

14 control. And you\'ll see as you go across the

15 country a number of different ways that hospitals

16 are handling the medication control issue. Some of

17 them\--the folks that I talked to last week, some of

18 them have a cart where they carry all their

19 plastics and other things that they need with a

20 locked drawer, and their medications are in that

21 drawer. Other ones are using Pyxsis, and some are

22 still carrying it physically on their person in a

87

1 side pocket or a fanny pack.

2 Your second question is, if they were

3 individually wrapped, I think that therapists would

4 use those either in any of those devices under

5 control. The problem is that they open, for

6 example, a packet of Xopenex with 12 vials in it.

7 That\'s just too much for them to carry when they\'ve

8 got so many different types to carry.

9 DR. HENDELES: If it\'s just one, they

10 would be able to?

11 MS. STEWART: I think they would be able

12 to carry it, yes.

13 DR. GROSS: Yes, Stephanie?

14 DR. CRAWFORD: Thank you. This question

15 is for Patrick Poisson, but, Ms. Stewart, don\'t go

16 too far just in case you want to add to it. I

17 thank each of the speakers for their presentations.

18 Mr. Poisson, with respect to your

19 presentation, the sixth slide was talking about the

20 advantages and disadvantages\--I\'m sorry, the

21 advantages and limitations. Each of the advantages

22 from my interpretation were in the manufacturing

88

1 process. As you presented, each of the limitations

2 was from the clinical use. So my question is:

3 From the recommendation\--potential alternatives

4 that you suggested, have you conducted, your

5 company, or performed any studies using clinical

6 groups such as the respiratory therapists to see

7 acceptability of each of these options?

8 MR. POISSON: One thing I probably failed

9 to mention is that Cardinal Health is a contract

10 manufacturer, and the products that we manufacture

11 are distributed by our customers. And it\'s

12 difficult for us to step in front of them and ask

13 for this type of work to be done.

14 Now, we have done some work with the

15 shrink wrap sleeve label, and the feedback from

16 that was very positive. However, that was a very

17 unique opportunity for us to get involved with

18 that.

19 In regards to the recommendations, yes,

20 some of them are manufacturing\--are good for the

21 manufacturing process. However, one that maybe

22 wasn\'t explained as well is the sterility of the

89

1 product. Using a blow-fill-seal technology to

2 manufacture products is recognized as providing a

3 better microbiological quality of product out to

4 the market versus a conventional process.

5 DR. GROSS: Michael? I\'m sorry.

6 Stephanie, another question?

7 DR. CRAWFORD: Thank you. Just one quick

8 follow-up. One of your recommendations was

9 increase text size. You mentioned that, of course,

10 something would have to come off if that were

11 happening\--would come off if\--

12 MR. POISSON: I think we\'d have to

13 undertake those discussions with the agency as to

14 what could come off.

15 DR. GROSS: Michael?

16 DR. COHEN: I\'ve been looking at these

17 LDPE plastics for several years, actually, and

18 trying to come up with solutions. And actually the

19 best thing I\'ve ever seen is that shrink wrap, that

20 overwrap, or sleeve, or whatever you want to call

21 it. Is that a proprietary system, or is that

22 available to any manufacturer? And can you foresee

90

1 the actual use across the entire spectrum of LDPE

2 containers, even the parenterals?

3 MR. POISSON: Well, we\'re very pleased

4 with the progress we\'ve made on the sleeve label.

5 It did involve some development that we regard as

6 intellectual property. So regarding availability

7 to the whole industry, I really can\'t speak on

8 that.

9 There will be potentially some leachable

10 extractables even from that system. There is ink

11 on that label. So that has to be evaluated for

12 each product that it\'s used for. It still may not

13 work for every product.

14 MR. SCHINDEWOLF: If I could just make a

15 comment on the proprietary nature, what\'s

16 proprietary about that vial is the rounded end. A

17 lot of the vials that you\'ll see and I think some

18 that were presented earlier can be on a flat end as

19 well. And we found that the rounded end helped the

20 legibility. As the sleeve shrinks, there tends to

21 be some\--what\'s the word I\'m looking for? The

22 print can be\--

91

1 MR. POISSON: It can be distorted.

2 MR. SCHINDEWOLF: Yes, \"distortion,\"

3 that\'s the word. So this was to help the

4 readability of the bar code label itself, so that\'s

5 what\'s proprietary in that particular design.

6 DR. GROSS: Yes, Henri?

7 DR. MANASSE: In terms of patient safety,

8 one of the biggest issues that I think most

9 practitioners confront is the kind of work-arounds

10 that people utilize to make things convenient for

11 them, and this notion of carrying drugs around in

12 your pocket is a very good example. But it seems

13 that the sleeve is a pretty critical issue with

14 respect to the capacity of adding more information

15 coupled with bar codes, symbologies, et cetera.

16 Have you all thought about how you can

17 eliminate the dissociation of the sleeve from the

18 package itself? Because the work-around, people

19 are tearing off the sleeves and then carrying the

20 package by themselves. And is there a way that you

21 can avoid that other than at the direct point of

22 care?

92

1 MR. POISSON: I\'ll try and address that.

2 One of the ways that these are used is that the cap

3 is actually twisted off of the vial. And one of

4 the problems I see with individually foil

5 overwrapping is the removal of that foil could

6 potentially damage the vial in that process. So

7 it\'s a difficult thing to overcome. We could

8 tighten the foil potentially around the vial, but

9 it just opens it up for damage in the transfer

10 process from the location within the hospital to

11 its use point.

12 You know, there are a lot of advancements

13 going on in packaging. Certainly five years ago I

14 don\'t think we would have all the options that we

15 have now. Maybe at some point in time we can get

16 to a better alternative with the foil.

17 DR. GROSS: Robyn?

18 MS. SHAPIRO: I have two questions. One

19 is actually Henri\'s. And this is to the agency.

20 What factors, if any, are considered currently in

21 the approval process with respect to these

22 problems?

93

1 And the second question is: It seems to

2 me that this morning we have much more information

3 about the potential error, problem, than the

4 leachability and contamination problem, and much

5 more potential risk. Has there been\--maybe this is

6 for Karen. Has there been litigation over this?

7 And, if so, what has happened?

8 MS. STEWART: I can\'t speak to any

9 litigation, and I think one of the concerns that we

10 have as therapists is that this probably goes underreported.

11 The therapist delivers that care

12 and leaves the bedside to treat the next patient.

13 So they may not see an adverse effect or, as stated

14 earlier by Dr. Sullivan, I believe, the patient

15 does not get the potential relief of the

16 medication.

17 In other words, if you have Tobramycin and

18 a bronchodilator in your pocket, they both look

19 alike, you give the Tobramycin to the patient who

20 needs the bronchodilator, you may not see the

21 effect. So it becomes underreported.

22 MS. SHAPIRO: And the patient may not

94

1 either. I mean, they may not realize\--the patient

2 or the family or whomever, the error may not be

3 disclosed to anyone.

4 MS. STEWART: Except the patient\'s

5 therapeutic treatment regime is going to be longer

6 with a longer length of stay because they didn\'t

7 get the proper\--

8 MS. SHAPIRO: Sure, but they may not know

9 why.

10 MS. STEWART: Right.

11 DR. GROSS: Are there any other questions?

12 MS. SHAPIRO: Can I have the first

13 question answered by Paul or somebody about what

14 currently is considered?

15 DR. SHAH: You are talking about in terms

16 of the quality controls?

17 MS. SHAPIRO: In the approval process for

18 any new drugs, what, if any, is considered with

19 respect to safety relating to this possibility for

20 error?

21 DR. SHAH: Let me just try to briefly

22 summarize.

95

1 When we get an application and we have

2 these kind of packaging components, then usually

3 the applicant may provide this information for all

4 the components of each and every packaging

5 component into the NDA, or they may choose to

6 provide that information, if it proprietary,

7 through a Drug Master File. Then we review the

8 chemical composition of each and very packaging

9 component in a Drug Master File, but we cannot

10 relay that information to the applicant.

11 Once we know from the composition that

12 there is a potential for volatile chemicals to be

13 present in the component and they may permeate

14 through the LDPE vials, then we ask the applicant

15 indirectly, without revealing the other

16 information, Have you studied any legibility or

17 extractable\--have you found any extractable, what

18 kind of solvent conditions you have used to extract

19 this leachable? And we encourage them to contact

20 the DMF supplier, work with them, and develop some

21 procedures to find out what can be present and

22 establish a profile. Once you establish a profile,

96

1 then you may identify, okay, these are the typical

2 components present into a component, packaging

3 component, and we are going to use that as a basis

4 for screening the incoming packaging material. And

5 then you may have some kind of acceptance criteria.

6 That may be a GC profile. Or if you have

7 identified a particular component by its chemical

8 structure, then you may say, okay, it is extracted

9 at, say, one milligram per ml or something like

10 that, okay? So then you will conduct some kind of

11 a study for the shelf life, over the shelf life,

12 whether that particular extractable gets into the

13 drug product or not. If it does not, then at least

14 you have established that if I control the amount

15 of incoming acceptance criteria, I have established

16 incoming packaging material, then I do not see the

17 leachable into the drug product. So then you don\'t

18 have to have a test for leachable into the drug

19 product, but you have to establish that

20 relationship.

21 So we go through a series of steps to

22 establish that, and once we are satisfied, then we

97

1 may decide, okay, you are going to control or

2 minimize this particular component at acceptance

3 level in incoming packaging material. Or you will

4 have to carry out the leachable testing.

5 MS. SHAPIRO: What about the analysis with

6 respect to the possible safety problems on account

7 of the error issues?

8 DR. SHAH: Okay. Once we get that, we see

9 that, okay, it is present into the drug product at

10 a certain level. And if we know the identity of

11 that chemical, then we ask our pharmacology and

12 toxicology person to review that data and decide

13 whether that will have any safety issue. And if

14 they decide that it may have a safety issue, then

15 they may ask the applicant to qualify that

16 particular material or chemical at that level.

17 MS. SHAPIRO: Okay. And all that has to

18 do with the leachability question. But what about

19 the question having to do with the confusion

20 problems on account of the labeling and its impact

21 on safety?

22 DR. SELIGMAN: For all drug products that

98

1 are approved by the agency, we look at the accuracy

2 of the label, whether it\'s misleading or not,

3 whether it\'s nonpromotional in nature. We look at

4 the name for potential confusion. We look at the

5 packaging regarding dose and frequency. And if at

6 the time we find, either at the time of approval or

7 even subsequent to approval, that there is such a

8 potential for either name confusion, for misleading

9 dose, or any kind of misleading information that

10 might lead to medication error, we make a

11 recommendation to the manufacturers to try to\--to

12 alter that.

13 I think the reason we\'re bringing this

14 particular issue to this committee is that this is

15 a particularly vexing issue. But for the vast

16 majority of products that we review, when we find

17 such potential for confusion or potential error, we

18 recommend to the manufacturer that that be

19 addressed prior to approval of the product.

20 MS. SHAPIRO: Have you ever, with

21 containers like this, sent it back and said, no,

22 this doesn\'t\--this won\'t do given these sorts of

99

1 problems?

T2B DR. SELIGMAN: I\'m not aware of any. Some

2

3 of them go through generics.

4 Carol, did you want to respond to that?

5 MS. HOLQUIST: Yes. Actually, our office

6 in Office of Drug Safety, we only get whatever\--we

7 only see the packaging material that comes in with

8 new products. A lot of these products have been on

9 the market for years and years. So if indeed one

10 of these products came in today with this packaging

11 labeling, yes, of course, that would be one of our

12 recommendations in our review that, based on

13 post-marketing reports and evidence, we wouldn\'t

14 recommend this. But then the agency\'s hands are

15 kind of tied because of the ingress issue. So

16 until we find an alternative packaging, it\'s a

17 conundrum we\'re in.

18 DR. GROSS: Gene, did you want to comment?

19 DR. SULLIVAN: Yes, I just wanted to

20 follow up on a couple things that have been said so

21 far: one, to just make sure the categories of harm

22 to patients are in the right column. There\'s the

100

1 harm that the legibility issue brings in, so the

2 harm that a patient suffers if he or she doesn\'t

3 receive Tobramycin but instead receives Albuterol.

4 And then what I was trying to touch on and the

5 thing that\'s hard to get your hands around is the

6 harm from the actual presence of these chemicals,

7 and that it\'s well known that a patient may come to

8 the emergency department and receive a few

9 treatments of Albuterol and recover and be

10 discharged. Another patient may come in and not

11 seem to respond and end up mechanically ventilated.

12 And to what extent that could be related to

13 contaminants in the drug product would be anyone\'s

14 guess and impossible to day. So I just wanted to

15 make sure we consider those two sort of as they\'re

16 the competing harms.

17 The other issue I just wanted to talk

18 about a little bit was the issue of the use of the

19 flange or labeling that\'s not directly applied to

20 the actual body of the nebule, be it with a shrink

21 wrap or an applied label and so forth; that there

22 is some intrinsic appeal because it seems to be

101

1 less in contact with the LDPE, but keep in mind

2 that if these are then put into an overwrap, a foil

3 overwrap, perhaps for other

4 reasons\--light-sensitive products and so

5 forth\--that then you have sort of a micro

6 environment, you know, like a little humidor with

7 these chemical vapors that could then make their

8 way\--even though they\'re here on the flange, they

9 could easily make their way into the product, and

10 that\'s sort of evidenced by that case where we had

11 the cardboard carton and that chemical made its way

12 in. So it\'s not, you know, a complete solution.

13 We have to keep that in mind.

14 DR. GROSS: Arthur, you had a question?

15 MR. LEVIN: One is just a point of

16 information. Mike, is that the packaging with that

17 label, that\'s what you are referencing when you say

18 so far that\'s the best\--

19 DR. COHEN: Not necessarily.

20 MR. LEVIN: Okay.

21 DR. COHEN: This is certainly acceptable

22 as a way to identify a container. But the ones

102

1 I\'ve seen have actually had a similar type of film,

2 but it\'s been around the body of the ampule device.

3 And there was a tear-off so that you would

4 literally pull the tab and tear off the top part of

5 the plastic. It was a total overwrap.

6 MR. LEVIN: But it\'s something more than

7 that.

8 DR. COHEN: Leaving the identify, even

9 though this was exposed.

10 MR. LEVIN: Okay. So the whole thing is

11 shrink wrapped to something.

12 DR. COHEN: That\'s correct.

13 MR. LEVIN: Right, okay. I didn\'t think

14 we had seen one of those.

15 DR. COHEN: We didn\'t.

16 MR. LEVIN: Yes, okay. So that clarifies

17 that.

18 The second thing is we seem to be sort of

19 entirely focusing in inpatient and, you know, the

20 issue of outpatient is certainly significant. And

21 I\'m just wondering from, you know, what you\'ve done

22 to look at how well these kinds of solutions work

103

1 in the outpatient pharmacy setting as opposed to

2 inpatient settings where it\'s really\--making sure

3 that the respiratory therapist who administers the

4 drug is clear on the right drug and the dosage et

5 cetera. What about an outpatient pharmacy?

6 MR. POISSON: Well, one of the reasons

7 why\--and someone may question why there\'s 12 vials

8 in a pouch or even 28 or up to 60. A lot of the

9 reason behind that is because of the use period in

10 the outpatient\--outside of the hospital. And based

11 on feedback we\'ve received, they view that as an

12 advantage to have that type of packaging in that

13 particular environment. And the possibility exists

14 that maybe some of these options we\'ve presented

15 today, such as the symbol on the vial would help

16 them in that area from using the wrong product.

17 So I think, you know, there\'s

18 opportunities for a number of these options to be

19 implemented based on the setting that they\'re used

20 in.

21 DR. GROSS: Okay. Henri, you have a

22 question?

104

1 DR. MANASSE: I just want to follow up on

2 Art\'s point in terms of outpatient use. I can\'t

3 imagine given the size of these containers, given

4 the unreadability of these containers, and the

5 obvious confusion that is brought to bear to those

6 problems, that outpatients, particularly elderly

7 outpatients, can manage this on their own. I think

8 somehow we\'ve got to contemplate where we go with

9 that because the increasing number of people who

10 are using these on an outpatient basis and the

11 increasing aging of the population presents us with

12 an incredible challenge.

13 DR. GROSS: Okay. Marci would like to

14 make a comment.

15 DR. LEE: Thank you. I just wanted to add

16 to that. Based on the medication error reports

17 that we have received most recently, there are many

18 comments about the elderly population using these

19 drugs. There are several reports from a pharmacist

20 saying that his patients are expressing that

21 they\'re afraid to use the product because they\'re

22 afraid that they\'re going to double their dose

105

1 accidentally because they\'re not sure what is in

2 each ampule.

3 Then, also, the letter in the background

4 package that was sent to Senator Harkin, that also

5 involved a woman who was writing in about her

6 elderly mother that was having the same problem

7 also from a mail-order pharmacy. So in addition to

8 a regular outpatient pharmacy where there\'s direct

9 interaction with the pharmacist, you have people

10 who are unable to get out of their home and receive

11 their medications by mail having the same

12 experiences.

13 Carol wants to add something.

14 MS. HOLQUIST: Also, just in relation to

15 the letters at the top of the vials themselves, we

16 actually have gotten some reports as well where

17 there\'s a question as to what the actual letter

18 stands for, like A, is it for Albuterol or for

19 Atrovent. So some simple fixes, sometimes you also

20 have to think beyond, that there\'s more than one

21 product that begins with that letter.

x DR. GROSS: Okay. We are a little bit

22

106

1 ahead of schedule, and we will proceed at this time

2 with the open public hearing. Dr. Eric Sheinin

3 will present. First I need to\--

4 MS. JAIN: We need to read a statement

5 first.

6 DR. GROSS: Both the Food and Drug

7 Administration and the public believe in a

8 transparent process for information gathering and

9 decisionmaking. To ensure such transparency at the

10 open public hearing session of this Advisory

11 Committee meeting, the FDA believes that it is

12 important to understand the context of an

13 individual\'s presentation. For this reason, FDA

14 encourages you, the open public hearing speaker, at

15 the beginning of your written or oral statement to

16 advise the committee of any financial relationship

17 that you may have with any company or any group

18 that is likely to be impacted by the topic of this

19 meeting.

20 For example, the financial information may

21 include a company\'s or a group\'s payment of your

22 travel, lodging, or other expenses in connection

107

1 with your attendance at the meeting. Likewise, FDA

2 encourages you at the beginning of your statement

3 to advise the committee if you do not have any such

4 financial relationships. If you choose not to

5 address this issue of financial relationships at

6 the beginning of your statement, it will not

7 preclude you from speaking.

x DR. SHEININ: Thank you, Dr. Gross. I

8

9 have no financial ties or interests in any

10 pharmaceutical company or any other company or

11 organization that would be interested in the

12 proceedings before the committee today, so I think

13 I\'m okay with that.

14 DR. GROSS: Thank you.

15 DR. SHEININ: My name is Eric Sheinin, and

16 I\'m here today to represent the United States

17 Pharmacopeia. At the UPS, I am the Vice President

18 for Information and Standards Development. We do

19 have an expert committee that deals with safety

20 issues, and much of what I\'m going to say today is

21 a direct result of work that they have done. But I

22 would like to give you some background about the

108

1 USP for those of you who may not be familiar with

2 us and also to have it in the record.

3 The USP is a nongovernmental organization

4 that promotes the public health by establishing

5 state-of-the-art standards to ensure the quality of

6 medicines and other health care technologies.

7 These standards are developed by a unique process

8 of public involvement and they\'re accepted

9 worldwide. Many other countries around the world

10 recognize the USPNF standards as their own

11 standards in terms of regulatory procedures within

12 those countries.

13 USP is a not-for-profit organization that

14 achieves this goal through the scientific

15 contribution of volunteers, and the volunteers

16 represent pharmacy, medicine, and many other health

17 care professions. These individuals work in

18 academia, they work in government, both U.S. and

19 international. In fact, there are many FDA

20 scientists who serve as volunteer to USP. They

21 also come from the pharmaceutical industry and

22 consumer organizations. In addition to standards

109

1 development, USP\'s has several other public health

2 programs that focus on promoting optimal public

3 health care delivery.

4 In our mission statement, it says the

5 mission is to promote the public health, and I

6 always liken that to the mission of CDER, which is

7 also basically to promote the public health. So I

8 believe we\'re all interested in the same types of

9 standards.

10 At the USP, the volunteers, many of them

11 serve on our Council of Experts and its expert

12 committees. The members of these committees are

13 USP scientific decisionmakers, and they form our

14 standard-setting body. Council members are elected

15 by USP\'s membership at our five-year convention.

16 They\'re elected on the basis of their knowledge and

17 expertise, and they serve five-year terms. So even

18 individuals who come from industry, from their

19 companies, when they volunteer to work with USP,

20 they represent themselves. They do not represent

21 their employer, their organization, or anybody else

22 when they work on our standards.

110

1 The 2000-2005 Council of Experts comprises

2 62 nationally recognized scientists, academicians,

3 and clinicians. Each one of these individuals

4 chairs an expert committee, and the expert

5 committees are made up then in turn of

6 distinguished experts.

7 One of the committees is named the USP

8 Safe Medication Use Expert Committee. This

9 committee is comprised of 18 members representing

10 pharmacy, nursing, and medicine. It includes an

11 FDA liaison, Carol Holquist. It includes Captain

12 Jerry Phillips, who was formerly the Associate

13 Director for Medication Error Prevention in FDA\'s

14 Office of Drug Safety.

15 For more than 30 years, USP has promoted

16 the importance of collecting and sharing

17 experiential data from health care professionals.

18 In the last decade, particular emphasis has focused

19 on medication error reporting and prevention as a

20 way for USP to positively affect the public health.

21 The data collected from two of our programs\--the

22 USP-ISMP Medication Error Reporting, or MER,

111

1 Program and MEDMARX\--are reviewed and analyzed by

2 USP staff and USP\'s Safe Medication Use Expert

3 Committee.

4 In October of 2002, USP sent a letter to

5 the chief of CDER\'s Compendial Operations staff,

6 Yanna Mille, to inform her, on behalf of the Safe

7 Medication Use Expert Committee, of the continuing

8 concerns of the committee and of health care

9 professionals and practitioners regarding both the

10 difficulty in identifying drug products packaged in

11 low-density polyethylene ampules and vials and the

12 resultant medication errors from their misuse.

13 Plastic ampule packaging is frequently

14 used for respiratory therapy drugs. The ampules

15 often do not bear labels but are labeled by

16 debossing or embossing the actual plastic

17 container. This debossing or embossing is

18 described by health care practitioners who have

19 reported to the USP reporting programs as being

20 unreadable, causing difficulty in identifying the

21 product within. Because this packaging is now

22 being used not only for respiratory therapy drugs

112

1 but also for injectables and oral solution, it is

2 even more important that the subject products be

3 easily identified and readily distinguishable from

4 each other.

5 USP has provided the Compendial Operations

6 staff, the Dockets Branch, and the Office of Drug

7 Safety with more than 42 specific case studies

8 where mediation errors occurred because of the use

9 of these products. We also have submitted copies

10 of the actual product containers involved in the

11 medication errors that were reported through the

12 two USP reporting programs.

13 In addition to providing comment on the

14 concerns expressed to USP by health care

15 practitioners, the USP Safe Medication Use Expert

16 Committee unanimously voted to encourage FDA to

17 establish an alternate method of labeling for the

18 various drug products packaged in the plastic vials

19 being discussed today. This would be in order for

20 these products to be clearly identifiable,

21 hopefully thereby reducing the numerous medication

22 errors that have occurred and likely will continue

113

1 to occur.

2 The expert committee also suggested that

3 the FDA cease approval of products in these

4 containers because their use continues to be the

5 subject of numerous medication error reports.

6 From April 20, 2002, through January 31,

7 2004, an additional 26 reports of actual and

8 potential medication errors have been received

9 through USP\'s medication errors reporting programs

10 regarding the similarity in the labeling of

11 products in low-density polyethylene vials. The

12 problems with these containers continue, and the

13 USP and the USP Safe Medication Use Expert

14 Committee recommends that FDA take any necessary

15 action to improve the labeling of low-density

16 polyethylene ampules and vials.

17 I thank you for your attention and your

18 consideration of USP\'s concerns. If you have any

19 questions, I\'ll certainly try to answer them.

20 DR. GROSS: Thank you very much.

21 Are there any questions from the panel?

22 Jackie?

114

1 DR. GARDNER: I would just like to ask,

2 Dr. Sheinin, does USP have a recommendation of one

3 of these methods over another?

4 DR. SHEININ: A recommendation?

5 DR. GARDNER: For solving this problem?

6 DR. SHEININ: Not at this point, not that

7 I\'m aware of. The obvious solution to me\--and I

8 actually worked at FDA for 30 years before I went

9 to USP\--would be to have a label on the containers.

10 But there are concerns with migration through the

11 low-density polyethylene. I\'m sorry I missed the

12 end of the previous presentation where they were

13 describing perhaps some way to help identify these

14 products.

15 DR. GROSS: Robyn Shapiro?

16 MS. SHAPIRO: I just have a question about

17 these report forms. Was patient counseling

18 provided? And then, if yes, before or after error

19 was discovered? Does that mean about what the drug

20 is, how to take it, how to read it? What does the

21 counseling refer to?

22 DR. SHEININ: I believe that the

115

1 counseling is provided by the professional who\'s

2 reporting the problem to us. I don\'t believe USP

3 does the counseling.

4 MS. SHAPIRO: So we don\'t really know what

5 that refers to.

6 DR. SHEININ: Unfortunately, the Safe

7 Medication Use Expert Committee is not under my

8 area of responsibility. But as far as I know, that

9 counseling would not be provided by USP, and we

10 probably do not know what the nature of that

11 counseling was. The form is asking if there has

12 been any counseling.

13 DR. GROSS: Henri?

14 DR. MANASSE: Good morning, Eric.

15 DR. SHEININ: Hi, Henri.

16 DR. MANASSE: Two questions. We\'ve talked

17 today about two major issues: one is the leaching

18 of chemical agents from various labeling techniques

19 and embossments; the other having to do with the

20 readability issues and the packages themselves.

21 Has USP convened any technical experts on

22 either one of those issues to contemplate what\'s

116

1 the existing science, what do we know, what do we

2 not know, as well as what our reasonable solutions,

3 given what\'s known, in other industries or other

4 options for dealing with this problem?

5 DR. SHEININ: Not that I\'m aware of. It

6 certainly is a good suggestion, and I will take

7 that back to the committee and to Diane Cousins,

8 whom I think many of you probably know, and see if

9 there is a way that we could proceed in that

10 manner. I think it\'s a very good suggestion and

11 something that should be done.

12 DR. GROSS: Okay. Thank you very much.

13 DR. SHEININ: Thank you.

x DR. GROSS: If there are no further 14

15 questions, since we remain ahead of schedule, Dr.

16 Paul Seligman will now introduce the issues and

17 questions that he has for the Advisory Committee.

18 DR. SELIGMAN: You should all, members of

19 the committee, have a one-page LDPE Discussion

20 Points. These, I believe, are in the packages as

21 well for public distribution. Why don\'t we simply

22 refer to these rather than booting up the slides.

117

1 You\'ve heard this morning about the issue

2 related to the ingress of volatile compounds as a

3 problem with these particular containers and

4 various approaches to deal with this issue as well

5 as not only\--to deal with both the preservation of

6 the purity of the drug, as well as ways in which to

7 improve the legibility of the label.

8 What we\'ve asked in the first question is:

9 Given the various approaches that you\'ve heard

10 today, including embossing and debossing of

11 containers, the use of unit package overwraps, the

12 elongation of the bottom tab and using that as an

13 place to print critical information, the use of

14 paper labels, the use of ink directly on the vial,

15 various potential approaches including tactile

16 recognition, shrink wrap labels, and then we

17 actually even saw the use of glass ampules or

18 vials, what we\'re interested in the committee

19 addressing first off is to discuss the potential

20 advantages or disadvantages of these approaches and

21 to identify in 1b any creative solutions or

22 alternate packaging design that would improve

118

1 legibility and address the problem of ingress of

2 chemical contaminants and at the same time not

3 create additional problems.

4 We\'d also like to have you put on your

5 thinking caps and consider if there are stakeholder

6 groups, such as manufacturers, practitioners,

7 consumers, and others, who might best advise FDA

8 about possible new packaging configurations that

9 might resolve some of these issues.

10 And then given what you\'ve heard today and

11 based on our discussion, describe and advise us on

12 an appropriate course of action to address not only

13 the problem of ingress of contaminants but also

14 medication errors due to legibility and similar

15 packaging issues.

16 So those are the issues before us. Peter?

17 DR. GROSS: We share in your perplexity.

18 DR. SELIGMAN: Thank you.

x DR. GROSS: This is a difficult issue.

19

20 Thank you very much for the questions,

21 Paul, and we will initiate the discussion. The

22 agenda allows two hours for discussion, so why

119

1 don\'t we do roughly an hour, and then maybe we can

2 have lunch and then finish up, if that\'s okay.

3 MS. JAIN: Lunch is on its way.

4 DR. GROSS: Okay. Well, whenever lunch is

5 here, we will re-evaluate our timing. But let\'s

6 begin the discussion now.

7 Anyone have any comments? Why don\'t we do

8 this in an orderly fashion and take the issues as

9 Paul presented them, with 1a being the first.

10 They\'re all sort of interrelated, but why don\'t we

11 get specific and talk about 1a first. Leslie?

12 DR. HENDELES: I\'d like to preface my

13 comments by saying that nebulization of

14 bronchodilators is an obsolete way of treating

15 acute bronchospasm, and part of whatever we do

16 needs to focus on an educational program designed

17 at using the meter-dose inhaler through a valve

18 holding chamber, which is far more efficient,

19 causes fewer side effects, less expensive way, and

20 it\'s the way the rest of the world treats acute

21 asthma. The United States has a fixation on

22 nebulizer therapy that they won\'t let go of, for

120

1 some reason, especially pediatricians, but there\'s

2 clearly 10 to 15 double-blind, placebo-controlled

3 trials, a Cochran review, et cetera, that indicate

4 that there are much more efficient ways and it

5 would, of course, circumvent this problem for

6 asthma.

7 Now, having said that, I really like the

8 idea of having that foil pack, like the Nephron,

9 with a single unit, and I think that would solve

10 the problem. It would allow for the bar coding.

11 And according to Karen, respiratory therapists

12 would be willing to carry that in their pocket. As

13 I understand it, the reason why they carry single

14 units in their pocket is because when they open the

15 foil pack, there\'s 12 of them there. If there\'s

16 only one, they would probably carry it. And, of

17 course, that could also be addressed through

18 professional education as well.

19 DR. GROSS: Leslie, for myself and anyone

20 else who is not 100 percent clear on what you said,

21 would you contrast the two methods of medication

22 delivery again?

121

1 DR. HENDELES: Bronchodilators as well as

2 inhaled steroids can be delivered by a pressurized,

3 meter-dose inhaler that\'s attached to a valve

4 holding chamber with an age-appropriate connection,

5 either a mouthpiece for older folks or a mask for

6 preschool kids that seals around their nose and

7 mouth, and you fire off a few puffs, such as four

8 puffs, into this chamber and it\'s equivalent in

9 efficacy to nebulizing a bronchodilator in the

10 emergency room. It causes fewer side effects. It

11 takes a minute or two to give the treatment instead

12 of 15 to 20 minutes, and it\'s far more convenient

13 for patients and cheaper. They don\'t have to buy a

14 compressor for \$150.

15 DR. GROSS: Could someone from the FDA

16 comment on whether or not they want to tackle that

17 issue?

18 DR. SULLIVAN: That may not be an issue

19 for the FDA really to address. I don\'t think there

20 would be any\--the evidence being what it is, that

21 MDIs may effect just as great a degree of

22 bronchodilation as a nebulizer, it would be

122

1 something that physicians should interpret and use

2 in their clinical judgment. I don\'t think there

3 would be any rationale for the agency to pull

4 nebulizer solutions off the market. I think that

5 would be very drastic. So from our perspective, we

6 have to deal with them.

7 Now, if the medical community starts to

8 learn that maybe they are overusing nebulizers

9 through Dr. Hendeles\' shaking the cage a little

10 bit, that\'s just great. But the issue will still

11 remain for us.

12 DR. HENDELES: And, indeed, there are

13 patients who might be unconscious, for example, or

14 would need the nebulizer, and there are drugs such

15 as Tobramycin that can\'t be delivered by MDI.

16 DR. GROSS: Arthur?

17 MR. LEVIN: I realize it isn\'t within the

18 scope of authority of the FDA to dictate clinical

19 practice, but part of the problem here is we\'re

20 dealing with a tension between an issue of

21 potential harm, which is the leaching of, you know,

22 substances that don\'t belong in the solution into

123

1 the solution and the documented potential harm of

2 error. And we\'re looking at a variety of

3 solutions, none of which is perfect and each of

4 which brings with it some question: You know, does

5 it solve the error problem entirely? Or by solving

6 the error problem entirely, does it still leave us

7 open to the problem of possible impurity?

8 In that context, I think the FDA does have

9 something to say, and then when we move to the

10 ambulatory setting particularly, where these issues

11 I think get even more complicated\--and we really

12 haven\'t talked about it\--that if there are better

13 ways to deliver the product that relief us of the

14 burden of trying to figure out the perfect solution

15 on these two different potential harms, that\'s

16 worthy of comment. I mean, nobody expects you to

17 be able to pull the product from the market, but in

18 dealing with improving safety of products, I don\'t

19 think it\'s entirely out of character for the FDA to

20 make a comment that one of the solutions here is to

21 use a different form of delivery that obviates the

22 need to talk about all of this. You may not be

124

1 able to say, \"You can\'t use the other,\" but you can

2 certainly say, \"Moving in this direction seems to

3 be a way to solve the problem,\" and I would say

4 particularly in the ambulatory populations.

5 DR. GROSS: Maybe we\'ll have one or two

6 more comments on this particular issue. Then we\'ll

7 have to get back to the questions raised by Dr.

8 Seligman in 1a.

9 Brian?

10 DR. STROM: yes, I\'d like to in my initial

11 start be more provocative. We\'re hearing, as

12 Arthur is saying, between two safety problems,

13 without good data on either side to quantify each

14 of them. We\'re using in one case physiological

15 chemical tests and the theory that leaching might

16 be a problem, and it\'s clearly understandable why

17 it can\'t be quantified more than that. And we\'re

18 hearing on the other side about medication errors

19 based on the spontaneous reporting system, which is

20 grossly incomplete. We don\'t know how many there

21 are out there other than the fact that we\'re seeing

22 a number, and there are clearly many more out there

125

1 than we\'re seeing that could be studied more

2 concretely, potentially. But, in either case, we

3 don\'t have good quantification, and so part of the

4 problem here is balancing two risks, neither of

5 which are quantified.

6 If we\'re hearing from Leslie\--and you\'re

7 not disagreeing\--that there is a better approach

8 which is more effective and is safer, why isn\'t

9 that a regulatory reason for the FDA to remove the

10 nebulizers\--this packaging?

11 DR. SULLIVAN: Well, I\'m not actually

12 agreeing. I\'m aware of the various articles that

13 are out there. I have not reviewed those studies

14 myself, seen the data myself. Certainly the agency

15 has not come to that conclusion that the MDIs have

16 these attributes, these costs, and effectiveness

17 and so forth. And that\'s an open question, I

18 believe. Dr. Hendeles probably knows that

19 literature even better than I.

20 But for the agency to come to a conclusion

21 like that is a very significant matter, and, again,

22 although we can make comments, it\'s not clear in

126

1 what context that comment will hold any water until

2 or unless we were to, as suggested, remove them

3 from the market. And I think that that\'s quite a

4 drastic step, and I think that as Dr. Hendeles

5 pointed out, there would be very good arguments

6 that there may be some populations who are only

7 served by the nebulizers, and, therefore, it would

8 be unwise to remove them from the market.

9 So let me say that we haven\'t made that

10 determination, number one, and that even if we made

11 the determination that for the average patient it

12 was efficient in some way that you would like to

13 define efficiency, it would be hard for us to move

14 on that.

15 So I understand your perspective and I

16 understand Dr. Hendeles\' perspective that perhaps

17 the American physicians are overutilizing them.

18 But I don\'t think that\'s going to get around the

19 issues that we have to face.

20 DR. GROSS: Okay. I think that maybe the

21 sense of the committee is that this is advice

22 they\'d like to give to the FDA to look into this

127

1 issue and decide how they want to proceed. But I

2 would like that the issue should be brought to the

3 attention of the national pulmonary organizations,

4 and they in their guidelines should make this

5 recommendation because in that setting they might

6 have a significant clinical impact.

7 DR. HENDELES: It shouldn\'t be limited to

8 physicians. I think health system pharmacists and

9 respiratory therapists and those organizations play

10 a role, too.

11 DR. GROSS: Absolutely. But that might be

12 the way to begin to make the change, if that\'s what

13 the scientific evidence indicates.

14 Okay. I know you\'ve all been trying to

15 avoid 1a, but we do have to address it.

16 \[Laughter.\]

17 DR. GROSS: And I saw Michael\'s hand up

18 first.

19 DR. COHEN: Thank you very much, sir.

20 First of all, let me just ask the

21 question: Are we talking only about the

22 respiratory ampules, the LDPE, or are you talking

128

1 about all LDPE? Because there\'s a difference

2 between the two, and the way they may be labeled

3 might be different as well. So that would be the

4 first question. Are there, in fact\--we need to

5 clarify that there are, in fact, LDPE ampules for

6 injectables and ophthalmics, et cetera? Is that

7 what we heard earlier? That\'s number one.

8 MS. HOLQUIST: Yes, and that was one of

9 our questions, too. Should we treat the pulmonary

10 products separately than these other products that

11 are packaged by other routes of administration?

12 DR. COHEN: I guess what I\'m saying is,

13 even if we do clarify what you just brought up, Dr.

14 Hendeles, we\'d still need to address the issue of

15 the labeling because there are other forms, if, in

16 fact, they\'re LDPE. So that was the first thing I

17 wanted to mention.

18 Can I make a suggestion to the Chair that

19 we go through each of these bullets, perhaps

20 separately? Or do you want us to comment on all of

21 them at the same time?

22 DR. GROSS: I think that\'s a very good

129

1 idea, Michael. Do you want to begin with embossed?

2 DR. MANASSE: Peter, I wonder if I could

3 just interrupt.

4 DR. GROSS: Yes, sure. Henri?

5 DR. MANASSE: I think before we jump to

6 choosing between evils, I think we have to lift up,

7 perhaps, to the 30,000-foot level a minute and,

8 that is, if we\'re going to continue to use these

9 low-density polyethylene containers in the sizes

10 that we\'re going to use them, if that\'s a given,

11 we\'re going to have to more carefully understand

12 and identify both the packaging and ingress issues.

13 I\'m a little bit uncomfortable jumping to

14 picking what we think is the best when we don\'t

15 have all the information. I don\'t think we\'re

16 totally educated on all the potential leaching

17 issues, all the potential chemical agents that

18 could cause degradation, et cetera, et cetera.

19 At the same time, I\'d hate to see us jump

20 to figuring out packaging solutions when at least

21 I, for one, have not been presented with all of the

22 packaging options that might be a possibility.

130

1 We\'re limiting ourselves largely to pharmaceutical

2 packaging, and I\'m amazed in this country how

3 creative packaging can become. All you have to do

4 is look at the cosmetics industry to see some of

5 that creativity. I\'m not sure that we\'ve exhausted

6 the dialogue around creative mechanisms by which

7 people can read this stuff, that they can handle it

8 without an intervening health professional, at

9 home, for example, and particularly relating to the

10 elderly. And I\'m not convinced that we know enough

11 yet about what kind of package designs are utilized

12 in other industries that might be applicable here

13 that could solve our problem in a much bigger way.

14 I don\'t want to be interruptive, Peter,

15 but it seems to me that we\'ve got to look at those

16 issues.

17 DR. GROSS: I think those are very

18 critical points, Henri. I know from my point of

19 view, I\'m not sure I got an answer as to why other

20 polymers have not been selected as opposed to

21 polyethylene, you know, like polypropylene or

22 polystyrene. Is there any potential there? Can

131

1 that be looked at? Is high-density any better than

2 low-density is another issue. Should the thickness

3 of the LDPE be made greater and that would probably

4 slow the migration? But would it make a

5 significant difference over a period of time or

6 not? So there\'s just a tremendous amount that\'s

7 not known.

8 But in the absence of all the knowledge

9 that we need, which is the situation in most

10 instances that we have to deal with in life, just

11 read Robert Rubin\'s book, we still do have to

12 address the questions posed to us.

13 Does anybody have any other comments

14 before we address those specific questions? Yes,

15 Jackie?

16 DR. GARDNER: Since we aren\'t experts on

17 this and what you\'re saying is correct, and since

18 Brian is leaving this committee and he always has

19 one mantra, and that is, we need data, where are

20 the data, and he won\'t be here anymore, so I\'ll

21 take that up for him, my suggestion would be that

22 we ask, maybe starting with Michael, of these

132

1 options which is probably the most satisfactory on

2 the face of it given everything we\'ve heard today,

3 recommend that maybe starting with that, some

4 studies be done to address the extent of the

5 ingress using that method, and has it solved that

6 problem? And so to that end, it sounds like either

7 the shrink wrapping of the ampule, as Michael

8 suggested, or the foil wrap, individual unit of use

9 sleeve, which I happen to like because it seems

10 like you could bar code it and also put

11 instructions and colors and other kinds of things

12 on it, but pick one, the best that we can come up

13 with and ask them to study it and then tell us how

14 bad it turns out to be.

15 DR. GROSS: Well, we don\'t even know the

16 toxicity of the chemicals that are ingressing. We

17 don\'t even have that information. Certainly a lot

18 of products that are available commercially have

19 low levels of toxin that are considered acceptable.

20 So, I mean, that\'s another big area where we just

21 don\'t have the information.

22 Leslie?

133

1 DR. HENDELES: Did we learn whether this

2 foil wrap actually prevents the problem or does it

3 add anything else to the vial, the solution?

4 DR. SHAH: Well, it depends.

5 DR. HENDELES: Yes, okay.

6 DR. SHAH: Again, it goes back to the

7 question of having adequate knowledge of the

8 chemical components which you have selected for

9 your foil laminate and, critically, the adhesive

10 layer which is used. Most of the time, the organic

11 solvents which are used in adhesives, they migrate

12 from the adhesive layer to the LDPE vial. As long

13 as the adhesive layer is on the other side of the

14 aluminum foil, they may not have to worry about

15 that. You can use a sort of adhesive layer, you

16 can use pressure-sensitive materials which can just

17 fuse together. Then you can avoid using adhesives.

18 Again, that\'s solving one problem coming

19 from adhesive. However, the other layers which are

20 used inside the aluminum foil, again, the product

21 composition, chemical composition does matter. If

22 there are small organic molecules which have a

134

1 volatile potential, there is a likelihood that it

2 may migrate. However, the applicant can do a

3 one-time study and demonstrate that whatever

4 leaches into the drug product is not significant

5 enough to pose a safety issue. If that is being

6 done, then that may be a possibility.

7 But we really don\'t know, I mean, in that

8 sense that it will solve the problem of not

9 leaching 100 percent.

T3A DR. GROSS: Okay. We\'ve been talking for

10

11 20 minutes, and we have still avoided the question.

12 So anybody have any other comments before we

13 address the question before us?

14 \[No response.\]

15 DR. GROSS: Okay. At Michael\'s

16 suggestion, if that\'s okay with everybody, starting

17 at the top, any comments on embossing? Michael?

18 DR. COHEN: I have a few comments, but,

19 again, we are talking about the respiratory use

20 specifically? That\'s fine if we are.

21 DR. GROSS: Well, go ahead and distinguish

22 what you want.

135

1 DR. COHEN: Well, I think for the

2 respiratory use, at least now there\'s not a great

3 variety of agents that are packaged in this type of

4 plastic, which may have an impact on my comments

5 with injectables, et cetera. I don\'t know what the

6 future growth will be.

7 But with the embossment right now, I think

8 it\'s pretty clear that we really can\'t leave things

9 the way that they are and that there are some

10 changes that we heard from\--I believe it was from

11 Cardinal Health that possibly could help here. One

12 of them was the large type, and I thought that was

13 a world of difference between that and the old

14 type.

15 However, I should point out that we\'re

16 talking about clear containers now, colorless

17 containers. We\'re not talking about color

18 containers, and there\'s a whole set of problems

19 with that that I don\'t even know if we\'re going to

20 get into. But I would certainly discourage the use

21 of color differentiation.

22 But, at any rate\--

136

1 DR. GROSS: Because?

2 DR. COHEN: Well, again, you know, the

3 area of growth, confusion with other medications.

4 Are you coloring them by class of drug or by

5 individual drug? If it\'s by individual drug, are

6 there enough colors? Et cetera, et cetera. But,

7 at any rate, we can get into that a little bit

8 later.

9 But I also want to point out that when you

10 take these clear containers, what we saw was the

11 container against a dark background. When you put

12 them against the table here or a lighter, white

13 background, the readability still leaves something

14 to be desired. Plus, you know, the way that the

15 photographer took the picture or something may have

16 impacted, you know, how we viewed that as well.

17 But I still think it really does have some

18 possibility for us there with the large type.

19 The other concern with that, though, is

20 that in using that large type, it forced them to

21 place the strength of the medication on the

22 opposite side. In reality, I still think there

137

1 will be some medication errors where people will

2 leave these on a counter or in a bin, for example,

3 see, you know, Ipatropium or whatever the

4 medication is, and not pick it up and turn it over.

5 So you\'ll have some confusion between strengths

6 still.

7 So, with those caveats, I think that is

8 one thing that should remain on the list, the

9 embossment with larger characters.

10 DR. GROSS: Anyone else want to comment?

11 Yes, Stephanie?

12 DR. CRAWFORD: I\'d actually like to

13 address my question to the agency. What would be

14 the feasibility from a regulatory perspective of

15 increasing the type, knowing that other content

16 would have to be removed from the immediate

17 container?

18 MS. HOLQUIST: Well, right now there is a

19 regulation for what\'s allowable for the smallest

20 size label, and it\'s pretty minimal. Basically

21 it\'s the name of the product, either the

22 proprietary name, the established name, the

138

1 manufacturer, the lot number, and expiration date.

2 I don\'t know how much less of that that you can

3 include because if there is a product problem with

4 a specific lot number, you\'re going to need that

5 information with each nebule. If it\'s on like one

6 of these flanges and it\'s removed, that information

7 is gone, so basically your stock is pretty much

8 wasted because you\'d probably have to throw it out

9 because it\'s in doubt whether it\'s that affected

10 lot.

11 It would be great if nobody put a

12 proprietary name on there, but we know that\'s not

13 going to happen. So, you know, it has to be the

14 name of the drug and it has to be the strength

15 because there are multiple products. So I really

16 don\'t know how we could eliminate much more than

17 what\'s required on there.

18 DR. GROSS: Robyn?

19 MS. SHAPIRO: This is probably a stupid

20 question. Can you different-color the embossed

21 figures so that you have embossments, or whatever

22 the noun is, in a different color so there is

139

1 contrast?

2 DR. SADEGHI: \[Inaudible, off microphone\]

3 like a stamp, you have an ink layer \[inaudible\].

4 MS. SHAPIRO: Right.

5 DR. GROSS: Brian?

6 DR. STROM: I want to come back to

7 Michael\'s suggestion, which I think makes enormous

8 sense. I think from the list of things you just

9 gave us that are now required, there is a very big

10 difference between the importance of the drug name

11 and the strength versus the lot number, for

12 example. And to say that they\'re equivalent, I

13 think from a clinical point of view, you don\'t need

14 the lot number. And if there\'s a problem, yeah,

15 you\'d like to know the lot number, but chances are

16 it\'s going to have been thrown away by then. The

17 container will have been thrown away regardless.

18 It would be nice to have the lot number on

19 it, but I would not by any means consider it

20 equivalent to the drug name. And so the idea of

21 having the drug name in big print like we saw and

22 the lot number on the flange on the bottom in small

140

1 print and the expiration date on the flange on the

2 bottom in small print\--again, I don\'t think it

3 should be unavailable, but I think the two are

4 dramatically different in their clinical

5 importance. And to differentiate between them in

6 the label personally I would think would make a lot

7 of sense.

8 DR. SULLIVAN: Let me see if I can

9 respond. I think we have to be a little bit

10 careful because there is a specific regulation

11 about minimum requirements in labeling, and we can

12 presume that a lot of thought went into that. And

13 the requirement is regarding drug products that are

14 so small that you have to really minimize what you

15 put on there. And through the process that

16 regulations were developed, it was determined that

17 this was the minimum set. And I think we ought to

18 be careful that in solving this problem we don\'t

19 perhaps brush aside what probably was considered

20 very carefully.

21 And I would think that in a setting of

22 particularly a drug recall that it would be

141

1 critical to be able to have the lot number there.

2 And this is just an off-the-cuff remark, but I do

3 want to respect the process that apparently was

4 undertaken to make the regulation to think

5 carefully about what\'s the minimum amount of data

6 that should be there.

7 DR. STROM: If I can follow up, let me

8 just clarify. I\'m not saying\--I\'m not disagreeing

9 with you. I\'m not saying that the data shouldn\'t

10 be there. What I\'m saying is the weighting of the

11 data and the importance of the data and the utility

12 of the data are very different, that the lot number

13 is important when you have a recall, which is

14 hopefully uncommon. The drug name and dose is

15 important every time you give it, and so the

16 data\--I\'m not saying the data should be eliminated.

17 I\'m saying there should be a differentiation

18 between the size and how they\'re provided. So if

19 you have a fixed amount of space, use most of it

20 for what is most important and you need every day;

21 and if you can\'t normally read the lot number

22 without a magnifying glass, who cares?

142

1 \[Inaudible comment off microphone.\]

2 DR. STROM: You can\'t anyway, yes. Yes.

3 DR. SHAH: I think currently we are doing

4 in a sort of way that the lot number and expiration

5 date is going to on the bottom flanges, which is

6 always tiny, small. So I agree with him that the

7 increase of the text size does make a dramatic

8 difference. So I think there is an opportunity

9 over there to make an improvement as far as the

10 medication error is concerned.

11 DR. SULLIVAN: Yes, I thought the basis of

12 that slide was that in order to increase this size,

13 we\'d have to eliminate some of what\'s currently

14 required. And if we were to say we agree with

15 that, we ought to think very carefully.

16 DR. GROSS: Leslie?

17 DR. HENDELES: A compromise might be to

18 use the first and second bullet where you increase

19 the print size, leave on the essential information,

20 but put one unit in a foil pack. That would solve

21 all of those problems.

22 DR. GROSS: Yes?

143

1 DR. STEMHAGEN: One of the things that\'s

2 not on the list is changing the size and shape and

3 differentiating by size and whether that\'s even a

4 possibility, you know, different doses at different

5 sizes and things. We saw a couple different

6 shapes, but we didn\'t really talk about that kind

7 of change in packaging.

8 DR. GROSS: Thank you, Annette.

9 Any other comments on embossing? Arthur?

10 MR. LEVIN: In terms of shape and size\--I

11 mean, it\'s a little off embossing, but are there

12 any studies that look at the ability of people to

13 recognize that in the field? It strikes me it\'s an

14 accident waiting to happen. But I just don\'t know

15 if there are studies out there that look at these

16 issues of differentiation by side and shape in the

17 clinical setting. If people are indeed carrying

18 dozens of vials in their pocket, you\'re asking an

19 awful lot if you expect that to make a difference

20 or reducing the possibility they may pick the wrong

21 dose or the wrong drug.

22 DR. GROSS: I guess part of that question

144

1 is: Does the FDA\--can the FDA sponsor research

2 studies to deal with some of these questions?

3 DR. SHAH: I\'ll just say one more thing

4 regarding the shape\--

5 DR. GROSS: No answer to that question?

6 DR. SHAH: No. I think we can take it to

7 the agency, but I think it\'s a policy issue, and I

8 think they will have to consider that.

9 DR. GROSS: Okay.

10 PARTICIPANT: \[Inaudible comment off

11 microphone\]\--once you do that, \[inaudible\] same

12 product, and then you have to standardize it across

13 the board. One manufacturer makes it this shape,

14 another makes a different shape, \[inaudible\].

15 DR. SHAH: I was just making the same

16 point, that, you know, if you are just going to

17 rely on the shape, oh, this particular shape is

18 associated with this drug product and somebody

19 decides to make for some other drug product a

20 similar shape, then we are still going to have a

21 similar problem.

22 DR. GROSS: Brian?

145

1 DR. STROM: Just involved with the shape

2 thing, I think it\'s probably\--I\'d be interested in

3 Michael\'s answer, but my reaction is it\'s similar

4 probably to the color issues, which I think is what

5 Michael is suggesting. To the degree you give

6 people an alternative cue, they\'ll use that cue

7 instead of the name, and you\'re more likely to have

8 errors, therefore, because people are using that

9 cue instead of the name. I would rather people

10 have to use the name but it be legible. They\'re

11 less likely to make errors, I think. But, again,

12 you know, I\'d like to see data.

13 DR. STEMHAGEN: I was thinking that we\'re

14 trying to squeeze a lot of information on a small

15 thing. If it were bigger, you\'d have a little bit

16 more space to make the print larger. That\'s where

17 the size issue was\--

18 DR. GROSS: Let me see if I can summarize

19 the sense of the group on the embossed issue: If

20 embossing is to be continued, it should be done

21 where the drug name and dose is much larger print,

22 and yet we still have to consider what to do about

146

1 expiration date and lot number, although that could

2 be smaller. Is that sort of the sense of the

3 group?

4 PARTICIPANT: Yes.

5 DR. GROSS: Okay. Let\'s go to number two,

6 unit package overwrap. Anyone want to comment on

7 that? Yes, Jackie?

8 DR. GARDNER: As mentioned earlier, I

9 favor this one in conjunction with the former so

10 that the embossed product that\'s inside would also

11 have the larger, more legible features that were

12 mentioned in bullet number one, and this would give

13 us the opportunity for a good deal more in the way

14 of information, identification, and bar coding.

15 DR. GROSS: Henri?

16 DR. MANASSE: I would urge us or urge the

17 agency and the manufacturing industry to explore a

18 mechanism whereby that outer overwrap cannot be

19 separated until actual use of the drug from the

20 original vial. So when you rip off the outer wrap,

21 that then opens the package for use.

22 DR. GROSS: So your comment addresses the

147

1 issue brought up by many of the respiratory

2 therapists that they\'ll take it out of the wrap and

3 put all of them in a jumble in their pocket, and

4 then the wrap is sort of useless for

5 identification.

6 DR. MANASSE: Exactly.

7 DR. GROSS: I don\'t know if that\'s\--I

8 guess anything\'s mechanically possible to attach

9 the two.

10 Any other comments on the wrap? Michael?

11 DR. COHEN: Just I absolutely agree with

12 what Henri was saying about, you know, having a

13 foil wrap but being able to tear it at the same

14 time as you open the container.

15 And just to point out that I have

16 absolutely no doubt that people will remove\--unless

17 we do that, people will remove them from the

18 overwrap. We\'ve seen that with, you know, nurses

19 administering drugs that are packaged in cartons,

20 for example, and sent as unit doses or some other

21 type of outer wrap.

22 DR. GROSS: Okay. So the sense of the

148

1 group is that the unit package overwrap is a

2 reasonable idea, but we still have to deal with the

3 issue of it being discarded well before the drug is

4 administered. Is that fair enough? Well, the new

5 data curmudgeon\'s comments, Jackie, about having

6 more data, we all agree with.

7 \[Laughter.\]

8 DR. GROSS: Okay. The next is the

9 printed, elongated bottom tabs. I know the one I

10 saw that I liked with the refresh label. The black

11 writing, although small, was pretty clear, even for

12 these eyes. Any other comments? Can you see it,

13 Arthur?

14 \[Laughter.\]

15 DR. GROSS: Okay. Any other comments?

16 DR. STROM: Is there a concern about

17 leaching in that setting?

18 DR. GROSS: Dr. Shah, could you answer

19 that? If you put a printed label on the tab

20 attached to the main vial, I guess it\'s

21 theoretically possible that some of that print

22 could eventually leach in, but it\'s less likely.

149

1 DR. SHAH: Again, if that is in an

2 overwrap pouch and then it is a closed environment

3 and if there are volatile solvents into the glue

4 which has been used, then, yes, that is a

5 possibility. That will be exactly the same thing.

6 Instead of the close contact, it is a little bit

7 away, but it still will have that possibility.

8 DR. GROSS: Okay. Any other comments on

9 the elongated tabs? Do people like them?

10 DR. STROM: Let me suggest, maybe this is

11 a summary, I think, of the sense that they look

12 attractive, but if they raise the same concern

13 about leaching, they\'re no advantage. So what\'s

14 needed before a decision is made is a similar study

15 to the kind that you did with the marketed products

16 to find out if, in fact, there\'s leaching, given

17 what we\'re hearing is it\'s just theoretical.

18 DR. GROSS: Right. More data.

19 DR. CRAWFORD: Dr. Gross?

20 DR. GROSS: Yes, Stephanie?

21 DR. CRAWFORD: Could I just add that I

22 think and the sentiment of the committee right now

150

1 is that we\'re not making a recommendation for this

2 because we don\'t have evidence that it won\'t cause

3 more problems than it solves for this particular

4 one.

5 DR. GROSS: So we need some data before a

6 sense can be formed, and that, you know, probably

7 applies to almost everything that we\'re going to

8 comment on.

9 Okay. Paper labels, not glued to the tab

10 but glued to the actual vial where the medication

11 is. Any comments on that?

12 DR. HENDELES: Isn\'t there a problem with

13 that?

14 DR. GROSS: Oh, well, this is what we\'re

15 supposed to say, yes. Right. So Leslie\'s vote

16 is\--

17 \[Laughter.\]

18 DR. GROSS: Leslie\'s vote is, hello,

19 there\'s a problem.

20 \[Laughter.\]

21 DR. GROSS: Okay, Michael?

22 DR. COHEN: Obviously there\'s a concern

151

1 about the safety at this point. I should point

2 out, though, that whether we put labels on it or

3 not, I think in some cases with unit-dose drug

4 distribution, the pharmacy is going to put labels

5 on them of their own. So that\'s going to probably

6 seep in if we don\'t do something to change it

7 otherwise.

8 DR. GROSS: Okay. So the\--yes, Henri?

9 DR. MANASSE: Michael raises a really

10 important point which hasn\'t been part of the

11 dialogue today. As manufacturers decrease the

12 production of unit-dose packaged drugs, it forces

13 hospitals into being in the packaging business.

14 And most hospitals are not experts in packaging,

15 and, consequently, this issue of the leaching and

16 the paper label attachment is probably a warning

17 that has to go out to hospitals who do engage in

18 the packaging business, because we\'ve now

19 introduced a packaging phenomenon that\'s not well

20 understood.

21 DR. GROSS: Leslie?

22 DR. HENDELES: By extension, then,

152

1 pharmacists in the community who compound nebulizer

2 solutions need to have that same warning. It

3 shouldn\'t be just in the hospital because that\'s a

4 whole other problem that\'s outside the control of

5 the FDA. But, still, if there\'s a potential

6 problem with commercial products, it\'s equally a

7 problem with compounded nebulizer solutions.

8 DR. GROSS: Yes, Arthur?

9 MR. LEVIN: I want to follow up because I

10 always thought we were hardly using unit-of-use

11 packaging from manufacturers as a source compared

12 to everywhere\--it\'s one of these things, America

13 versus everywhere else in the world where

14 unit-of-use packaging is the standard. And you\'re

15 saying it\'s getting\--actually, there\'s less

16 unit-of-use packaging being delivered by\--which is

17 really troubling. You know, if that\'s the trend,

18 then looking at solutions that are dependent on

19 manufacturers to do the right thing is crazy,

20 because then we need to really be looking at where

21 they get\--at the repackaging problem. So, I mean,

22 I think that\'s another piece of data that we need

153

1 to have, that if we\'re looking to have

2 manufacturers use unit-of-use packaging as part of

3 the solution or most of the solution to the

4 problems we\'re discussing, and indeed they\'re doing

5 less and less of that and there\'s repackaging at

6 the community pharmacy level, the mail-order

7 pharmacy level, or at the hospital or other

8 dispensing level, then all of this is besides the

9 point. So we need to know more about that.

10 DR. GROSS: Michael, another comment?

11 DR. COHEN: The term unit of use is

12 different than unit dose. We were speaking about

13 unit dose, meaning the individual dose for that

14 patient. Unit of use would be package that

15 contains perhaps a supply of medications just for

16 that patient.

17 DR. GROSS: Okay. So the sense of the

18 group with paper labels seems to be it\'s less than

19 ideal and it\'s probably something that should be

20 avoided. But, once again, there is no data to show

21 the human toxicity from the observed leaching of

22 compounds, and that would just make, you know, life

154

1 easier if it was at all possible to get that, which

2 it may not be.

3 Ink without label is probably even worse

4 than paper labels, but, Curt, did you want to say

5 something?

6 DR. FURBERG: I just want to say that for

7 the paper labels, is it possible to have a warning

8 box like we have for drugs, warn against using

9 paper labels directed at the pharmacists.

10 DR. GROSS: Gene?

11 DR. SULLIVAN: You\'re saying that if

12 manufacturers proceeded\--or continued to use

13 embossed or debossed and the pharmacist chose\--they

14 thought it was best to take their own label and

15 stick it on?

16 DR. FURBERG: Yes, that\'s correct. I

17 mean, have you ever addressed that, warnings

18 directed at the middleman, the pharmacist, rather

19 than at the health care provider and the patient,

20 warn them against doing things to the vial?

21 DR. SULLIVAN: Right. I think\--

22 DR. FURBERG: Any label, doing whatever,

155

1 removing the overwrap, et cetera.

2 DR. SULLIVAN: You\'re right. It seems

3 unwise for people who are not expert to be using

4 materials that are not well characterized and

5 applying them directly to a permeable container

6 closure system, and certainly that is something

7 that\--a practice that shouldn\'t be undertaken. I

8 think that we\'re today trying to talk about what to

9 ask the manufacturers to do in regards to what they

10 can do to improve the legibility so that perhaps

11 pharmacists won\'t feel compelled to do what maybe

12 they are doing.

13 DR. SHAH: Can I add to that? Especially

14 on the labeling, there is clearly a warning that

15 says open just prior to use, so they are not

16 supposed to remove it from the container.

17 DR. FURBERG: You can add to that.

18 DR. SHAH: Yes, we can add it, but this is

19 just the practice and that\'s what happens, I guess.

20 And I guess at that point I don\'t think the agency

21 has a control over that, and I think that\'s another

22 way to educate the people and then get the message

156

1 around, I would think.

2 DR. SULLIVAN: It\'s been our informal

3 assumption that if they were individually wrapped,

4 it would greatly decrease the likelihood of

5 respiratory therapists, you know, going in the

6 morning and unwrapping 20 and then putting them in

7 their pocket to care for patients through the day.

8 I think that\'s probably less likely, and we could

9 get some input from the speaker from the

10 Respiratory Care Association. Intuitively, it

11 seems less likely that would occur. I think you

12 can\'t, just as you can\'t\--you know, patients at

13 home may take out five pills from their bottle and

14 they\'re divorced from the labeling, that could

15 happen. It\'s been our assumption that it would be

16 much less likely if there was just one vial per

17 pouch.

18 DR. FURBERG: But you could still use the

19 overwrap to have a warning.

20 DR. GROSS: Karen?

21 MS. STEWART: \[Inaudible, off microphone.\]

22 I think if it\--the problem comes when they package

157

1 multiple \[inaudible\].

2 DR. GROSS: This is another favorable push

3 for a unit package overwrap.

4 Is there anyone who would like to speak in

5 favor of ink without label directly on the LDPE

6 vial? Michael?

7 DR. COHEN: I don\'t want to speak in favor

8 of it, but one of the examples that was shown was

9 an injectable with the ink embossed\--or printed

10 right on the label. That was the Naropin

11 injection. And I\'m wondering, you know, if there\'s

12 a concern with patients with respiratory disorders,

13 is there a concern with systemic use of a drug like

14 that? Do we know anything about that, as a matter

15 of fact?

16 DR. SULLIVAN: So the question is: Is

17 there a difference in our concern regarding the

18 level of contaminants? I think from a

19 pulmonologist\'s perspective there is, that

20 particularly because of the nature of the patients

21 we treat, who can be very sensitive\--you know, I

22 touched on it my talk. We haven\'t spoken too much

158

1 more about it, but patients that actually develop

2 specific immunity. So they\'re allergic to things,

3 and atopic patients, asthmatics, are more likely to

4 develop specific immunity, and probably

5 physiologically, humans are more likely to develop

6 specific immunity when drugs are administered by

7 the inhalation route than by other routes, like

8 oral or even IV. So I understand your point about

9 separating these drugs. The issue of there being

10 multiple routes of administration is important

11 because you mix up between the routes.

12 The specific concern about the chemical

13 impurities to me is particularly important for

14 inhalation drugs.

15 DR. COHEN: I guess it leads me to ask the

16 question then: Will you allow\--I mean, we have

17 already several injectable products in this type of

18 plastic. There will be saline and heparin and, you

19 know, various products like that. And I\'m

20 wondering, I guess, if you would allow then the use

21 of ink on these containers, because that would

22 solve our problem if there\'s no concern at FDA for

159

1 the ink and the volatiles from the ink. With

2 systemic use.

3 DR. GROSS: Yes, Brian?

4 DR. STROM: Speaking not as a

5 pulmonologist but a general internist, I worry

6 about IV injection of contaminants more than

7 pulmonary. I mean, yes, it may be less sensitizing

8 perhaps than the lungs, but, still, IV injection of

9 contaminants I would think would be at least as

10 worse.

11 DR. SULLIVAN: Well, I mean, of course,

12 all the products are carefully controlled, and I

13 don\'t have the expertise\--maybe Dr. Shah

14 does\--about the particular controls that are put on

15 oral products or IV products. But we very closely

16 control inhalation products because of the issues

17 of irritants and because of the issues of

18 sensitization. And which is a greater risk I guess

19 I won\'t firmly state, so\--

20 DR. GROSS: The sense of the group seems

21 to be, in the absence of human data of actual risk,

22 our recommendation would be to avoid the ink

160

1 without label directly on the vial containing the

2 medication. Is that fair? Anybody disagree with

3 that?

4 DR. COHEN: I have a\--

5 DR. GROSS: Michael disagrees.

6 DR. COHEN: These types of packages are

7 used widely in other countries for parenteral

8 medications, and I don\'t know that there\'s been

9 anything ever reported, you know, as an adverse

10 effect specifically tied to the inks. I don\'t

11 know. But, you know, I express the same concern

12 that Dr. Strom has. If there\'s any evidence at all

13 that there\'s leaching of the ink through the

14 plastic, through the semipermeable membrane, that

15 would be a concern systemically. I just didn\'t

16 know.

17 DR. GROSS: Leslie?

18 DR. HENDELES: There\'s actually precedent

19 with sulfites and tartrazine, other substances in

20 medications that cause reactions in selected

21 patients. So I think if there\'s any way of

22 avoiding putting something in that you don\'t know

161

1 to be safe, you should avoid it because there are

2 examples of other contaminants causing the reaction

3 than the drug.

4 DR. GROSS: The question is for the

5 specific ones, do we know them to be unsafe? Yes,

6 Brian?

7 DR. STROM: I guess my sense in a

8 data-free world that we\'re operating in here is to

9 share the concern that you expressed, Peter, of a

10 consensus of let\'s not use it here because of the

11 risk of contaminants. But I would take that

12 further in two ways. One is I would extend that

13 for intravenous use; and, second, I would call for

14 data. It would be nice to know if any of these

15 things mattered, not just in terms of measuring

16 contaminants but even in animal studies, if we

17 can\'t identify it.

18 I would think in the respiratory situation

19 would be one of the hardest places to get data on

20 the clinical importance of them. But perhaps in an

21 intravenous setting, it might be more possible to

22 get some data in terms of different products of the

162

1 same drug, for example, that have ink on the label

2 versus don\'t have ink on the label and is there a

3 difference in subsequent allergic reactions to

4 them.

5 DR. GROSS: Okay. The next one is tactile

6 recognition, use of textures on the LDPE vials.

7 Anyone want to comment on that? And maybe could

8 someone from the FDA elaborate on what you mean by

9 textures. Do you mean smooth versus rough? Or do

10 you mean feeling the letters? What\'s meant by

11 that?

12 MS. HOLQUIST: A combination of any of

13 those things, by using the type of letters that you

14 can feel, by the different shapes, or should we

15 make the vial feel from for different products? We

16 just threw it out there as another suggestion.

17 DR. GROSS: Jackie?

18 DR. GARDNER: It seems that the point that

19 was brought up about standardization with various

20 manufacturers applies here as well and should be

21 considered.

22 DR. GROSS: Good point.

163

1 Michael?

2 DR. COHEN: Again, I\'ll join the data

3 camp. I don\'t think we know much about the tactile

4 cues. I mean, from a human factor standpoint it

5 certainly makes sense, but using them on actual

6 drug products, I don\'t know of any history with

7 other products where that\'s been successful.

8 Perhaps the shape of the container as a

9 tactile cue, the octagonal shape, the hexagonal

10 shape, et cetera, square. We used to do that with

11 insulin vials, for example. That might have been

12 effective. But if that\'s the case, I don\'t think

13 you have enough different shapes that could be

14 used, and it also puts burdens on the manufacturers

15 and elevates the cost when you have these different

16 shapes.

17 DR. GROSS: Again, a suggestion to the FDA

18 from a research point of view. When we had that

19 conference\--I guess it\'s almost a year ago now\--on

20 look-alike, sound-alike drugs and someone spoke on

21 human factor engineering, it might be interesting

22 to get some input from that kind of person and have

164

1 them test some of these issues.

2 Brian?

3 DR. STROM: I would also echo my comment

4 before, like with color. Anything that takes

5 people\--there aren\'t enough options in textures in

6 order to replace the use of names. And anything

7 that removes people\'s attention from the drug name

8 I think might be more likely to cause problems than

9 less, though, again, that\'s supposition without

10 data to prove that.

11 DR. GROSS: That brings up an issue that

12 the Joint Commission has dealt with on using two

13 patient identifiers. Should there\--you\'re

14 suggesting you\'ll confuse people, and, you know,

15 does that rule apply at all to drug use that there

16 be two kinds of identifiers, or at least not

17 another identifier that might confuse them?

18 DR. STROM: I guess my\--I think the

19 difference versus the Joint Commission situation,

20 the Joint Commission is asking for two unique

21 identifiers for the patient. What we\'re talking

22 about here would be one unique identifier, which is

165

1 the name, and another unique identifier, the

2 texture or the color\--which isn\'t unique. There

3 aren\'t enough unique options in order to make it

4 unique. If it really was possible to have\--you

5 know, how many products are we talking about here,

6 30, 40? There aren\'t that many textures. And if

7 it were really possible to have enough unique

8 colors or unique textures, you might think about

9 that, though I would still think then training

10 people to remember which texture corresponds to

11 which name would be hard as well.

12 So it\'s different than the Joint

13 Commission situation where you\'re talking about a

14 patient\'s name, which is unique to that patient,

15 and both identifiers have that same name. The

16 equivalent here would be having the drug name both

17 embossed and also on the overwrap. And we are

18 suggesting that that makes sense here.

19 DR. GROSS: So the sense of the group

20 seems to be that tactile recognition is not

21 recommended and may confuse. Does anybody disagree

22 with that?

166

1 \[No response.\]

2 DR. GROSS: Okay. The next item is shrink

3 wrap labels as an example that was circulated

4 around, and not attached to the LDPE vial itself

5 but to a tab or an appendage attached to the vial.

6 Is that what the FDA means by that? Anybody have

7 any comments? Michael?

8 DR. COHEN: This would be my number one

9 preference, as I mentioned before, because it gives

10 you so much flexibility. You can easily see the

11 black type on a white background. You can put bar

12 codes on it, et cetera. But, you know, I have a

13 concern if FDA has a concern about the volatility

14 of those inks, except, you know, I\'d love to see

15 the studies that you were talking about because it

16 just seems to me that this is not an ink that is in

17 direct contact with the LDPE plastic. It\'s on the

18 overwrap itself. I understand that it still might

19 be volatile within that micro environment, et

20 cetera, but it might be at a level that\'s not even

21 close to, you know, causing a problem. I just

22 don\'t know. But I\'d love to see the studies.

167

1 MR. LEVIN: Just a point of information.

2 I would guess that there are inks and there are

3 inks. Are there vegetable dye inks? Are there

4 different kinds of inks that may increase or lessen

5 the potential toxicity?

6 DR. SHAH: Yes, as I mentioned in my

7 presentation, there are water-based inks and there

8 are organic solvent-based inks. So if you have

9 carefully selected ink formulations in which you do

10 not have volatile components, then there is pretty

11 much not any likelihood of any volatile to be

12 present in the ink formulation that may migrate to

13 the vial. So that is a possibility. People can

14 think about that.

15 MR. LEVIN: Is that something that the

16 agency could stipulate, that inks used\--I mean, for

17 example, if this was the model and then further

18 stipulate that inks used would have to not\--you

19 know, would not contain volatile substances to

20 minimize risk? It\'s a question.

21 DR. SHAH: I don\'t know. I will have to

22 ask our, you know, upper office and then find out

168

1 about that. I\'m not sure about that.

2 DR. GROSS: Any other comments? Yes,

3 Brian?

4 DR. STROM: I just want to echo the

5 comment that in many ways this is attractive. It

6 just would be nice to see before that the kind of

7 studies of contaminants that we saw before

8 deciding. So I guess my recommendation would be a

9 conditional, this is preferable after those studies

10 are done. Without those studies being done, we

11 don\'t know that this is any better than the current

12 approach in terms of leakage.

13 DR. GROSS: And that\'s part of one of the

14 requests, that whatever we recommend doesn\'t create

15 additional problems. So we do need that data.

16 Okay. So what Brian said I think sums up

17 what the group thinks. Fair enough? Okay.

18 The last is glass ampules, and perhaps

19 someone could comment from the FDA or Michael or

20 anyone, why did we move away from glass ampules in

21 the first place to plastic? Was it accident prone

22 or what?

169

1 DR. COHEN: I\'m sorry. I raised my hand

2 too\--I don\'t know why we moved away from it, but

3 I\'d hate to be a respiratory therapist if I had to

4 crack open all those glass ampules.

5 DR. GROSS: Right. So it\'s an accident

6 issue.

7 MS. HOLQUIST: Also, I think it lends to

8 errors, as you saw by Marci\'s slide with the

9 acetylcysteine where it comes in an IV route and a

10 respiratory route, and so it was confused because

11 it looked like an IV product.

12 DR. GROSS: Okay. Any other comments on

13 glass? Brian?

14 DR. STROM: In follow-up to that comment,

15 should we think about a recommendation that the

16 plastic\--especially if the plastic is being widely

17 used now in respiratory and it\'s not being widely

18 used elsewhere but beginning to, that, in fact,

19 that distinction\--we\'re talking about tactile and

20 whatever\--be kept clean, i.e., that the plastic be

21 used for respiratory and for parenteral use it be

22 glass?

170

1 MS. HOLQUIST: I think it\'s a good

2 recommendation, but, again, it\'s something we have

3 to bring back to the agency and provide to all the

4 other review divisions that are involved. It\'s not

5 just the pulmonary division.

6 DR. GROSS: Okay. I guess you\'re all

7 getting hungry. I\'m not sure if lunch is here, but

8 we\'ll probably break pretty soon.

9 Annette, did you have a comment, or

10 anybody?

11 \[No response.\]

12 DR. GROSS: Okay. So the sense then is

13 the last comment that Brian made, if glass is used

14 at all, there probably should be a distinction that

15 plastic be used as pulmonary inhalation medication

16 and glass be used for other uses, such as

17 intravenous use. Is that fair?

18 \[No response.\]

19 DR. GROSS: Okay. Why don\'t we take a

20 break and we\'ll address 1b, 2, and 3 afterwards.

21 We have an hour for lunch.

22 \[Luncheon recess.\]

171

1 AFTERNOON SESSION

2 \[12:50 p.m.\]

3 DR. GROSS: Okay. We will begin where we

4 left off, and that is Item 1b. The question was:

5 Please identify creative solutions or alternative

6 packaging designs that improve legibility and

7 address the problem of ingress of chemical

8 contaminants, and at the same time, do not create

9 new problems.

10 Would anyone like to comment? Leslie?

11 DR. HENDELES: How about tying a ribbon

12 around the end of the plastic vial, and on that

13 ribbon you can imprint \"Albuterol, 0.083 percent.\"

14 DR. GROSS: I don\'t know whether to say

15 thank you or less levity.

16 \[Laughter.\]

17 DR. HENDELES: Yellow ribbon.

18 DR. GROSS: Okay. So you\'re tying a

19 yellow ribbon around the medication.

20 DR. HENDELES: Yellow for Ipatropium, red

21 for Albuterol.

22 DR. GROSS: All right. That\'s a creative-

172

1 DR. HENDELES: Red and yellow for the

2 Duovent.

3 DR. GROSS: Okay. Are there any other

4 creative suggestions? Jackie?

5 DR. GARDNER: You know, there are

6 thousands, and I have information that the

7 manufacturers are actually working on some of them.

8 And so I think rather than trying to come up with

9 good ideas, however good that was, Les, maybe what

10 we should do is encourage the people who have the

11 most to gain from this to bring forward creative

12 solutions that put all these objectives into play

13 and give us some things to choose from\--maybe not

14 today but when they\'re ready\--because they will

15 have tested them as well.

16 DR. GROSS: Like we saw this morning,

17 okay.

18 Henri?

19 DR. MANASSE: I think as we consider new

20 options and new directions in this area, I would

21 hope that the industry and the FDA would very

22 carefully consider symbologies that are

173

1 electronically readable for patient verification.

2 I think the system is moving in that direction.

3 There are available technologies for that

4 verification, and particularly patient-level

5 verification. Adding these technologies is going

6 to be important. I know what the issues are in

7 terms of the bar code and the size of the bar code,

8 but there are other symbologies that can be

9 applied, like dot matrix technologies, et cetera,

10 that wouldn\'t take the kind of space. But as we

11 get creative in this packaging, I think we should

12 be real sensitive and help motivate and move the

13 verification mechanisms along.

14 DR. GROSS: Any other comments? Yes, Art?

15 MR. LEVIN: Just to reiterate the

16 importance of also looking at the community

17 pharmacy, ambulatory population, including the

18 elderly, that use these products where the

19 solutions may have to be different, frankly, than

20 they are in the inpatient clinical setting. And

21 remember that that\'s probably an increasing

22 population of use, and that we need probably to

174

1 look at the research that\'s going on now in health

2 literacy and cultural competency, et cetera, et

3 cetera\--in other words, a very broad view of what

4 we need to know and sort of think out of the box on

5 how to make this happen.

6 DR. GROSS: I think that\'s a very good

7 point. Just like they say children are not little

8 adults, the elderly are not young adults, and we

9 have different considerations for all those groups.

10 I\'m amazed\--oh, thank you, Brian, for

11 coming up with something.

12 \[Laughter.\]

13 DR. STROM: I just wanted to return to

14 Leslie\'s comments about the relative benefit and

15 safety of these products as a class versus the MDIs

16 and whether there should, in fact, be at least

17 labeling comments or instructions that might

18 provide some of the alternative data or in some way

19 begin to push the field toward using the safer

20 alternatives instead.

21 DR. GROSS: Okay. There being no more

22 comments for Item 1b, we\'ll move to number 2.

175

1 Please consider which stakeholder groups\--we\'ve

2 discussed some of this already, but we should

3 emphasize it now\--be they manufacturers,

4 practitioners, consumers, or others, can best

5 advise the FDA about possible new packaging

6 configurations that may resolve the issues we\'ve

7 discussed.

8 Jackie already suggested we should

9 encourage the manufacturers themselves to do this.

10 And consumers.

11 Yes, Henri?

12 DR. MANASSE: Peter, I again want to

13 reiterate I think we ought to bring in the cosmetic

14 industry packaging people. They have done some

15 incredibly innovative things in packaging.

16 I think another sector that has a lot of

17 experience in packaging has been the Department of

18 Defense as we look at pouching food, for example,

19 and sustaining it and everything else. So I think

20 our colleagues in the military may be helpful here

21 as well.

22 DR. GROSS: I heard someone say space,

176

1 involve NASA.

2 DR. MANASSE: NASA.

3 DR. GROSS: Okay. Leslie?

4 DR. HENDELES: In regards to the

5 consumers, there are two lay organizations of

6 people interested in asthma. One is Mothers of

7 Asthmatics, and the other one slips my mind. But

8 there are two organizations, and getting their

9 input might be worthwhile. I can e-mail you the

10 name of that second organization.

11 DR. GROSS: Fine. Michael?

12 DR. COHEN: I just want to say whatever

13 anyone comes up with, I really think it will be a

14 great idea to involve organized respiratory

15 therapy, organized pharmacy, and probably\--I don\'t

16 know if FDA can do this, similar to what they do

17 with the drug names, as we heard at the last DSaRM

18 Committee meeting, the idea of failure mode and

19 effects analysis for any of these packaging changes

20 that are made to make sure that\--or minimize the

21 chance that there might be a

22 medication-error-related problem with them.

177

1 DR. GROSS: Yes, a rigorous FMEA approach

2 could be very helpful.

3 Yes, Curt?

4 DR. FURBERG: I just wonder whether this

5 is a unique problem in the U.S. If it\'s not, let\'s

6 check and see what other countries are doing, other

7 regulatory agencies, other countries.

8 DR. GROSS: Okay. Good point.

9 Brian?

10 DR. STROM: One of the things we talked a

11 lot about this morning is the need for additional

12 data here. Some of it clearly needs to be

13 generated by the manufacturer, but I wonder if

14 there might be funding agencies\--ARC, for

15 example\--more applied perhaps to CERTs. Perhaps

16 there\'s people in the CERTs who might be interested

17 in studying some of these issues.

18 DR. GROSS: Good idea.

19 Michael?

20 DR. COHEN: Just think a little bit more

21 about that. It isn\'t even just these products.

22 It\'s other medication-error-related problems with

178

1 labeling, packaging, you know, where is color

2 appropriate, all that kind of stuff. It would just

3 be so helpful beyond this if we could get the right

4 research done. It just doesn\'t seem like things

5 have been moving in that direction for whatever

6 reason.

7 DR. GROSS: Curt?

8 DR. FURBERG: One way of getting research

9 is to set up a meeting and invite people to come

10 and present, and maybe it\'s time now to have a

11 two-day workshop on these packaging issues and

12 invite industry representatives, scientists, and

13 others. It\'s one way of advancing knowledge.

14 DR. GROSS: Like was done for look-alike,

15 sound-alike names a year ago.

16 Brian?

17 DR. STROM: Following up on Mike\'s idea of

18 broadening the question, if the question were broad

19 enough, you might be able to get the right group at

20 NIH to be interested, focusing not so much on the

21 specifics of the drug and the drug label because

22 they\'re not going to care about that in the drug

179

1 labeling, but issues of patient perception

2 and\--well, safety is really an ARC issue. NIH

3 isn\'t interested in patient safety. But it\'s\--but

4 NIH would be more interested in sort of

5 understanding patient perceptions and, you know,

6 what is it that\--you know, issues of color and

7 tactile and sort of, you know, more broader,

8 definitive, and maybe the National Institute of

9 Mental Health, maybe issues\--maybe the NHLBI given

10 the importance of this for respiratory, but NHLBI

11 probably would care less about that kind of thing.

12 But NIMH or the National Institute of Nursing

13 Research might be another that might be interested.

14 Another might be NIA, actually, the National

15 Institute of Aging, which has a pharmacology

16 program and the issues here in terms of the elderly

17 being able to read labels correctly and perceive

18 drugs correctly would be a big one. So in terms of

19 looking at sort of who could potentially fund this,

20 fund the necessary collection of data in a way that

21 FDA can\'t, the NIA might be a logical one.

22 DR. GROSS: Any other comments?

180

1 \[No response.\]

2 DR. GROSS: Well, that was very creative.

3 Thank you. That was very helpful.

4 The last question, number 3, is: Given

5 what you have heard today, please describe an

6 appropriate course of action to address the

7 problems of ingress and medication errors due to

8 legibility and similar packaging issues.

9 Henri?

10 DR. MANASSE: Peter, I\'d like to focus on

11 the ingress issue. I guess I\'m impressed by how

12 little we know about ingress in these kinds of

13 plastics, the kind of chemicals that are creating

14 the problem, the impacts that the ingress has on

15 active ingredients. And it seems to me that FDA

16 ought to be stimulating knowing more about this and

17 then from that making a determination as to whether

18 or not the appropriate statutory and regulatory

19 things are in place to be able to pursue requests

20 about these issues, particularly the toxicities,

21 through the application processes and the master

22 file, et cetera.

181

1 DR. GROSS: Leslie?

2 DR. HENDELES: I recommend that the agency

3 just revise that draft guidance to take into

4 account some of the issues that we discussed under

5 1a. I mean, I think that would be the appropriate

6 direction.

7 DR. GROSS: Okay. Art?

8 MR. LEVIN: As we encourage manufacturers

9 to be innovative in finding solutions, I\'m worried

10 about the issue of standardization because I think

11 when everybody\'s looking at error prevention,

12 standardization is certainly one of the big fix

13 items. So I\'m just raising the question of how do

14 we balance the tension between innovative solutions

15 and creating industry standards so that we don\'t

16 have ten different ways that people are doing

17 things, causing even more confusion than we have

18 now. And I think it speaks to Henri\'s point about

19 how the agency perceives its authority to require

20 standards. Once finding the gold standard, then

21 what does the agency do with that, and does it need

22 additional authority, for example, to require that

182

1 that be the gold standard for all of these products

2 which have basically been out there on the market?

3 They\'re not going to be new drug applications. But

4 could they go back and say, In the future over a

5 period of time we expect you to convert to this

6 gold standard of packaging?

7 DR. GROSS: Any other comments?

8 \[No response.\]

9 DR. GROSS: Okay. Well, I want to thank

10 the presenters as well as the Advisory Committee

11 members for this thoughtful exchange of

12 information. And at this particular point, we are

13 going to adjourn for a bit because the Lotronex

14 part of the agenda was scheduled to begin about 3

15 o\'clock. I think we\'ll be able to begin at 2:30.

16 Is that it? 2:20. Okay.

17 If there\'s any change in that, we\'ll get

18 the word around because everybody\'s staying pretty

19 close. Okay. Thank you.

20 \[Recess.\]

x DR. GROSS: Good afternoon. I think we\'ll

21

22 call the meeting to order. I\'d like to begin by

183

1 reintroducing the people who are sitting around the

2 table because we have a new group as part of the

3 open public hearing. So if we can begin\--oh, there

4 he is. Next to Brian is?

5 DR. KRIST: My name is Alex Krist. I\'m

6 with Virginia Commonwealth University. I\'m a

7 member of the Gastrointestinal Drugs Advisory

8 Committee, and I\'m a family physician.

9 DR. GROSS: Brian?

10 DR. STROM: Brian Strom, University of

11 Pennsylvania.

12 DR. MANASSE: I\'m Henri Manasse. I\'m the

13 executive vice president and chief executive

14 officer of the American Society of Health-System

15 Pharmacists.

16 MS. SHAPIRO: Robyn Shapiro, Director,

17 Center for the Study of Bioethics, Medical College

18 of Wisconsin.

19 DR. STEMHAGEN: I\'m Annette Stemhagen from

20 Covance, a contract research organization, and I\'m

21 the industry representative to this committee.

22 DR. GARDNER: Jacqueline Gardner,

184

1 University of Washington, Department of Pharmacy.

2 MR. LEVIN: Art Levin, Center for Medical

3 Consumers, and I am the consumer member of this

4 committee.

5 DR. FURBERG: Curt Furberg, professor of

6 public health sciences at Wake Forest University.

7 DR. GROSS: Peter Gross. I\'m Chair of

8 Medicine at Hackensack University Medical Center

9 and New Jersey Medical School, and I\'m Chair of

10 this Advisory Committee.

11 MS. JAIN: Shalini Jain, Executive

12 Secretary, Drug Safety and Risk Management Advisory

13 Committee.

14 DR. CRAWFORD: Stephanie Crawford,

15 University of Illinois at Chicago, College of

16 Pharmacy.

17 DR. SELIGMAN: Paul Seligman, Director,

18 Office of Pharmacoepidemiology and Statistical

19 Science, Center for Drugs at the FDA.

20 DR. BEITZ: Julie Beitz, the Deputy

21 Director in the Office of Drug Evaluation III in

22 CDER.

185

1 DR. JUSTICE: Robert Justice, Director of

2 Division of Gastrointestinal and Coagulation Drug

3 Products at FDA.

4 DR. TRENTACOSTI: Ann Marie Trentacosti,

5 Medical Officer, Division of Gastrointestinal and

6 Coagulation Drug Products at the FDA.

7 DR. AVIGAN: Mark Avigan, Director of the

8 Division of Drug Risk Evaluation in the Office of

9 Drug Safety.

10 DR. GROSS: Okay. Shalini Jain will read

11 the conflict of interest statement.

x MS. JAIN: The following announcement

12

13 addresses the issue of conflict of interest with

14 regard to this meeting and is made a part of the

15 record to preclude even the appearance of such at

16 this meeting. Based on the submitted agenda for

17 the meeting and all financial interests reported by

18 the committee participants, it has been determined

19 that all interests in firms regulated by the Center

20 for Drug Evaluation and Research present no

21 potential for an appearance of conflict at this

22 meeting with the following exceptions:

186

1 In accordance with 18 U.S.C. 208(b)(3),

2 Dr. Brian Strom has been granted a waiver for

3 consulting with two competitors on unrelated

4 matters. He receives less than \$10,001 per year

5 from one firm and between \$10,001 and \$50,000 per

6 year from the other.

7 Dr. Maria Sjogren has been granted a

8 waiver under 208(b)(1) for consulting with the

9 sponsor on unrelated matters. She receives less

10 than \$10,001 per year.

11 A copy of the waiver statements may be

12 obtained by submitting a written request to the

13 agency\'s Freedom of Information Office, Room 12A-30

14 of the Parklawn Building.

15 We would also like to note that Dr.

16 Annette Stemhagen has been invited to participate

17 as an industry representative, acting on behalf of

18 regulated industry. Dr. Stemhagen is employed by

19 Covance Periapproval Services, Incorporated.

20 In the event that the discussions involve

21 any other products or firms not already on the

22 agenda for which an FDA participant has a financial

187

1 interest, the participants are aware of the need to

2 exclude themselves from such involvement, and their

3 exclusion will be noted for the record.

4 With respect to all other participants, we

5 ask in the interest of fairness that they address

6 any current or previous financial involvement with

7 any firm whose products they may wish to comment

8 upon.

9 Thank you.

10 DR. GROSS: Dr. Paul Seligman will give an

11 introduction to the Lotronex issue.

x DR. SELIGMAN: Good afternoon. It is my

12

13 pleasure to introduce the second topic for today\'s

14 meeting. This afternoon we\'ll be hearing an update

15 on the Lotronex Risk Management Program. On April

16 23, 2002, the Gastrointestinal Drugs Advisory

17 Committee and this committee met and recommended

18 reintroduction of Lotronex tablets to the market

19 with certain restrictions, such as having patient

20 and physician registries and physician

21 certification training for prescribing.

22 On June 7, 2002, FDA approved the

188

1 restricted marketing of Lotronex with a risk

2 management program that was mutually agreed upon by

3 the Lotronex manufacturer, GlaxoSmithKline, and the

4 FDA. The details of this plan will be described in

5 the subsequent presentations.

6 Today, GSK will be presenting an update

7 report on how the drug is being prescribed within

8 the parameters of the risk management program and

9 what the impact of this program has been. The

10 purpose of this discussion is primarily

11 informational in nature to provide the committee an

12 update. As a consequence, we have allocated a

13 limited amount of time for presentations and

14 discussion.

15 The risk management program that was

16 implemented contained many but not all of the

17 elements recommended by the Joint Advisory

18 Committees in April of 2002. As we gain experience

19 with risk management programs, we think that it is

20 important that there be a public airing of how well

21 these programs function and whether they meet the

22 goals that were set out for them.

189

1 With that, I thank you for your attention

2 and I thank the committee for being here today. We

3 will have both the speakers at the open public

4 hearing as well as the speakers who are on the

5 agenda to have them use this podium in front of the

6 committee.

7 So, with that, Mr. Chairman, I turn the

8 proceedings over to you.

9 DR. GROSS: Thank you, Dr. Seligman.

x We will proceed with the open public

10

11 hearing now. First I need to read this statement.

12 Both the Food and Drug Administration and

13 the public believe in a transparent process for

14 information gathering and decisionmaking. To

15 ensure such transparency at the open public hearing

16 session of the Advisory Committee meeting, the FDA

17 believes that it is important to understand the

18 context of an individual\'s presentation. For this

19 reason, FDA encourages you, the open public hearing

20 speaker, at the beginning of your written or oral

21 statement to advise the committee of any financial

22 relationship that you may have with the sponsor,

190

1 its product, and if known, its direct competitors.

2 For example, this financial information

3 may include the sponsor\'s payment of your travel,

4 lodging, or other expenses in connection with your

5 attendance at the meeting. Likewise, FDA

6 encourages you at the beginning of your statement

7 to advise the committee if you do not have any such

8 financial relationships. If you choose not to

9 address this issue of financial relationships at

10 the beginning of your statement, it will not

11 preclude you from speaking.

12 The first speaker is Dr. Sidney Wolfe.

13 DR. WOLFE: Right on time. In August

14 2000, almost four years ago, we petitioned the FDA

15 to ban alosetron because, in our view, its serious,

16 life-threatening adverse effects outweighed the

17 marginally better-than-placebo effectiveness. At

18 the time of our petition, FDA was aware of 26 cases

19 of ischemic colitis in people using the drug. In

20 the major randomized, placebo-controlled trials

21 prior to approval, there had been three cases of

22 ischemic colitis in 832 patients, or 1 per

191

1 277\--again, with good ascertainment, in contrast to

2 what we are having here\--but none in 700 placebo

3 patients. According to an FDA memo, in one large

4 trial with adequate ascertainment\--this is a

5 different trial\--adequate ascertainment of ischemic

6 colitis, 10 out of 1,819 women being treated with

7 alosetron for diarrhea-predominant irritable bowel

8 syndrome developed ischemic colitis over the

9 24-week duration of the trial. There were no cases

10 in the 899 patients in the trial treated with

11 traditional therapy. By the time marketing was

12 stopped in November 2000, there were 85 cases of

13 ischemic colitis reported to the FDA among the

14 estimated 275,000 patients who has used the drug.

15 Even though this is called the Drug Safety

16 Committee, you know as well or better than I that

17 this all has to be viewed in the context of drug

18 benefit and, therefore, review of the evidence for

19 benefit for at least one of the major trials for

20 this drug is appropriate.

21 In an analysis we published in the Lancet

22 of data from one of the clinical trials, which had

192

1 been misleadingly portrayed in a previous article

2 in the Lancet by percent change as opposed to

3 absolute scores, the figure of our look at the

4 actual data can be seen on the second page of the

5 testimony. And what you can see is there is barely

6 a perceptible\--it\'s statistically significant, but

7 no one can possibly believe that this is clinically

8 meaningful, the difference at 1, 2, 3, months

9 between those given 2 milligrams of alosetron,

10 twice the dose being used now, for starters, and

11 those being given the placebo.

12 This excellent, hard-to-exceed placebo

13 response rate\--and that\'s certainly the challenge

14 of treating this illness, is that the placebo

15 response rate is extraordinarily high. This is

16 consistent with findings from a published review of

17 27 randomized, placebo-controlled studies testing

18 various treatments for irritable bowel syndrome in

19 which the median placebo response rate was 47

20 percent, percentage improved, with rates as high as

21 84 percent, and 11 studies had placebo response

22 rates of 60 percent or higher. Unlike alosetron,

193

1 placebos do not cause ischemic colitis.

2 Because IBS is a poorly defined disease,

3 which, although capable of causing significant

4 distress in some individuals, is neither progressive nor

5 life-threatening, the occurrence of

6 serious adverse reactions such as ischemic colitis

7 and bowel obstruction without ischemic colitis,

8 sometimes requiring surgery, tips the benefit-risk

9 equation against the use of this drug.

10 The experience during the first one-plus

11 years of this risk management program has hardly,

12 as Glaxo claims in its statement, \"been

13 successful.\" Among the problems, somewhat

14 predictable because of the lack of the kinds of

15 controls that could realistically be taken only

16 under an IND, were the following:

17 Twenty percent of the patients getting the

18 drug not have all of the three criteria specified

19 for getting the drug, which include frequent/severe

20 abdominal pain, and frequent bowel urgency or fecal

21 continence; and disability/restriction of daily

22 activities. They may have one or two, but these

194

1 were the criteria, and 20 percent did meet these

2 criteria.

3 Secondly, only 42 percent of patients with

4 a Lotronex prescription has pre-enrolled in the

5 survey program and only 36 percent completed the

6 baseline questionnaire.

7 From the prescribing doctor\'s perspective,

8 again, because this is not required, it happens, 20

9 percent of prescribing doctors were not enrolled in

10 the prescribing program for Lotronex. That may or

11 may not have something to do with the fact that so

12 many of these average reactions were not reported

13 by physicians.

14 These are all elements that certainly were

15 thought of if it not specifically suggested by FDA

16 staff and ourselves at the meeting a couple of

17 years ago, and you can\'t do these things unless the

18 drug is there under an IND. Marketing isn\'t

19 compatible with those kinds of restrictions.

20 The most alarming finding during this

21 period was the reporting of eight cases of ischemic

22 colitis and, according to the manufacturer, eight

195

1 additional cases of \"complications of

2 constipation.\" I say according to the manufacturer

3 because they list eight, and the FDA talks about

4 five. The latter included a case of partial

5 intestinal obstruction, one in which there was

6 exploratory surgery for small intestinal

7 obstruction, and a patient with diarrhea and

8 intestinal obstruction.

9 Assuming the accuracy of the estimate of

10 9,365 patients getting alosetron during the risk

11 management program, the rate of ischemic

12 colitis\--again, this is a low estimate\--spontaneous

13 reports was 8 per 10,000 or 8 per 9,365, or about

14 0.8 per thousand, and it\'s actually higher than

15 the, again, spontaneous rate of reports during the

16 earlier mktg phase, which was 85 per 27,000.

17 There are, of course, differences in the

18 conditions for reporting that might explain some of

19 this discrepancy, but I don\'t believe begin to

20 explain all of it. Enrolled physicians agreed to

21 report all serious adverse events as a condition of

22 participation, but obviously 20 percent didn\'t

196

1 participate, and even those who did, so it appears,

2 four of the eight cases of ischemic colitis were

3 reported by patients, not physicians. Similarly,

4 none of the eight cases of serious complications of

5 constipation were reported by the prescribing

6 physician. One was reported by a nurse. Either

7 the patients did not tell the physicians who

8 prescribed the drug that they had gotten ischemic

9 colitis or physicians violated their agreement to

10 report such cases.

11 The fact that 11 of 16 cases of ischemic

12 colitis or complications of constipation were

13 reported by patients as part of the Lotronex

14 patient follow-up survey program may compensate for

15 some, but we don\'t believe all or even most of the

16 serious reporting deficiencies by participating

17 physicians. There is little question that just as

18 the 85 cases of ischemic colitis reported during

19 2000 were but a fraction of the actual cases, so,

20 too, are these recent RMP, risk management program,

21 ischemic colitis cases.

22 For effective, life-saving drugs, such as

197

1 some cancer therapies or the anti-psychotic drug

2 clozapine, risk management is a critical part of

3 their use, and we strongly support, as the FDA

4 knows, risk management in those kinds of

5 circumstances. But alosetron joins an increasing

6 number of other drugs, none with unique, clinically

7 significant benefits, that have been the subject of

8 ultimately failed FDA-approved risk management

9 programs\--the diabetes drug Rezulin, the painkiller

10 Duract, the GI drug cisapride, the blood pressure

11 drug Posicor\--and were taken off the market.

12 When I testified before this committee in

13 2002, I stated, \"The reintroduction of Lotronex

14 into the market, even with the restrictions

15 proposed by Glaxo, would be a serious public health

16 mistake, likely, if not certain, to result in the

17 need to ban the drug again.\" It is time to end

18 this failed effort to resuscitate markets and to

19 take alosetron off the market. As we suggested in

20 2002, there is no reason why, under a carefully

21 controlled IND, the drug could not be made

22 available to, I would estimate, the several

198

1 thousand, at most, people who might still choose to

2 use it. This has previously been done for the

3 diabetes drug phenformin and the GI drug cisapride

4 after they were taken off the market.

5 I\'d just like to emphasize that of the

6 reported 9,000-10,000 people using the drug, in the

7 FDA\'s Executive Summary it says only 10 to 20

8 percent of these people were refilling it. So we

9 may, in fact, be talking about a group of people

10 that is one, two, three thousand people, not the

11 100,000 that the company claimed would be using the

12 drug and which they used to help fend off an IND

13 approach back a couple years ago.

14 Given the marginal evidence of

15 effectiveness and the continuing serious risks of

16 the drug, Glaxo\'s suggestion to relax the

17 restrictions on availability of alosetron to

18 increase its use is nothing but ghoulish. A quote

19 from the end of their statement: \"The primary

20 concern at present relates to the low rate of

21 product prescribing given our understanding of the

22 target population\...This may reflect unintended

199

1 barriers to prescription\...\" and they elucidate

2 some of the unintended barriers, which is the time

3 the physician has to spend explaining to the

4 patient the benefits and risks of the drug and so

5 forth. I find that this attitude, certainly it\'s

6 consistent with trying to sell more drug, but it\'s

7 inconsistent with the public health. And just in

8 closing, I would just repeat it\'s time for this to

9 be taken off the market. It gives risk management

10 a bad name to keep doing things like this.

11 I\'d be glad to try and answer any

12 questions. That\'s just about ten minutes.

13 DR. GROSS: If there are no questions,

14 thank you very much, Dr. Wolfe.

15 The next speaker, Dr. Lawrence Wilderlite.

16 DR. WILDERLITE: Good afternoon. My name

17 is Lawrence Wilderlite. I am a practicing gastro-

18 enterologist in Chevy Chase, Maryland. We\'re part

19 of a private practice group of 13 gastroenterologists with

20 three offices in the

21 metropolitan area, downtown Washington, in Chevy

22 Chase, and on Executive Boulevard here in

200

1 Rockville.

2 In the past, I was a speaker for

3 GlaxoSmithKline upon the introduction of Lotronex

4 in 2000 and presently am a consultant for

5 GlaxoSmithKline.

6 I have been asked to talk today about the

7 prescribing habits of this drug and the inability

8 of patients to actually have access to the drug

9 because of the restrictions that have been placed

10 on this.

11 I have had extensive experience with the

12 use of alosetron when it was first introduced, and

13 our group has used it, given the patient clientele

14 we have, many times. And we have had a favorable

15 response with the drug and felt the drug to be

16 quite helpful in our patient population.

17 Inasmuch as there has been no new

18 medication or no recent introduction of any drug of

19 this type over the last 20 years for the treatment

20 of irritable bowel syndrome, we felt that this was

21 going to be a very important agent and something

22 that we would be able to use to help patients that

201

1 suffer from irritable bowel, in which we have no

2 effective treatment today. Initially upon the

3 introduction of this drug, it was embraced by the

4 GI community and was embraced by gastroenterologists that I

5 can talk to in the Washington

6 area.

7 When Lotronex was recalled in 2000, it

8 left a void, and that void is still vacant today.

9 I feel our patients have no alternative to treat an

10 illness that at times can be very devastating.

11 Although not life-threatening, it is basically

12 destructive to patients\' lives and destructive to

13 their ability to function in an environment in

14 which they live.

15 The present registration system for this

16 drug is extremely tedious. It takes a lot of time

17 to register a patient for this. The patient needs

18 to fill out papers. The GI doctor has to fill out

19 the papers. The patient has to be advised about

20 the side effects of the drug. The doctor has to

21 register to be an appropriate agent to distribute

22 the drug.

202

1 At the end of all this, we in our office

2 do refer patients to a website where they can get

3 more information about Lotronex, where they can

4 understand what the complications and the possible

5 side effects of the drug are before they enter into

6 the program or begin taking the medication. We

7 find\--and I am not a member of that prescribing

8 group. There are only two people in our group of

9 13 that elected to be registered for distribution

10 of the drug, and of those two people, it came

11 because they were quite friendly with one of the

12 Glaxo representatives who asked them if they would

13 register for this.

14 We find that patients become stigmatized

15 after they read the side effects of the drug. As

16 appropriate to Dr. Wolfe\'s comment, that many

17 patients will not fill the prescription when

18 they\'re given it. Many patients will not take the

19 medication appropriately. Many patients will stop

20 taking the medication. Patients will forget to

21 take it or take it on an alternate-day basis rather

22 than appropriately because they\'re afraid of having

203

1 some side effect and feel less is better than more.

2 And eventually some of them will not come back or

3 will not fill the prescription or, like many

4 irritable bowel patients, these patients fail to

5 come back again or don\'t show up in an office and

6 go home and continue to suffer the symptoms they

7 have.

8 Physicians, because they won\'t register

9 for this program, go back to treat these patients

10 with conventional methods, of which we have no

11 conventional methods. Increasing fiber,

12 anti-diarrheal type of agents that have been on the

13 market and have been shown to be of little help to

14 patients who suffer from this disease.

15 The physicians fear\--and when talking to

16 other doctors\--that because of all the publicity

17 given to the side effects of the drug, should a

18 patient encounter a side effect or an adverse

19 reaction to this medication, the physician is now

20 liable for some litigation or malpractice suit,

21 and, therefore, they\'re not pushing to use the

22 drugs. They\'re not rushing in to join this type of

204

1 prescribing program.

2 The amount of time that this prescribing

3 program takes is enormous. It takes a lot of time.

4 There are many physician phone calls. There\'s a

5 lot of interaction with the patient. Unfortunately, in

6 today\'s environment where there is

7 little compensation for the amount of time paid

8 because of the insurance environment that we have,

9 this type of interaction is difficult, and

10 physicians shy away from spending the amount of

11 time that is necessary to educate the patients for

12 this.

13 The process is extremely cumbersome, and I

14 find that in a group of physicians that we\'re

15 friendly with in the Washington area, very few will

16 enter into this registration process. What I do is

17 refer patients to other people in our group. It

18 changes the physician-doctor relationship, or I

19 refer them to other doctors that I can find who are

20 outside of our group to take care of these

21 patients, or we continue to use the remedies that

22 we have in place.

205

1 I feel that whether it be alosetron or

2 not, the GI community desperately needs a

3 medication to treat diarrhea-dependent irritable

4 bowel syndrome; that the mechanism that is in place

5 today needs to be streamlined to allow access to a

6 medication that I feel can help irritable bowel

7 sufferers.

8 The use of this drug is extremely limited

9 and extremely confined to approximately\--given Dr.

10 Drossman\'s (ph) classification, less than 5 percent

11 of people are available to receive this drug. I

12 feel personally that this is too confining and that

13 the drug or the use of this drug should be opened

14 up. As different from the previous speaker, I

15 think the drug is helpful and the drug needs to be

16 freed up a little bit more in a more streamlined

17 process to allow access to patients.

18 I thank you and I am open to any comments

19 that you have.

T4A DR. GROSS: There being none, thank you

20

21 very much, Dr Wilderlite.

22 We will proceed now with the sponsor

206

1 presentation. Dr. Craig Metz, the Vice President

2 for U.S. Regulatory Affairs at GlaxoSmithKline,

3 will present their risk management program for

4 Lotronex.

5 MS. JAIN: Dr. Metz, before you do your

6 presentation, we just wanted to introduce another

7 committee member that joined us in the interim.

8 Dr. Maria Sjogren joined our group. She is a

9 representative for the GI community and also is a

10 member of the GI Advisory Committee. Thanks for

11 participating.

x DR. METZ: Good afternoon. My name is

12

13 Craig Metz, and I am going to be providing the

14 sponsor\'s update on our experience with the

15 implementation of the risk management program for

16 Lotronex today.

17 Joining us today are a number of external

18 consultants who are involved with various aspects

19 of the risk management plan for Lotronex and would

20 be happy to answer any questions that you might

21 have regarding their specific areas of responsibility for

22 the RMP or any general questions that

207

1 you might have for them. I\'m going to take just a

2 quick moment to introduce our consultants.

3 We have Dr. Robert Sandler with us from

4 the University of North Carolina. Dr. Sandler is

5 involved with our Risk Management Plan Advisory

6 Board.

7 We have Dr. Lin Chang from the University

8 of California at Los Angeles, who has been involved

9 with our educational program as well as a general

10 consultant to us for some time on Lotronex.

11 We have Dr. Andrews from Research Triangle

12 Institute. She\'s involved with our epidemiology

13 program, specifically the patient follow-up survey

14 for Lotronex, and she serves as the data

15 coordinating center for the follow-up claims-based

16 research.

17 We have Dr. Jerry Gurwitz with us from

18 Meyers Primary Care Institute, University of

19 Massachusetts. Dr. Gurwitz is also involved with

20 the epidemiology program.

21 And, finally, we have Dr. James Lewis here

22 from Georgetown University who chairs our Safety

208

1 and Review Committee.

2 Three underlying themes will form the

3 basis of my presentation today. Those themes are

4 the successful implementation of the risk

5 management plan for Lotronex from the standpoint of

6 the appropriateness of the prescribers, the

7 patients, and the behaviors that have been produced

8 through this program; the impact of the RMP itself

9 on the safety profile and on the prescriber and

10 patient, as well as on individual components of the

11 risk management program itself; and the cycle of

12 continual RMP evaluation and revision that is a

13 normal part of the stewardship involved with

14 conducting a risk management program.

15 During the course of my presentation, I\'m

16 going to share information with the committee that

17 we didn\'t have when we last met to consider a risk

18 management program for Lotronex, and that

19 specifically is data on the impact of the

20 interventions that we\'ve attempted to put into

21 place here. It\'s our hope that this data will

22 guide our discussions with the agency and the

209

1 proposed modifications that we might make to this

2 RMP as we move forward. But as importantly, the

3 RMP for Lotronex has been a very rich learning

4 laboratory for us with regard to general issues

5 regarding conducting a risk management program and

6 the impact of these different interventions in

7 real-term use. So we hope that this information

8 will tend to serve to inform discussions regarding

9 the applications of these interventions elsewhere.

10 In my presentation, I\'m going to provide a

11 very brief background summary. I\'m going to

12 identify the goals of the RMP and describe the key

13 elements of the RMP with results to date where

14 appropriate. I will finish with some conclusions

15 regarding the implementation of the RMP and a

16 discussion of what we\'ve identified as emerging

17 issues.

18 Many of you will be familiar with the

19 chronology of key regulatory events. Dr. Seligman

20 has already covered some of these. Again, the

21 product was voluntarily withdrawn in November of

22 2000. The agency and GlaxoSmithKline were

210

1 inundated with calls from patients demanding that

2 the drug be made available to them again.

3 Subsequently, we submitted an sNDA in

4 December of 2001 and met with some members of this

5 committee and the GI Drugs Committee in April of

6 2002 to discuss the information included in that

7 sNDA as well as the general framework that was

8 being proposed for the RMP for Lotronex. In June

9 2002, that supplemental NDA was approved and the

10 product was actually reintroduced in November of

11 2002 with a revised indication statement and a risk

12 management program in place.

13 What we were striving to achieve when we

14 developed the risk management program for Lotronex

15 was a framework that would mitigate the risks

16 associated with complications of constipation and

17 ischemic colitis, but would do so in a way that

18 would not create extraordinary barriers to patient

19 access. And I think as we consider the information

20 being presented today, success should be measured

21 against this intent.

22 We intended to achieve this through a

211

1 focus on the following four goals: making Lotronex

2 available to those patients for whom the

3 benefit-risk is most favorable; prescribing

4 Lotronex to appropriate patients by qualified

5 physicians; educating physicians, pharmacists, and

6 patients about the risks and benefits of Lotronex

7 and how to manage those risks; and providing a

8 framework for ongoing RMP evaluation.

9 A key element of making Lotronex available

10 to a patient population for whom the benefit would

11 clearly outweigh the risk was revising the

12 indications statement to establish women with

13 severe diarrhea-predominant IBS as the target

14 population for treatment. On that basis, Lotronex

15 is currently available for women with severe

16 diarrhea-predominant IBS who have chronicity of

17 symptomatology, generally lasting six months or

18 longer; have had anatomic of biochemical

19 abnormalities of the GI tract excluded; and have

20 failed to respond to conventional therapy.

21 Additionally, diarrhea-predominant IBS is

22 defined as severe if it includes diarrhea and just

212

1 one or more of the following: frequent and severe

2 abdominal pain or discomfort, frequent bowel

3 urgency or fecal incontinence, disability or

4 restriction of daily activities due to IBS. And,

5 again, I would stress that only one of these

6 criteria are required for the patient to qualify

7 for treatment\--not two, and certainly not all

8 three. Only one. Later in my talk, I\'m going to

9 come back to this description of a 5-percent

10 estimate for the severe diarrhea-predominant IBS

11 population.

12 And, finally, the indications statement

13 states that in men, the safety and effectiveness of

14 Lotronex has not been established.

15 So the four key components of the RMP that

16 we\'ve developed for Lotronex are: enrollment of

17 qualified physicians in a physician prescribing

18 program; a program to educate physicians,

19 pharmacists, and patients about IBS and about the

20 benefits and risks of Lotronex; a reporting and

21 collection system for serious adverse events

22 associated with the use of Lotronex; and, finally,

213

1 a plan to evaluate the effectiveness of the RMP for

2 Lotronex. In the rest of my presentation, I\'m

3 going to go through each of these components in

4 order.

5 To begin with, we have the prescribing

6 program for Lotronex, and this was developed to

7 address the goal of prescribing Lotronex to

8 appropriate patients by qualified physicians. This

9 is a picture of the key steps card that helps the

10 prescribers navigate their way through the

11 prescribing program for Lotronex. It\'s going to be

12 difficult for me to use the pointer here in a very

13 effective way, but you have the slide in front of

14 you, and I\'m going to walk you briefly through some

15 of the steps.

16 So the physician, in the upper-left-hand

17 portion of this chart, decides to enroll in the

18 prescribing program for Lotronex. They receive a

19 prescribing kit that I\'m going to describe to you

20 in a minute. The physician identifies an

21 appropriate patient for treatment, goes through a

22 counseling activity with that patient, gets the

214

1 patient to sign the patient-physician agreement

2 with the physician. That agreement is then placed

3 into the patient\'s chart, and a copy of that is

4 given to the patient. The physician at that point

5 affixes a Lotronex sticker to an original

6 prescription, and at that point the physician also

7 encourages the patient to enroll in the patient

8 follow-up survey for Lotronex.

9 At that point the patient has a

10 prescription with a blue sticker on it that they

11 take to the pharmacist so that the pharmacist can

12 fill that prescription. And, again, even the

13 pharmacist has the opportunity to encourage the

14 patient to enroll in that patient follow-up survey.

15 As you can see, this is a fairly complex,

16 multi-step process. The act of physician

17 enrollment actually involves the physician signing

18 an attestation form that attests to his ability to

19 diagnose and treat IBS, to diagnose and manage

20 ischemic colitis, to diagnose and manage

21 constipation and complications of constipation, as

22 well as acceptance of responsibilities that include

215

1 education, completing the patient-physician

2 agreement that I\'ve just described, reporting

3 serious adverse events, and affixing stickers to

4 prescriptions. In a while I\'ll share feedback that

5 we\'ve received from physicians relative to the

6 impact of this process on their practice.

7 The prescribing kit for Lotronex that the

8 enrolled prescriber gets contains the key steps

9 card that we\'ve just discussed, prescribing

10 information, medication guides, patient-physician

11 agreement forms, the prescribing program stickers,

12 and the patient follow-up survey pre-enrollment

13 cards.

14 These are some of the steps that I\'ve

15 already described on the key steps card, but,

16 again, there are a couple of things I\'d like you to

17 note. First of all, this is what\'s in the retail

18 pack that the patient receives. It\'s a box that

19 contains 30 tablets, a package insert, a medication

20 guide, and the patient survey card. I have to

21 remind you that no refills are allowed currently

22 for Lotronex. All prescriptions have to be

216

1 original, and all prescriptions have to have an

2 affixed sticker. There is no faxing, no electronic

3 transmission of prescriptions for Lotronex. Those

4 are not allowed.

5 In the event that a physician uses up the

6 supplies in their initial kit, they can call the

7 coordinating center for the PPL, and that

8 coordinating center will check their name against

9 the list of enrolled prescribers, and if they\'re on

10 that list, they\'ll be sent a refill kit.

11 In the next portion of my presentation,

12 I\'m going to address the educational program that

13 was developed to support the introduction of

14 Lotronex.

15 The educational program for physicians is

16 anchored by these two modules: Lotronex Tablets:

17 Understanding the Risks and Benefits, and Current

18 Thinking about IBS: An Educational Review on

19 Irritable Bowel Syndrome.

20 In addition to that, 345,000 \"Dear Doctor\"

21 letters were mailed at the time of product

22 reintroduction, and we\'ve put a reminder program in

217

1 place that I\'ll discuss with you in a moment that

2 provides additional access to key educational

3 messages for physicians.

4 For the patient, education consists of the

5 medication guide, which, again, they can get from

6 two sources. They can get that from the physician,

7 and it\'s also included in product packaging.

8 Physician counseling and the requirement

9 to sign the patient-physician agreement further

10 reinforces the key product messages contained in

11 the medication guide.

12 On the pharmacist level, at the time of

13 product reintroduction 113,000 \"Dear Pharmacist\"

14 letters were mailed. Through an initiative that\'s

15 well outside the scope of normal product launch

16 activities, we also had 25,000 outbound telephone

17 calls to pharmacists. Those calls resulted in over

18 12,000 requests for additional information on

19 Lotronex. We were impressed with this, and we

20 think that this clearly indicates the potential

21 power of these types of outreach activities focused

22 at the pharmacist level.

218

1 In addition, we sent an informational

2 piece on Lotronex to the National Board of State

3 Pharmacists to be cascaded into the newsletters of

4 its individual member states. And, finally, as

5 with the physician, reminder letters to pharmacists

6 also provide important information regarding

7 Lotronex.

8 There are a large number of additional

9 educational activities that GSK has implemented to

10 provide further support for the appropriate use of

11 Lotronex. These include a telephone conference

12 series with physicians, speaker programs,

13 informational booths at professional society

14 symposia. There\'s a website, and we have call

15 centers that can answer questions and provide

16 information on the PPL itself. It can provide

17 medical information, and they provide the sources

18 of information to the practitioner and health care

19 community.

20 And, finally, we\'re also providing

21 independent grants for IBS education that\'s

22 delivered at professional society symposia and

219

1 through other communication media. Again, while

2 components of this educational program are

3 obviously targeted towards a prescriber audience,

4 the materials are available to the general health

5 care practitioner community as well.

6 The next element of the RMP that I\'d like

7 to discuss is the reporting and collection of

8 serious adverse events and adverse events of

9 special interest associated with the use of

10 Lotronex. This essentially comprises a safety

11 overview.

12 Again, it\'s important to remember that

13 there are some differences in the conditions under

14 which AEs are reported currently versus the

15 conditions that existed when the product was

16 initially marketed. We currently have a different

17 target population for Lotronex: females with

18 severe diarrhea-predominant IBS, with the

19 qualifiers that I\'ve already discussed. Through

20 our educational program, we believe that we have

21 better-informed patients and physicians. We have

22 an agreement from physicians to report serious

220

1 adverse events, and we have the patient survey,

2 which is proving to be a non-traditional source of

3 AE information, and the way we\'re handling that

4 information will be discussed in just a moment.

5 So what are our sources for adverse

6 events? They consist of the typical spontaneous

7 reports and reports arising from a clinical trials

8 program, but they also include the patient

9 follow-up survey program.

10 The focus of our adverse event reporting

11 is on these diagnoses and outcomes of special

12 interest that were highlight as an area of concern

13 during the initial marketing period, and those

14 include ischemic colitis, mesenteric ischemia,

15 occlusion or infarction, serious constipation,

16 complications of constipation, as well as outcomes

17 of special interest like intestinal or anorectal

18 surgery and death.

19 Adverse events are reported in a typical

20 fashion stipulated by the regulations. We have

21 expedited reporting for serious, unexpected,

22 spontaneous reports, and we also have expedited

221

1 reports for serious, unexpected, and attributable

2 survey and clinical trial reports. But, in

3 addition, we have a special agreement to expedite

4 reports for all adverse events of special interest,

5 regardless of their seriousness or expectedness.

6 The patient survey that we\'ve been

7 discussing a little bit is intended to measure

8 patient knowledge, behavior, and certain RMP

9 process elements. But through the process of

10 either completing these forms in writing or over

11 the phone, patients occasionally report adverse

12 events. As part of the continual process of RMP

13 evaluation and revision, we have developed a system

14 for processing this adverse event information

15 arising from the survey. To maintain patient

16 confidentiality within the survey, Research

17 Triangle Institute de-identifies the information on

18 the adverse event report and forwards it to GSK.

19 The GSK pharmacovigilance staff assess these

20 reports for seriousness as well as special interest

21 diagnoses.

22 For those cases assessed as serious or

222

1 possibly including diagnoses of special interest,

2 RTI requests patient consent for GSK follow-up with

3 the prescriber. When that consent is granted,

4 GSK\'s Pharmacovigilance Department follows up with

5 the patient\'s prescriber in a fashion similar to

6 that that would be used during a spontaneous

7 reporting context. And, again, adverse events

8 arising from the survey are reported to the FDA as

9 the data warrant.

10 So what is our experience to date? From

11 November 20, 2002, until February 6, 2004, we have

12 approximately 10,000 patients treated with

13 Lotronex, or about 34,000 prescriptions. This has

14 generated 127 post-marketing AEs, which include all

15 spontaneous reports plus all patient survey reports

16 that are deemed to be serious or reports of special

17 interest as I just described on the previous slide.

18 Of the 127 post-marketing reports that

19 we\'ve received, 37 have been considered serious.

20 Seventy-five percent of these 37 reports were GI in

21 origin. What we\'re going to focus on are the 19

22 patients or cases that had diagnoses and outcomes

223

1 of special interest.

2 Of the eight reported ischemic colitis

3 cases, six were medically confirmed. Those same

4 six patients had colonoscopic or biopsy findings

5 consistent with ischemic colitis. Three of the

6 eight cases resulted in hospitalization. All of

7 the cases of ischemic colitis resolved without

8 sequelae. We have no reports of mesenteric

9 ischemia. We have no reports of serious

10 constipation. We do, however, have eight reports

11 of complications of constipation. Three of those

12 eight reports have been medically confirmed. Three

13 involved fecal impaction. Three were associated

14 with intestinal obstruction; there was one ileus,

15 one ulcerated colon. Three of these eight patients

16 were hospitalized, and three patients were managed

17 in the ER only.

18 Four outcomes of special interest have

19 been reported. There is one report of surgery

20 which could not be confirmed by the patient\'s

21 physician. This same patient also had a diagnosis

22 of special interest involving a complication of

224

1 constipation. No deaths attributable to Lotronex

2 have been reported. Of the three deaths that have

3 occurred in patients taking Lotronex, two of those

4 deaths came through the survey process and were

5 reported by family members. One of those was in a

6 patient with cancer, multiple myeloma. The other

7 was in an AIDS patient. The other report that we

8 have is a physician report of a suspected pulmonary

9 embolism in an obese patient with a very complex

10 medical history.

11 So, in summary, with regard to the safety

12 of Lotronex, we have not seen any new safety

13 issues. Recognizing that we have a very low rate

14 of prescribing, we feel that the ischemic colitis

15 and complications of constipation cases that we\'ve

16 seen are similar to those seen during the original

17 marketing period, and we believe that the outcomes

18 associated with those cases are generally less

19 severe. We\'re also pleased by our review of the

20 individual cases that suggest that prompt and

21 appropriate action is being taken by the patient

22 and the physician. What we\'re hoping to achieve

225

1 here is to change patient and physician behavior.

2 We believe, in fact, that is what\'s going on.

3 But the final component of the risk

4 management plan involves the implementation of a

5 plan to evaluate the effectiveness of the Lotronex

6 risk management program. This plan consists of

7 three components: a retrospective study to compare

8 the roster of physicians identified in a general

9 prescription database as prescribers of Lotronex

10 with a roster of physicians enrolled in the PPL,

11 the prescribing program for Lotronex; the patient

12 follow-up survey program that we\'ve mentioned; as

13 well as a longitudinal, claims-based observational

14 study program.

15 First, the physician roster comparison.

16 This is a study to compare physicians prescribing

17 Lotronex within and outside of the prescribing

18 program for Lotronex. The way that\'s accomplished

19 is when the M.D. sends the enrollment form to the

20 database vendor, the vendor sends that enrollment

21 data to GSK. In parallel with that, GSK purchases

22 a prescription data set from MDC Health. Those two

226

1 data sets are compared against each other, and

2 through that process we determine who is

3 prescribing within and outside of the program, and

4 that information is reported to the FDA on a

5 quarterly basis.

6 So what have we learned? These are the

7 data that we have generated to date. As you can

8 see, the number of prescribing program for Lotronex

9 enrolled prescribers has generally remained at or

10 above 80 percent since the program was initiated.

11 We\'re actually quite pleased with this aspect of

12 the RMP. This is the pattern of prescribing by

13 physician specialty for the quarter beginning

14 October 2003, which is representative of our

15 overall experience. Prescribing, as you can see,

16 is being driven primarily by the

17 gastroenterologists. I think what is even more

18 important is, of the prescriptions that have

19 actually been written, 87 percent of those

20 prescriptions had been written within the

21 prescribing program for Lotronex, and we believe

22 that that\'s a very good result.

227

1 In the initial marketing period, 50,000

2 physicians were prescribing Lotronex. Currently,

3 only 5,053 have even enrolled to prescribe Lotronex

4 through the prescribing program for Lotronex. What

5 is particularly disconcerting is the fact that

6 approximately half of the few prescribers who have

7 enrolled have not written a single prescription.

8 This may be a reflection of some of the RMP

9 barriers that I\'m going to discuss in a few

10 moments.

11 And, again, part of the evaluation and

12 revision of an RMP program, we\'ve developed a

13 follow-up system for non-prescribing-program

14 prescribers. When these prescribers are first

15 identified, an enrollment kit is forwarded to the

16 prescriber. In addition, we forward a reminder

17 letter to the prescriber\'s local pharmacy. If

18 there is a second occurrence of prescribing by a

19 particular non-enrolled prescriber, we forward them

20 a reminder letter. If they transgress a third

21 time, we forward a firmer reminder letter to them.

22 Now, the response to this process to date

228

1 is hard to determine, but overall what we\'re seeing

2 is 75 percent of these non-enrolled prescribers

3 comply in some way; 25 percent of them actually

4 enroll and 50 percent of them stop prescribing

5 Lotronex. And, again, this is a very dynamic

6 situation. It can wax and wane over quarters, but,

7 in general, this has been the response to this

8 follow-up process.

9 Let\'s talk about the patient follow-up

10 survey program, which is the next element of the

11 RMP that we\'d like to discuss.

12 The objectives of this program are to

13 assess patient knowledge of the risks and benefit

14 of Lotronex to assess patient behavior in relation

15 to the recommendations in the risk management

16 program and assess the extent to which the patient

17 satisfies the product labeling requirements for

18 treatment with Lotronex.

19 This is a flow diagram of how this survey

20 process works. We receive the pre-enrollment card,

21 and upon receipt of that, an enrollment package is

22 forwarded to the patient, and that starts the

229

1 survey cascade, as you\'ll see on the left-hand

2 side. If we don\'t receive survey forms back from

3 the patient in prescribed time frames, there\'s

4 actually a contact from RTI to the patient to

5 encourage them to complete and return those forms

6 to us.

7 So, to date, we have a 42-percent

8 pre-enrollment rate for all patients who have

9 received a prescription for Lotronex; 55 percent of

10 those were issued by the prescribing physician.

11 And, again, we didn\'t expect that. That\'s a little

12 bit atypical. It\'s much higher than we expected.

13 Most of the patients that we see in the

14 survey are middle-aged patients that are typical of

15 the population that you would expect to be

16 receiving drug and having diarrhea-predominant IBS.

17 Eighteen percent of the patients are over the age

18 of 65 years, and 7 percent of the patients are

19 indeed male. Thirty-six percent of the patients

20 that receive a prescription have actually completed

21 the baseline survey form and entered the survey

22 proper.

230

1 So, again, I think you can see from this

2 table that what we\'ve enrolled in this patient

3 follow-up survey program is a very motivated cohort

4 of patients. Recognizing the grace period for

5 receipt of follow-up questionnaires from patients

6 for whom that follow-up period has expired and

7 questionnaire responses were due, I think you can

8 see that almost all of those responses have been

9 received across time. So, again, it seems like a

10 very motivated cohort of patients, and they\'re

11 doing their homework and sending it in.

12 What have we learned about these patients?

13 Well, this table indicates that there\'s a very high

14 rate of compliance with the key elements of the RMP

15 process and also demonstrates that the discussions

16 and activities that we wanted to have occur are

17 indeed occurring. I think you can see 97 percent

18 of the patients discuss with the doctor how

19 Lotronex can help them; 95 percent discuss the

20 reasons with the doctor why you would discontinue

21 Lotronex; 91 percent have received the medication

22 guide; 87 percent recall that a blue sticker was,

231

1 in fact, put on their prescription. So, again,

2 from a compliance perspective, we\'re pleased at

3 what we see coming through the patient follow-up

4 survey.

5 Importantly, as far as patient

6 appropriateness for treatment is concerned, this

7 table shows that this survey cohort comprises an

8 appropriate patient population for treatment with

9 Lotronex. Ninety percent of these patients met the

10 treatment and severity criteria. And, again, if

11 you look at the individual criteria for treatment,

12 95 percent have diarrhea; 98 percent had IBS for

13 more than six months, the chronicity that we were

14 looking for; 96 percent had previous treatments for

15 IBS; and 97 percent have said they had inadequate

16 relief of symptoms. And, again, we believe that

17 these are clear indicators of patient

18 appropriateness.

19 If you look at the severity conditions

20 that are required\--and, again, I\'ll remind you that

21 only one of these is required to qualify the

22 patient for treatment, not all three. You have

232

1 cramps or bloating present in 87 percent, ranging

2 up to a somewhat or very hard life in almost all of

3 these survey patients. And if you look at the

4 presence of all three severity conditions within an

5 individual patient, you see that 80 percent of

6 these patients have what you would describe as

7 very, very severe DIBS. They have all of the

8 severity conditions. And, again, I\'ll remind you

9 that only one was required to qualify a patient for

10 treatment. So I think this is a potential RMP

11 impact issue that we\'re going to come back to at

12 the end of the discussion.

13 The final component of the RMP evaluation

14 is a program of longitudinal claims-based

15 observational studies. The objectives of this

16 program are to describe or characterize patients

17 receiving Lotronex, to describe or characterize

18 compliance with the prescribing program for

19 Lotronex, and to evaluate the incidence of events

20 in patients treated with Lotronex versus an

21 appropriate comparison group.

22 These are three database sources that

233

1 comprise the longitudinal studies. In the

2 aggregate we have approximately 8.5 million covered

3 lives in this program. Again, recognizing that

4 there\'s a lag period of about six months from the

5 prescription to potential data extraction, 121

6 users of Lotronex have been identified through

7 September of last year, the majority of which have

8 come from the Engenics(ph) database. These 121

9 users received 277 dispensings of Lotronex and

10 seemed to fit a pattern consistent with data that\'s

11 been collected from other portions of the RMP; 89

12 percent of the patients are female; 69 of the first

13 dispensings are coming from gastroenterologists.

14 Importantly, this is an RMP process check: 70

15 percent of the patients\' records did contain a

16 signed patient-physician agreement. And,

17 obviously, it probably goes without saying that

18 program viability is being impacted by low product

19 uptake.

20 At this point, I\'d like to take a moment

21 to give you our overall evaluation of the

22 implementation of the risk management program for

234

1 Lotronex.

2 We certainly believe that we have

3 successfully implemented all of the elements of

4 this complex, integrated risk management program.

5 We are pleased by the number of physicians

6 prescribing within the PPL context, but we\'re even

7 more reassured by the fact that the overall number

8 of prescriptions coming out of the PPL is so high

9 at 87 percent. Data from the patient follow-up

10 survey program indicates that the key product use

11 that we wanted to have delivered to the patient by

12 the physician is, in fact, being delivered and that

13 the patients being selected for treatment are

14 appropriate.

15 We believe that patient and physician

16 behavior is consistent with the goals of the RMP.

17 Recognizing once again that we have a very low

18 prescribing rate, we still feel that qualitatively

19 the adverse events and special interests that we

20 have observed are few and the outcomes being

21 observed are generally less severe.

22 We have entered into this process of

235

1 continual RMP evaluation and revision, and through

2 that process we\'ve devised a program for follow-up

3 for non-prescribers. We\'ve revised the patient

4 survey questionnaires to include new questions.

5 And we\'ve developed a reporting paradigm for

6 adverse event information arising from the patient

7 follow-up survey.

8 While we certainly believe that the RMP

9 has been successfully implemented, we also feel

10 that there is still much work to be done to

11 optimize product availability to appropriate

12 patients. For the remainder of the presentation,

13 I\'m going to focus on the key issues that have

14 arisen regarding the impact of the risk management

15 program on product use relative to Lotronex. These

16 issues are certainly instructive in a general sense

17 when one considers the use of these risk management

18 interventions for other products.

19 So the issues that I\'m going to focus on

20 really are impact of the RMP on the practitioner

21 and patient, which can be collectively viewed as

22 potential product access issues, and the impact of

236

1 the RMP on some of its individual components.

2 These are sources of feedback and data

3 that we\'ve been collecting on the RMP. We\'ve done

4 some fairly unique physician- and patient-focused

5 field research. We have information coming out of

6 our clinical trials programs. We have interactions

7 between our sales force members and practitioners.

8 We have information coming into our customer

9 response center. And we have interactions with our

10 key opinion leaders.

11 What are we learning? At the prescriber

12 level, we\'ve received considerable feedback on this

13 attestation process. Physicians are unaccustomed

14 to signing a document like this and feel that

15 somehow there\'s been a unique transfer of liability

16 from GSK to the prescriber. One might wonder if

17 that isn\'t being somehow reflected in the fact that

18 treatment seems to be being reserved right now for

19 patients that only have the most severe

20 presentation of severe diarrhea-predominant IBS.

21 In addition, physicians feel that having to sign an

22 attestation form is an affront to their

237

1 professional training and somehow constitutes an

2 unnecessary duplication of the licensure process.

3 So one of the questions that we\'re dealing with

4 right now is: Is there a less intrusive way to

5 ensure prescribing by appropriate physicians with a

6 focus more on education rather than attestation?

7 As you\'ve already heard this afternoon,

8 we\'ve learned that fulfilling the RMP requirements

9 is time-consuming and falls well outside of the

10 normal clinical practice patterns. There\'s also

11 some uncertainty regarding the origin and purpose

12 of the RMP. Some people believe it\'s an IND study.

13 People genuinely misunderstand the current

14 marketing context for Lotronex. To us, this

15 represents a communication or education challenge

16 that needs to be addressed for Lotronex. But,

17 again, it needs to be proactively considered in the

18 implementation of other RMPs. We need to address

19 that confusion before it occurs.

20 As previously mentioned, physicians have

21 also expressed some confusion about the importance

22 or utility of certain labeling statements like the

238

1 statement that the severe diarrhea-predominant IBS

2 population comprises about 5 percent of the total

3 IBS population. They really don\'t know how to use

4 that information when considering whether or not

5 the patient that they\'re looking at should be

6 treated with Lotronex. So it\'s information that

7 confuses rather than enlightens.

8 From the patient perspective, we\'ve

9 learned that the language in the product labeling

10 tends to frighten the patients rather than inform

11 them. We are getting this message clearly from our

12 field research, but even more importantly, this is

13 a clear message coming out of our clinical trials

14 program, and that\'s a context where we believe that

15 patients typically feel safer receiving medication

16 because of the oversight that they get.

17 In our current clinical trial program, 28

18 percent of the patients who were screened for study

19 inclusion who the physicians believe would

20 otherwise be appropriate for Lotronex therapy

21 refused to participate because, after reading study

22 information that\'s similar to product labeling,

239

1 they stated that they were afraid to take Lotronex.

2 And, again, this is a phenomenon that we don\'t have

3 any precedent for within our GSK clinical research

4 programs.

5 And, finally, there is this requirement to

6 sign a special document, this patient-physician

7 agreement, that is somewhat disconcerting to some

8 potential patients. Again, it\'s something unusual,

9 they don\'t typically have to do it, and it gives

10 them pause.

11 As far as the claims-based observational

12 studies are concerned, again, it\'s obvious that the

13 low physician-patient uptake has had a serious

14 effect on this program. Currently we have 10,000

15 patients and have extracted data from 121. At the

16 current rate of prescribing, where we need 2,000

17 patients to support meaningful analyses, we would

18 need 155,000 patients treated with the drug, and

19 that could take 15 years at the current rate. So,

20 again, this is a problem that we\'re going to have

21 to address as we move forward.

22 Again, you know, we certainly believe that

240

1 we\'ve successfully implemented the RMP for Lotronex

2 and are effectively managing risk. However, we

3 have identified a number of RMP-related issues that

4 may be posing a barrier to access by appropriate

5 patients. And our ultimate goal is to modify the

6 RMP to improve product access for appropriate

7 physicians and patients while continuing to

8 effectively manage the risk.

9 Ten thousand patients have received

10 Lotronex since the product was reintroduced.

11 Current estimates from the literature suggest that

12 the severe DIBS population ranges in size from

13 111,000 to perhaps as high as 2.9 million. It is

14 not 10,000. We will continue to work with the FDA

15 to close this apparent gap between patients who

16 need Lotronex and those who are receiving it.

17 And with that, in the interest of time and

18 out of respect for the mental health of the

19 Advisory Committee, I will stop talking and yield

20 to the podium to Dr. Justice.

21 DR. GROSS: Thank you very much, Dr. Metz.

22 The next speaker is Dr. Robert Justice,

241

1 Director, Division of Gastrointestinal and

2 Coagulation Drug Products, who will give the FDA

3 update on Lotronex.

x DR. JUSTICE: Good afternoon. I would

4

5 like to take a few minutes to discuss our view of

6 the Lotronex update that you\'ve been provided.

7 I will cover six topics: background on

8 the adverse event and marketing situation around

9 the time of withdrawal and on discussions about how

10 to provide access; risk management goals and how

11 they are being met; patient access issues;

12 physician enrollment process issues; labeling and

13 the tension between informing and frightening; and,

14 finally, our conclusions.

15 This slide is taken from a presentation at

16 the April 2002 Joint Advisory Committee meeting and

17 presents data on the number of cases of ischemic

18 colitis, small bowel ischemia, and serious

19 complications associated with\--complications of

20 constipation associated with Lotronex during the

21 period of initial marketing in 2000.

22 For ischemic colitis, there were 18 cases

242

1 in the clinical trials, 84 cases in post-marketing,

2 for a total of 102 cases, with 11 surgeries and two

3 deaths. For serious complications of constipation,

4 there were 11 cases in the clinical trials, 113

5 post-marketing, for a total of 124 cases, with 35

6 surgeries and two deaths.

7 In 2000, there were approximately 534,000

8 prescriptions and 275,000 patients. Off-label uses

9 included diarrhea, inflammatory bowel disease,

10 custodial care, managing nursing home patients, and

11 constipation-phenomenon irritable bowel syndrome.

12 The prescribers at that time were

13 predominantly primary care physicians: 32 percent

14 were general practitioners or family practitioners,

15 24 percent were internists, and 31 percent were

16 gastroenterologists.

17 Given the adverse events of ischemic

18 colitis, small bowel ischemia, and serious

19 complications of constipation, four options were

20 considered: restricted distribution to

21 gastroenterologists only; IND access; suspension of

22 marketing until a hearing before an advisory

243

1 committee; and withdrawal.

2 As you\'ve heard GlaxoSmithKline chose to

3 withdraw the drug from the market in November of

4 2000. In 2001, access became an issue, and

5 approximately 5,000 e-mails from patients were

6 received by the FDA.

7 In 2002, GlaxoSmithKline and the FDA

8 agreed upon a restricted distribution and risk

9 management program, and Lotronex was reintroduced

10 into the market.

11 The Lotronex risk management program

12 includes four goals. The first is enrollment of

13 qualified physicians in a physician prescribing

14 program. A decision was made to allow enrollment

15 of physicians possessing certain qualifications for

16 diagnosing and managing IBS and drug adverse events

17 as opposed to certifying physicians by developing a

18 whole new program of education and certification.

19 Physician attestation of qualifications is allowed,

20 and this is not a precedent for FDA or for

21 physician maintenance of privileges or licensure.

22 Participating physicians must attest that they are

244

1 knowledgeable of the benefits and risks of Lotronex

2 and about the management of IBS and drug adverse

3 events. The attestation and the patient-physician

4 agreement include features of informed consent so

5 that patients and physicians are fully able to

6 decide about the appropriateness of Lotronex

7 treatment.

8 The second goal is the implementation of a

9 program to educate physicians, pharmacists, and

10 patients about the risks and benefits of Lotronex.

11 The third goal is the implementation of a

12 reporting and collection system for serious adverse

13 events.

14 The fourth goal is the implementation of a

15 plan to evaluate the effectiveness of the Lotronex

16 risk management program. We believe that these

17 goals are being achieved.

18 Regarding the issue of patient access,

19 GlaxoSmithKline estimates that there are 185,000

20 women with severe IBS in the U.S.; however, as

21 you\'ve heard, only about 10,000 have tried the

22 drug. Whether additional women will seek treatment

245

1 is unclear. Some will decide not to start Lotronex

2 after discussion of the risks and benefits. Others

3 who start the drug may not continue. In the

4 clinical trials that excluded severe diarrhea

5 patients, those on Lotronex had a 13- to 16-percent

6 increase over placebo in the median percentage of

7 days with urgency control. In the subset of

8 patients with urgency at baseline on five or more

9 days per week, there were 13 to 21 percent more

10 patients on Lotronex compared to placebo, with

11 urgency no more than one day in the last week of

12 the trial.

13 The goal of GlaxoSmithKline and FDA is to

14 ensure access to patients whose

15 diarrhea-predominant IBS is so severe that they

16 will reap the benefits of the drug over its risks

17 and be under the care of qualified physicians. We

18 are working together to try to identify unintended

19 barriers to patient access.

20 Regarding the physician enrollment

21 process, physician responsibilities in the

22 prescribing program must be clear, and the program

246

1 still needs to ensure that only qualified

2 physicians are enrolled. These doctors must attest

3 to their abilities and knowledge and take on

4 responsibilities such as patient counseling,

5 reporting of adverse events, and applying Lotronex

6 blue stickers on prescriptions so pharmacists will

7 know that they\'re enrolled in GSK\'s prescribing

8 plan.

9 Not all physicians may wish to accept

10 these responsibilities or are able to manage the

11 disease and drug adverse events. However,

12 GlaxoSmithKline and FDA are looking at ways to

13 improve the physician enrollment process and are

14 evaluating other possible means of attestation to

15 ensure qualifications. For example, phone-in

16 attestations may be an option as well as the

17 current fax-in forms.

18 As was mentioned, there is a perception of

19 liability transfer to the physician. Perhaps the

20 fact that liability is not being transferred can be

21 made clearer.

22 Regarding the issue of labeling, there\'s a

247

1 tension between describing risks that may be

2 frightening and providing adequate information to

3 allow patients and physicians to make informed

4 decisions. FDA will consider labeling changes that

5 enhance clarity and education. However, any

6 changes in the labeling such as the indications

7 must be supported by clinical trials data on

8 effectiveness and safety. In addition, the

9 labeling must include accurate information on the

10 magnitude and severity of adverse events.

11 In conclusion, we recognize that there is

12 a tension between managing risk, providing access

13 to the drug, ensuring appropriate use, and business

14 considerations. How drugs are used is influenced

15 by many parties in the health care system. We

16 think there may be room for improvements in the

17 risk communication and processes and are working

18 with GlaxoSmithKline on them. Overall, at the

19 present time the risk management program appears to

20 be managing risk and assuring appropriate use.

21 At this point I would like to open it up

22 to committee questions of GlaxoSmithKline, FDA, and

248

1 for further discussion. Thank you.

x DR. GROSS: Thank you, Dr. Justice. 2

3 Are there any questions from the committee

4 members for any of the speakers? Jackie?

5 DR. GARDNER: Two points of clarification,

6 if Dr. Metz could help me. The first is whether

7 there is any restriction on the quantity of drug

8 that can be prescribed. I appreciate that your

9 packages come in 30s, but a prescription for 90 is

10 allowable, for example. Is the quantity

11 restricted?

12 DR. METZ: Right now, what we\'re requiring

13 is a prescription\--what we\'re providing to the

14 patient is a package of 30. It is possible that a

15 physician could prescribe multiples of that. But I

16 don\'t think we have any direct data on whether that

17 is, in fact, happening and on what scale it\'s

18 happening.

19 DR. GARDNER: But it\'s not prescribed by

20 the program.

21 DR. METZ: No.

22 DR. GARDNER: And the second question I

249

1 have relates also to access but to the

2 post-marketing surveillance. Regarding your

3 population-based surveillance, do you know whether

4 this drug is on the formularies of those HMOs?

5 DR. METZ: You\'re going to have to speak

6 to a microphone, Bob.

7 DR. SANDLER: Right now our estimate is

8 that 87 percent of prescriptions are reimbursed in

9 some fashion when covered through managed care. So

10 it may not necessarily be on a formulary, but it

11 will be covered.

12 DR. GROSS: Stephanie?

13 DR. GARDNER: Dr. Metz, I\'m sorry. That

14 doesn\'t answer our question, because if it\'s not on

15 those formularies, you\'re not going to find scrips,

16 and there\'s no point in doing the post-marketing

17 surveillance

18 DR. METZ: Dr. Gurwitz?

19 DR. GURWITZ: My name is Jerry Gurwitz. I

20 represent the HMO research network CERT, the Center

21 for Education and Research on Therapeutics, that is

22 conducting one of the studies, and nine health

250

1 plans are involved in our study, our component of

2 the epidemiology program. In all of the health

3 plans involved in our study, the drug is available.

4 The access to prescribing the drug varies according

5 to the plan. Many of the plans require prior

6 approval for a prescription. But none of the plans

7 forbid prescribing, and all of the plans, if

8 approval is given, will allow it to be prescribed.

9 DR. GROSS: Okay. Stephanie?

10 DR. CRAWFORD: Thank you.

11 Dr. Metz, in slide 46 on patient

12 appropriateness\--this is the one where you have the

13 categories for men and women and overall met

14 treatment and severity criteria for women, 90

15 percent, men, 84. I have actually two questions.

16 My first one is: Why is the men not zero

17 based on the label indications?

18 DR. METZ: Well, there\'s a difference

19 here. It\'s not indicated for use in men, but men

20 that are using it can still meet the criteria for

21 treatment. So there\'s a difference here. You

22 know, the question is: If we had a box in there

251

1 that said women for whom it was\--or patients for

2 whom it was indicated, then you\'d have a number for

3 females, but for men you would have zero because

4 it\'s not indicated for use in men. But now the

5 real question is: Of the men that receive

6 Lotronex, did they have the disease that would have

7 qualified them for treatment for Lotronex? And the

8 answer to that is 84 percent of them did have the

9 disease. Is that\--

10 DR. CRAWFORD: I understood how it was

11 meant. I guess I\'m asking are you\--the second

12 question, which is not so quick, is: You were

13 rather general in some of the things you were

14 alluding to, saying perhaps things from the

15 sponsor\'s perspective could be handled through

16 education, et cetera. Can you be more specific?

17 And as part of that, are you also saying that

18 perhaps the indications should include men or not?

19 DR. METZ: No, again, right now we\'re not

20 considering any change in the indications statement

21 because, as Dr. Justice has suggested, those types

22 of changes are going to require data from

252

1 additional clinical research.

2 I think what we\'re looking at and, again,

3 what we\'re working with the FDA on is looking at

4 the product information, the product labeling, and

5 trying to provide a little more balance, trying to

6 present the information in such a way that it\'s not

7 naturally intimidating or frightening to the

8 patients. So, you know, we\'re looking at making

9 modifications that provide balance and clarity, and

10 I think that\'s the approach that we\'re trying to

11 take as far as the risk management program is

12 concerned.

13 And as far as the attestation process, as

14 Dr. Justice mentioned, we\'re taking a look at that

15 and seeing where the points of tension are between

16 the physician attestation process and see if

17 there\'s another way to address it to take some of

18 the venom out of that, if you will, and make it

19 more acceptable to the practitioner.

20 Again, that\'s an area that we just have to

21 focus on because the feedback that we\'ve gotten

22 from the field indicates that that\'s an issue for

253

1 some of the practitioners.

2 DR. GROSS: You mentioned that 80 percent

3 of the prescribers were in PPL.

4 DR. METZ: Right.

5 DR. GROSS: How did the other 20 percent

6 write for the drug? And why was it honored?

7 DR. METZ: Okay. Well, they can write a

8 prescription for the drug. There is no mechanism

9 that we have to keep them from doing that. But it

10 would be akin to a physician writing an off-label

11 prescription for a product, which they have the

12 right to do.

13 Now, at the pharmacy level, obviously,

14 there is a little bit of tension created because

15 for the pharmacists that are aware of the program,

16 they\'re faced with filling a prescription that

17 doesn\'t have a sticker on it and what they\'re going

18 to do about that.

19 So, again, we\'ve addressed that with some

20 of our follow-up information. We have that

21 follow-up letter that goes to the pharmacist when

22 we\'ve identified non-enrolled prescribers, just

254

1 reminding them that this is the program that\'s in

2 place for Lotronex and, you know, encouraging them

3 to hopefully contact the prescriber and say, you

4 know: Are you enrolled? I got a letter from GSK

5 or from the prescribing program for Lotronex that

6 says there ought to be a sticker on these

7 prescriptions.

8 But, again, we can\'t force that

9 conversation to occur, and what we\'re finding is 13

10 percent of the prescriptions that are written are

11 coming outside of the program.

12 But, again, you know, we have no benchmark

13 against which to judge that, but 87 percent is

14 pretty encouraging to us, frankly. We\'re very

15 relieved because we had no idea what would happen.

16 DR. GROSS: And from the patient\'s point

17 of view, I guess it\'s not possible in the current

18 program, but would it be possible once the patient

19 and the physician work out their agreement to have

20 the patient obtain prescription renewals, let\'s

21 say, for the next two monthly ones, attain them

22 without a visit and maybe just see the physician

255

1 four times a year instead of monthly for

2 prescription renewal?

3 DR. METZ: That\'s an excellent point, and

4 oddly enough, we\'re in some discussion around how

5 to address that issue. Because, again, I think

6 with these risk management programs, you start out

7 in one place, and after you\'ve had some experience

8 with the product being marketed under those types

9 of programs, you use the data to decide where to go

10 next. And I think we feel that maybe the time is

11 right to take a look at this refill procedure and,

12 as you\'ve suggested, make sure that the important

13 conversations occur first early on. But then after

14 that, once the patient is in a \"stable situation,\"

15 perhaps you could provide for refills and, again,

16 reduce the need for those recurrent visits. I

17 think that\'s a very good point.

18 DR. GROSS: Henri?

19 DR. MANASSE: Dr. Metz, I have two

20 questions. One relates to the intense time that it

21 takes both physicians and pharmacists to

22 participate in this program and do the required

256

1 safety net activities. What kind of dialogue has

2 gone on within GSK to deal with the time, cost,

3 financing component of the management of the

4 program? Question number one.

5 Question number two: Have you explored

6 all of the different places and mechanisms by which

7 prescriptions get filled by patients and the fact

8 that all of these different ways probably require

9 different ways of managing the program? I refer

10 specifically to where the patient has a choice in

11 terms of going to pharmacies, both in hospitals and

12 in communities, versus forced mail-order, for

13 example, in some health plans\--my point being,

14 again, and my question relating then to how have

15 you thought about these issues, and are there ways

16 that these can be tinkered with, if you will, to

17 enhance the participation of providers?

18 DR. METZ: Let me try to answer the first

19 question first, as best I can remember it, and that

20 was with regard, if I understand it, to the

21 internal burden with GSK of running this very

22 complex program\--

257

1 DR. MANASSE: It\'s placed on the providers

2 and the time and energy that it takes and the

3 problems of remuneration we heard from one of the

4 speakers today.

5 DR. METZ: Well, you know, again, if I

6 understand the question, we are looking into that

7 issue, and we\'re trying to decide which of these

8 points should be addressed\--you know, what points

9 could be addressed to relieve as much of that

10 burden or tension as possible, while maintaining

11 the integrity of the RMP framework itself. And,

12 you know, it\'s a balancing act, and we\'re into

13 those discussions with the agency, and we\'re going

14 to look for ways to make this less onerous without

15 undermining the integrity of the system that we

16 believe has worked fairly well up to this point.

17 DR. GROSS: Brian\--

18 DR. METZ: Now, there was a second

19 question, and that second question was really have

20 we looked into the other mechanisms or avenues for

21 patients filling prescriptions and whether, in

22 fact, there are any barriers there that we didn\'t

258

1 envision that we should perhaps address moving

2 forward. And, honestly, we have not looked into

3 that right now. We\'d be interested in hearing some

4 views on that because I think that\'s a very

5 important point. And, again, we\'ve been, you know,

6 dealing with this, but I think as we move forward

7 and if we consider some other ways to address the

8 refill phenomenon, that\'s got to come into play.

9 So, again, we\'d be interested in hearing

10 some advice about that.

11 DR. STROM: I have two questions. One is:

12 When we met about this two years ago, one of the

13 ideas of the attestation and the debate about

14 attestation and certification and

15 gastroenterologists, primary care doc, was the goal

16 to have this drug prescribed by a subset of

17 physicians who really knew how to use the drug.

18 And given the numbers you just described about

19 10,000 patients and 5,000 docs, or even 2,500 docs

20 prescribing it, that\'s an average of four patients

21 per physician, which isn\'t very impressive.

22 What proportion of patients are getting

259

1 their prescriptions from physicians who are

2 prescribing it to more than one patient?

3 DR. METZ: I think we have a slide on

4 that. Yes, we\'ve got a bar graph with the numbers

5 of prescriptions. Just a second. We\'ll see if we

6 can find that.

7 But you\'re right, again, if

8 you\--recognizing that no refills are allowed, some

9 of those numbers that you see are original

10 prescriptions for the same patients, so you\'re

11 absolutely right, the number of patients per

12 physicians who do choose to treat is pretty low.

13 DR. STROM: But, if anything, that argues

14 there should be fewer certified physicians rather

15 than more.

16 DR. METZ: Okay. Here we go. Here\'s the

17 prescribing activity, and what we see here, this is

18 total numbers of prescriptions. And, again, it

19 gets hard to put a denominator with that because we

20 don\'t have any refills that are allowed. But,

21 anyway, I think what you can see is in the one to

22 five range, very negligible. There are a few, a

260

1 few more actually, roughly twice as many dedicated

2 prescribers, if you will, that are driving

3 prescriptions beyond six to ten, out to greater

4 than 15 prescriptions. But it\'s a very small

5 cohort.

6 DR. STROM: The second question: As you

7 were talking about, one of the key issues here is

8 mitigate risk, and when dealt with this two years

9 ago, one of the concerning questions, obviously

10 through no fault of anybody, is that there was no

11 way to predict\--let me back up. It appeared that a

12 relatively small subset of patients actually

13 benefited from it. We saw two sets of data

14 indicating only about 10 percent of patients

15 continued the drug long term for a symptomatic

16 drug, and it looks like that\'s what happening again

17 now that the drug is on the market. So there\'s

18 only a small subset of people who get the drug who

19 will benefit. And there were no risk factors that

20 were identified in the data then that could predict

21 who was likely to benefit and who was not.

22 In the same way, the risk of suffering a

261

1 serious event is obviously much less than 10

2 percent, but even in your new experience here with

3 incomplete reporting, it\'s still one in 300

4 patients suffering serious events. And part of the

5 problem is, at least as of two years ago, we

6 couldn\'t predict who would benefit. We also

7 couldn\'t predict who would be hurt. So that the

8 only way to mitigate the risk was to restrict its

9 access and to, in fact, limit it to as few people

10 as possible, because 100 percent of the people who

11 got the drug would be at risk of getting the

12 adverse events, where only roughly 10 percent of

13 the people who got the drug would benefit from the

14 drug.

15 In the interim, where you\'ve got other

16 clinical trials underway and additional experience,

17 are there any more data you could share with us

18 that would give information about predictors of

19 either who is likely to be that 10 percent who

20 benefit or who is likely to be in that one in 300

21 who will suffer serious adverse events?

22 DR. METZ: No, we don\'t have any new

262

1 information. Our clinical trials program is

2 ongoing, and, again, we just simply don\'t have that

3 information available as we sit here today. And,

4 again, you\'re absolutely right, the ischemic

5 colitis we believe is idiosyncratic; therefore, we

6 can\'t predict.

7 However, what we do think that we\'re

8 seeing here is some improvements in the outcomes,

9 and, again, our goal for this risk management

10 program was not based on a target number but was

11 based on changing behavior, prompt recognition and

12 action on behalf of the patient and physician. So

13 that\'s where we are right now.

14 DR. STROM: But just as a follow-up

15 comment, the logic of two years ago, which you\'re

16 describing to me still holds, is if you can\'t

17 predict who\'s going to benefit and you can\'t

18 predict who\'s going to be hurt from it, the only

19 answer is\--we didn\'t want it unavailable because we

20 thought there were people who clearly needed it,

21 but the only alternative was to greatly limit its

22 access as much as possible.

263

1 DR. METZ: Well, again, you know, we feel

2 that with this specified target population, we\'ve

3 got a target population for whom we believe the

4 benefits will outweigh the risk. And we believe

5 it\'s an appropriate target population for

6 treatment, and we believe within this framework

7 that we have developed here, risk can be

8 effectively managed and people can have the

9 opportunity to benefit from Lotronex. And I think

10 that\'s what we\'re trying to provide here is that

11 opportunity. So, you know, we\'ll finish our

12 clinical trials program and hopefully be generating

13 some data that we can share in the future. But we

14 are where we are.

15 DR. GROSS: Robyn has the next question.

16 MS. SHAPIRO: I think this may pick up

17 some of that. As I understand it, then, part of

18 the qualification requirements for the doctor is so

19 that he or she could properly manage in the event

20 of something bad happening. But it\'s not clear to

21 me from your presentation about what you want to do

22 about what you\'ve already put in place to try to

264

1 make that happen. In other words, the perception

2 of the liability transfer I think is ridiculous,

3 and they will always be afraid about that and upset

4 about that. You\'re not going to answer that.

5 Anytime when you want to require qualified

6 people, that\'s an affront, I guess, to licensure

7 and training. But if you believe that that\'s

8 important to be able to pick up\--I don\'t think that

9 any of these issues are significant enough or even

10 credible to go back on the required training thing.

11 DR. METZ: Let me just address that

12 question in two ways. First of all, we\'re not

13 talking about completely walking away from

14 something. What we\'re talking about is trying to

15 modify what seemed to be perhaps the most offensive

16 elements of it. They don\'t like the signature

17 process. So, you know, as Dr. Justice has

18 suggested, is there another process to ensure that

19 they\'re qualified yet somehow or another doesn\'t

20 serve as an affront to them and recognizes some of

21 those sensitivities. But, actually, I\'d like to

22 let Dr. Sandler address just some comments from his

265

1 perspective on this process and some of these

2 intangibles, if you will.

3 DR. SANDLER: I think that as a physician

4 the program has incredible barriers and I think

5 it\'s hard to convey. And to sit down with a

6 patient and ask them to sign this form I think is

7 insulting for physicians and somewhat demeaning.

8 I think to be able to give the patient an

9 information sheet and to sit down with them and say

10 if you get constipation, stop the drug and call me,

11 if you get bad abdominal pain, stop the drug and

12 call me, that permits me to educate that patient,

13 just the way I do with every other patient. This

14 program becomes special, and by doing that we set

15 up barriers. And we\'re denying access to a drug

16 that helps a lot of people. Dr. Stronk (ph), whom

17 I admire a lot, said that everybody has a risk but

18 nobody has a benefit. Well, going into it, the

19 probability is everybody has a chance to benefit

20 and everybody has a chance to risk. We can\'t

21 predict.

22 MS. SHAPIRO: But you\'re talking about

266

1 what was going to be my second point. My first

2 point is: Do we do away with the required

3 qualifications attestation? And that\'s different

4 than the agreement and the time that it takes to do

5 that. But let me just talk about that, too, and

6 then you can come in on both.

7 One of the points in here is that it must

8 scare patients away because after they go through

9 this process, whether it\'s the signing of the form

10 or hopefully, more importantly, the discussion,

11 some of them don\'t want to take the drug. Well,

12 that\'s informed consent.

13 DR. SANDLER: That\'s fine.

14 MS. SHAPIRO: I mean, that is what the

15 plan is. When they hear things\--

16 DR. SANDLER: What about the patients that

17 are denied the chance to even get the drug because

18 Dr. Wilderlite, he\'s a competent gastroenterologist, and

19 he\'s afraid to use the drug. He\'s afraid

20 of litigation, he\'s afraid of\--and the process is

21 so time-consuming that we\'ve set up barriers so he

22 doesn\'t want to use the drug.

267

1 MS. SHAPIRO: The time-consuming thing

2 just gnaws at me because while I\'m very cognizant

3 of the fact that, particularly today, doctors don\'t

4 want to talk to patients because they don\'t get

5 paid for it, they have to talk to patients, and

6 particularly when they\'re dealing with a risky

7 drug, they have to talk to patients. And our

8 reimbursement system should figure out a way to

9 make it worthwhile. But even before it does, they

10 have to talk to patients.

11 DR. SANDLER: I couldn\'t agree more. So

12 let me answer your question about the attestation

13 and then answer your question about talking to the

14 patients. There\'s probably a way to do this short

15 of a doctor saying, \"I attest that I know how to

16 take care of IBS patients. I know how to take care

17 of ischemic colitis,\" signing a form. I think

18 there are ways that the agency and the sponsor

19 could work to figure that out.

20 MS. SHAPIRO: Without assuring that they

21 do? Without kind of assuring that they really do

22 know how to pick up on the signs and symptoms that

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1 would suggest that a patient\'s in trouble?

2 DR. SANDLER: Well, the system now doesn\'t

3 assure it either. They just sign the form and say

4 they can do it.

5 MS. SHAPIRO: Okay. Well\--

6 DR. SANDLER: There\'s no way to guarantee

7 it. They\'re licensed\--

8 DR. GROSS: I think we\'re going to have to

9 go on to the next question. Alex, do you have a

10 question?

11 DR. KRIST: The question that I was

12 wondering leads a little bit on what Brian was

13 saying. Back in 2002, there were discussions about

14 whether the lower dose, which is now the starting

15 dose, would have less risks of adverse events and

16 whether the risk of adverse event would go down

17 over time or whether most of the risk was when a

18 patient initially started the medication. And I

19 heard you say earlier that we don\'t necessarily

20 have information about who\'s going to be at risk.

21 But part of my question that I\'m wondering is I\'m

22 just interested in the systems in place for

269

1 watching this to see if the lower dose will result

2 in less adverse events and if the risk of adverse

3 events will change over time that a patient is on

4 the medicine.

5 DR. METZ: Well, you know, again, we have

6 a survey that gives us information about the

7 starting dose that patients are taking, and we\'re

8 reassured by looking at that patient survey data

9 that they are indeed starting with that initial

10 dose that we wanted them to use. But I think in a

11 longitudinal way, I\'m sure that we have the ability

12 to monitor across time in the fashion that you\'ve

13 suggested.

14 Elizabeth?

15 And, again, that\'s some information

16 hopefully that we\'ll get out of that ongoing

17 clinical program that was part of our series of

18 Phase IV commitments. You know, that\'s the richest

19 context for that type of information, but I\'ll let

20 Elizabeth\--

21 DR. ANDREWS: We do at every follow-up in

22 the survey, we ask what their current dose is, and

270

1 I don\'t have the exact percentage. I can get it.

2 But a substantial number of people are still on the

3 lower dose. I think your question was something

4 else, which was what is the efficacy at the lower

5 dose.

6 DR. KRIST: The risk across time.

7 DR. METZ: Risk of adverse event on the

8 lower dose and the risk of adverse event over time.

9 And, again, within the survey context, we don\'t

10 have the ability to do that, but we have a very

11 large clinical trials program underway, and those

12 doses are included there, and that is going to be

13 the richest source of that information. But those

14 studies are not completed yet. They are enrolling.

15 DR. GROSS: Curt?

16 DR. FURBERG: We heard quite a bit about

17 the good news, and I want to commend GSK and the

18 agency. We didn\'t hear much about the troubling

19 news, at least two aspects of it. One is the very

20 low participation rate and the patient follow-up

21 survey program, 36 percent responded. I find that

22 very, very troubling. And the other one is the low

271

1 physician reporting rate those serious adverse

2 events. Most of the serious events came from

3 patients.

4 So my question then is to you and your

5 company: What are you doing about it? One thing

6 is to take care of the issues and increase the use,

7 but you also have to get better information, better

8 data for us that we can assess the impact of the

9 program.

10 DR. METZ: Well, as far as, you know, the

11 general perspective on survey participation in this

12 type of context, I think I\'ll let, again, Dr.

13 Andrews address that. But I would tend to disagree

14 with you. You know, given the experience with

15 these types of instruments, we\'re not disheartened

16 by 36 percent.

17 Now, you know, are there other things that

18 we should look at or could look at to change

19 participation rates in future surveys and what are

20 the dynamics around the patient\'s willingness to

21 participate in these surveys? I think these are

22 interesting research questions that I think we need

272

1 to look into as this field evolves. But I\'ll let

2 Dr. Andrews talk\--

3 DR. FURBERG: I think you\'re saying you\'re

4 going to overcome barriers for the other areas.

5 This is an area that also has barriers, as you

6 said, and you need to overcome them. And 36

7 percent is unacceptable, in my view.

8 DR. METZ: I\'ll let Dr. Andrews address

9 that.

10 DR. ANDREWS: Well, 36 percent is\--the

11 issue is whether the patients are representative.

12 Are there biases because of the low participation

13 rate? A 36-percent participation rate doesn\'t

14 necessarily mean that it\'s biased, just as a

15 90-percent participation rate might not mean that

16 it is completely unbiased.

17 What we have looked at in terms of

18 representativeness is we\'ve looked at the age and

19 gender of the patients, geographic region of the

20 prescriptions, and specialty of the physicians, and

21 compared with sales, and we see the patterns are

22 almost identical. So that is\--

273

1 DR. FURBERG: It doesn\'t carry the day at

2 all. I mean, those are fairly insignificant,

3 nonspecific factors. The reason why someone

4 doesn\'t respond could be that they had a bad

5 experience and just said, \"I\'m just out of it.\"

6 And we never find out about it. I think we have an

7 obligation to get as complete information as we can

8 from that part of the program.

9 DR. METZ: Again, that\'s a point well

10 taken. Would we be happier if it was 50 percent or

11 60 percent? We would both be happier.

12 DR. FURBERG: I\'m just suggesting devote

13 some effort to that as well.

14 DR. METZ: Yes, I agree. And the second

15 point that you made, I\'m sorry, Dr. Furberg, was?

16 DR. FURBERG: The physicians, the lower

17 reporting of adverse events. Most of the events

18 are coming from patients, which is unusual. And

19 here are they objecting to it, or is it just\--

20 DR. METZ: Again, I\'m not a physician. I

21 don\'t even play one on TV. But I\'m going to

22 pretend for just a moment.

274

1 You know, when we talk about seriousness,

2 seriousness means different things to different

3 people. To a practitioner, they have a practical

4 definition of seriousness based on the practice of

5 medicine. We have a regulatory definition of

6 seriousness based on the regulations, and perhaps

7 what we haven\'t done a good job of doing is

8 communicating to the practitioner community what it

9 is we want them to report here. We\'ve said you

10 should report, but I\'m not sure that we educated

11 them as far as what to report.

12 DR. GROSS: Our next question is from

13 Maria.

14 DR. ANDREWS: I was going to make the

15 comment, I just wanted to make sure that you are

16 aware that the participation in the survey is

17 voluntary.

18 DR. FURBERG: I understand that.

19 DR. ANDREWS: And so for a voluntary

20 program, the participation rate is actually quite

21 high.

22 DR. FURBERG: I\'d disagree with that,

275

1 DR. SJOGREN: Actually, I\'ll take up that

2 point because where I work, we have several

3 programs in which we do follow-up, and it is across

4 the board 30-percent response. When I looked in

5 the literature, it is 30 percent no matter what.

6 And so we put a follow-up program in place thinking

7 that we were going to do better, and it came out

8 right at 30 percent. So their 36 percent I think

9 falls within the literature, at least from what I

10 recall in my research. It\'s unfortunate, but

11 that\'s us, that\'s human beings. We don\'t like to

12 answer questionnaires; we don\'t like to be followed

13 up. And I think that\'s part of the problem that

14 you\'re facing, and I don\'t think you\'re going to be

15 able to solve it. Just look in the literature and

16 you\'ll see everybody\'s 30 percent. Actually, you

17 are 6 percent above.

18 But the question I wanted to\--or the

19 analysis that I did looking at the data and looking

20 at what the FDA gave me to review is that indeed,

21 although there were patients that has ischemic

22 colitis, all of them resolved. And I think, you

276

1 know, talking as a clinician\--I mean, I wear

2 several hats, but one of them is as a clinician.

3 If things resolve, you don\'t think that they are

4 serious. So that\'s possibly the cause why my

5 colleagues are not reporting to you.

6 Now, if we are in the midst of a clinical

7 trial and you have an ischemic colitis or you have

8 a hospitalization, then you absolutely report as a

9 serious adverse event, but not in the practice of

10 medicine. And these observations are part of the

11 program that you and the FDA put together.

12 The fact that, when I did some rough

13 calculations, you had less than 4 percent adverse

14 events in this program and then, as was pointed out

15 before, the serious adverse events\--by seriousness

16 considering ischemic colitis or some other

17 diagnosis\--was 0.3 percent. So the program is a

18 success in regards to if you apply this medication

19 to the appropriate patient. Then you have a small

20 rate of adverse events in general and not

21 dismissible but a small rate of serious adverse

22 events especially when those serious adverse events

277

1 resolve, because you remove the drug and the

2 patients just can go back to their normal life.

3 So I think, you know, the program that you

4 put together is very good because it proved the

5 point that the appropriate patient that takes the

6 drug, then the risks are minimized.

7 So talking now on the subject of being a

8 clinician and having ten gastroenterologists that

9 work with me and many friends in the community,

10 I\'ve asked in the past if they use Lotronex, and

11 they\'ve all told me no because when they enroll or

12 attempted to enroll, they got boxes and boxes and

13 boxes of paperwork to fill out, that it is

14 horrendous. They\'re very upset, the community of

15 gastroenterologists in general, because there are

16 patients in which, although the disease may not be

17 life-threatening in the sense that they die, it is

18 life-threatening in the sense that the guys cannot

19 get out of the house or have to have an office

20 right next to a bathroom. There are things in

21 gastroenterology that should not escape us, and I

22 think the appropriate patient with this drug should

278

1 have access to it.

2 And I think that the reason for meeting

3 today is to find a way to make it more accessible.

4 Obviously, there were very serious side effects

5 before. There was misunderstanding. There were

6 physicians that perhaps were not following the

7 letter of the intent of the FDA. But those things

8 I think we can work with and make the program more

9 feasible for our patients and for our physicians.

10 DR. METZ: Okay. That\'s our intent. It\'s

11 a continual cycle of evaluation and revision. The

12 advantage that we have right now is at least for a

13 change we have some data that we can deal with as

14 far as the potential impact of these things. And,

15 yes, there are things both good and bad that we

16 need to address as we move forward. But we think

17 it\'s important to continue to make this available

18 to these patients because this disease really

19 insulates them from their activities of daily

20 living.

21 DR. GROSS: Mark, did you have a comment

22 you wanted to make?

279

1 DR. AVIGAN: Right. I just wanted to

2 speak to the observation of the adverse events, the

3 eight cases of ischemic colitis that were basically

4 predicted and pretty much on track with the usage

5 that currently exists. And then the question came

6 up of the distribution of severity of outcomes out

7 of those eight cases.

8 Just to point out that the severe

9 outcomes, the bad clinical actors that were

10 observed in the previous experience, and just to

11 sort of go back to the April 2002 tabulation, so in

12 the post-marketing sort of ratios, out of 84 cases

13 of ischemic colitis, 10 developed surgical outcomes

14 and two were associated with death. So it\'s a

15 subset of the denominator of ischemic colitis. So

16 there may\--there are two possibilities. One is the

17 early observation of ischemic colitis by the

18 clinician, the patient really mitigates the risk

19 for a bad outcome. But the other is that because

20 there were less patients exposed, you don\'t have

21 the full distribution of severity of outcomes

22 because of purely the number that actually got the

280

1 adverse event.

2 I just wanted to point that out, and I was

3 going to ask you if you\--and we already spoke about

4 this a bit, whether you could distinguish between

5 these two because that\'s an important point about

6 your evaluation of the success of the risk

7 management.

8 The second question\--and I just raise it

9 as a question raised before\--you mentioned that of

10 the patients who are currently treated, 80 percent

11 have all three severity criteria. So my

12 question\--and you may not have the answer, but one

13 that should be raised\--is: Of those patients who

14 have frequent and severe pain, which is the first

15 criteria, what percentage of those have frequency

16 urgency or incontinence and/or the third criteria,

17 which is the restriction in lifestyle? In other

18 words, what is actually the\--if you already have

19 one, what is the percentage of all three in order

20 to understand whether you\'re being overly stringent

21 because 80 percent have all three?

22 DR. METZ: Let\'s take the second question

281

1 first. And, Dr. Chang, maybe from your clinical

2 perspective, it\'s the issue that we\'ve discussed

3 around what\'s the likelihood that a patient would

4 have one or two of these things versus having all

5 three. Again, so the issue is, you know, is it

6 fair to hypothesize that this all-three phenomenon

7 does really represent a severe end of the spectrum?

8 Or is there something else going on here?

9 DR. CHANG: There have actually been

10 studies that have shown that if you have pain,

11 that\'s a predictor of impact of quality of life.

12 So I would imagine that the patients with severe

13 irritable bowel syndrome who have severe pain or

14 frequent pain are really going to have number

15 three, which is disability or disturbance of

16 quality of life.

17 There hasn\'t been data on the urgency or

18 fecal incontinence, but you can imagine that you if

19 you have fecal incontinence, you\'re going to have

20 an impact on your quality of life every time you

21 step out the door. But if you\'re going to assess

22 urgency and that with pain, I don\'t think they\'re

282

1 really tied together. I think it\'s tied with

2 discomfort. But with quality of life, you have to

3 only look at a subgroup of IBS patients, which are

4 the diarrhea predominant group. And my guess would

5 be, my impression is that urgency is probably a

6 strong predictor of impact on quality of life in

7 that group of patients.

8 DR. METZ: So it sounds like one and three

9 and two and three go together, but one, two, and

10 three seem to define, you know, a severe end of the

11 spectrum. And I guess as far as\--you know, we\'ve

12 been talking about these diagnoses of special

13 interests and these outcomes, and if I could just

14 have Dr. Lewis make a comment from his perspective,

15 having reviewed this and chairing that Safety

16 Review Committee.

17 DR. LEWIS: Thank you. I chair a Safety

18 Review Committee which we look at all the events of

19 special interest regarding what is reported to be

20 ischemic colitis or constipation complications.

21 And in doing that, it\'s revealing that certainly

22 not all the cases that are filed as that diagnosis

283

1 turn out to be that diagnosis. We spent weeks

2 developing criteria, methodology to put together a

3 true way to diagnose these conditions, which can be

4 done for any adverse event. I mean, we do it for

5 liver disease and other things.

6 And with the cases that we\'ve seen in this

7 program, while many of them were ischemic colitis,

8 several of them were not by the criteria that we

9 use. The first and foremost is somebody has got to

10 look in the colon and see if it even looks like

11 ischemic colitis. People can have rectal bleeding

12 from lots of different reasons, and pain. It could

13 be diverticulitis, for example. So we have

14 criteria that we use.

15 We also then\--what\'s not shown here is we

16 made a causal relationship jump to whether Lotronex

17 might have been responsible for the constipation or

18 the ischemic colitis, and there we have similar

19 criteria and methodology we put together, and only

20 a minority of those cases could we actually say

21 Lotronex seems to be responsible in a probable or a

22 definite manner.

284

1 We still don\'t know why ischemic colitis

2 occurs. The latest epidemiologic studies suggest

3 that it might even be the very far spectrum of what

4 we call irritable bowel syndrome. Remember, we

5 still are learning about this syndrome. We now

6 know it\'s not just with Lotronex. Tegasorade

7 (ph)\--I just got my letter yesterday, the \"Dear

8 Doctor\" letter telling me Tegasorade, which works

9 on a different serotonin receptor, is also

10 associated with the condition. I haven\'t reviewed

11 those cases so I don\'t know how accurate it is.

12 But it is a learning process. I think we\'re

13 learning more about ischemic colitis in the last

14 couple of years and into the future than we ever

15 expected to, and it\'s important that we do that.

16 But just in terms of what we continue to

17 do is try to identify in the future what patients

18 might be at risk, and that will be very important

19 to know so that we might not give certain patients

20 Lotronex or the other drugs as well, because right

21 now we don\'t know. And some form of monitoring is

22 certainly important. An educational program that

285

1 we\'re doing and telling patients what to expect and

2 stopping the drug if they get those symptoms is

3 crucial.

4 DR. GROSS: We have three more questioners

5 before we close for the afternoon: Art, Annette,

6 and Jackie.

7 MR. LEVIN: I\'ve been struggling with how

8 to put this as a question rather than a rant, but

9 first of all, just a few comments and then my

10 question.

11 I assume you\'re aware that in the context

12 of risk management programs, this is risk

13 management lite compared to some others. There are

14 other programs out there that manage the

15 prescribing and dispensing of medications about

16 which we serious questions as to the trade-offs

17 between risks and benefits and a lot of unknowns

18 that manage it much more rigidly than this does.

19 And the notion that we\'re scaring patients away, I

20 mean, I would call your attention to the Med Guide,

21 which I think is mild and doesn\'t even follow the

22 guidelines in having the black box warning at the

286

1 top of the Med Guide. It gets into the risks, I

2 think, in a very general way.

3 That said, it strikes me in listening to

4 your presentation that you\'re looking to the wrong

5 entity to fix the problem, if there is indeed a

6 problem with access, because I think having

7 barriers is what risk management is about. I mean,

8 it sort of defines it.

9 I think we have to recognize that this was

10 an extraordinary case, the first time in history

11 where a drug which had been withdrawn came back on

12 the market and about which there was little known

13 about how to predict risk, and that everybody,

14 including all of the patients that testified that

15 day, seemed willing to ensure this special program

16 in order to have access to the drug.

17 I think the problem is in the prescribing

18 community. I mean, I would ask you to think about

19 where is the problem. And I am somewhat\--I\'ll use

20 the word\--angry that the prescribing community

21 describes a conversation with a patient about

22 benefit and risk and signing their name to a

287

1 page-and-a-quarter attestation as so burdensome

2 that they opt out of this program. And it strikes

3 me that if a physician believes that this is a drug

4 for the patient sitting in front of them, it

5 borders on either misconduct or malpractice not to

6 prescribe that drug because they have to sign an

7 attestation or they have to go into a program which

8 is designed to protect them and to protect the

9 patient from harm.

10 I would argue that your education\--it\'s

11 not a matter of relaxing the risk management

12 program. It\'s a question of educating the

13 prescribing community that the things they\'re

14 afraid of they should not be afraid of, that this

15 program is in place to benefit everybody, and

16 they\'ve got to give it a chance. And maybe if we

17 do learn how to identify patients that are at risk

18 and can be more scientific in selecting who gets

19 this drug and not, we can change the program.

20 To date, there\'s no more data than we\'ve

21 ever had, and I would argue to look to altering the

22 risk management program at this stage is simply

288

1 unacceptable in terms of protecting the public

2 health. And I think really what we should be

3 thinking about is how do we educate the prescriber

4 community to get over their fear and to prescribe

5 this drug when they believe it\'s appropriate for a

6 patient. You guys are very good at educating

7 doctors about your products. You detail very well.

8 And I don\'t know why you can\'t be doing educational

9 detailing to that effect.

10 DR. METZ: On that?

11 MR. LEVIN: Yes.

12 DR. METZ: I didn\'t hear the question so\--

13 \[Laughter.\]

14 VOICE: It qualifies as a rant.

15 DR. METZ: You said you weren\'t going to

16 do that, but I feel\--so do you feel comfortable

17 with my answer then? Thank you. I mean\--

18 DR. GROSS: You can advise physicians

19 there are billing codes for time they spend with a

20 patient, which goes along with Art\'s comment.

21 Annette?

22 DR. STEMHAGEN: I just wanted to confirm,

289

1 in terms of the evaluation criteria, we\'re

2 talking\--I think you have Slides 45 and 46\--about

3 compliance and appropriateness. And very high

4 percentages, everybody looks great. But my

5 understanding is this is only based on that 36

6 percent. So we could be getting the best compliers

7 because they\'re the people feeling motivated, I\'m

8 doing what I should and I\'m going to tell you about

9 it. So understanding all the limitations of survey

10 research, I do it all the time, trying to urge that

11 there be some other mechanisms put in place to

12 evaluate it, to get a higher percent so we can

13 really feel comforted by the percentages.

14 DR. METZ: You know, we put that program

15 in place. That\'s the claims-based epidemiological

16 research which was to look at that at the back end,

17 if you will. But, unfortunately, that aspect of

18 the program is dependent on patient uptake, and

19 right now it\'s not providing any value.

20 DR. STEMHAGEN: Well, I\'m not sure

21 exactly\--in terms of the claims database, there are

22 patients\' self-reported criteria for whether you

290

1 are the right candidate, and that\'s not going to be

2 captured in the claims database. You\'ll have to go

3 back to the records, and that may still not be

4 captured unless the physician specifically asks

5 those questions.

6 So while I agree it\'s another evaluation

7 tool and I think it\'s an important one, I\'m not

8 sure it\'s going to get to all of these questions,

9 either.

10 DR. METZ: You know, again, you\'re right.

11 We have to make some qualitative assumptions about

12 the generalizability of that cohort, you know, to

13 all patients that are receiving Lotronex. And you

14 heard Dr. Andrews speak to the kinds of things that

15 we\'re looking at. But, you know, you can\'t say

16 definitely, you know, these people are

17 representative. We hope that they are, obviously.

18 DR. GROSS: Jackie?

19 DR. GARDNER: In 2002, when we met, one of

20 the discussions was around whether to restrict

21 prescribing to gastroenterologists, and I recall

22 that the Chairman of the Gastroenterology Advisory

291

1 Committee, I think\--I may be ascribing it

2 incorrectly to him\--said that won\'t work because

3 some of us have taken our practice in some other

4 directions\--and I wanted to say liver disease or

5 something that he said. And so that\'s why it

6 wasn\'t restricted to gastroenterologists;

7 therefore, an attestation program was set up with

8 their concurrence because not every gastroenterologist knows

9 guts and so on\--

10 DR. METZ: Is going to look at IBS, right.

11 DR. GARDNER: Right, exactly. And some

12 family practitioners really do.

13 I\'m struck by the difference in this

14 meeting and one we had a couple of months ago

15 around Accutane, in which those prescribers also

16 are severely restricted. They have the same kind

17 of sit-down and sign things. They\'ve got to do

18 pregnancy tests. And we heard a lot about a lot of

19 things at that time, but I didn\'t hear this kind of

20 resistance to getting involved in these programs.

21 So my point is that FDA, with a risk

22 management program that is at least as onerous as

292

1 this one, nonetheless, has somehow managed to find

2 a way to make it more acceptable to the

3 constituency such that, as you know, not only is

4 Accutane tremendously prescribed, more even than we

5 probably would want it to be, perhaps, but it also

6 has four generics and yada, yada. I mean, it\'s not

7 running into this prescribing limitation issue.

8 And so I would suggest that you all look to models

9 within FDA for ways to handle this attestation to

10 make it\--to eliminate this accessibility burden.

11 DR. METZ: And, again, we take the point

12 on perhaps an additional educational focus. We do

13 have a large educational program ongoing, and,

14 again, that\'s another area where one could make

15 modifications and see if you can get some

16 incremental gain out of that. But that\'s a

17 multifactorial problem. Let\'s face it. There are

18 lot of things intersecting here that need to be

19 addressed in a careful, prudent way. And I think

20 that\'s what we\'re about here.

21 DR. GROSS: A special request from

22 Stephanie for the last word.

293

1 DR. CRAWFORD: Thank you, Mr. Chairman.

2 Actually, I was just asking for a word, not

3 necessarily the last.

4 I would like to actually give you a kudo

5 because I\'ve read some of the press that appear

6 today\--that made it appear that the risk management

7 program is negative before we had this meeting. I

8 want to congratulate you on your risk management

9 program for alosetron because many aspects of the

10 program seem to be working.

11 From the information presented, one of the

12 major concerns that this committee expressed two

13 years ago was what appeared to be a very large,

14 inappropriate prescribing. Without a question,

15 that has gone down. I am not convinced that the

16 low numbers of prescriptions of patients is due

17 mainly to unreasonable barriers. It could be that

18 it\'s being prescribed more appropriately and

19 patients are making good, informed decisions. We

20 don\'t know. I know all the discussion we\'ve had

21 from that.

22 That said, however, I am in favor of any

294

1 improvements to the existing programs. Specifically for me,

2 I would be in favor of revising any

3 language that would ensure that the patient

4 agreement forms are clear and informative, and I

5 will just leave it at that, and also possibly

6 extending the supply, dispense. I don\'t want to

7 discuss in terms of what you say, the refill

8 phenomenon as much as I prefer that any changes be

9 in terms of the day supply, because it\'s a huge

10 difference if the physician prescribes a 30-day

11 supply and you can refill it three times versus if

12 he or she prescribes a 90-day supply that you\'re

13 refilling three times. So think in terms of day

14 supply, not refill, if there is any change to that.

15 Thank you, Mr. Chairman.

16 DR. GROSS: A pleasure, Ms. Vice Chairman.

17 \[Laughter.\]

18 DR. GROSS: We began the meeting and we\'ll

19 end the meeting with a thank you to Brian Strom for

20 his invaluable service to the committee. We really

21 appreciate having you as a colleague over the last

22 few years. Would you like to make any comments?

295

1 DR. STROM: Sure. Thank you. I guess I

2 began with a comment, and it\'s only fitting I end

3 with a comment.

4 I just wanted to follow up on a few loose

5 ends and some comments that were made. One is I

6 think compared to Accutane, and in response to

7 Art\'s comment also, there\'s a big difference here

8 in efficacy. And I think to blame it on the

9 physicians and to say the physicians don\'t want to

10 prescribe it\--well, there may be a reason they

11 don\'t want to prescribe it. That\'s something to

12 keep in mind.

13 Second, I think the use of the claims

14 databases make sense. I think it is striking that

15 the proportion of users in the claims databases,

16 given the population numbers we saw, is much lower

17 than the proportion of the general population we\'re

18 seeing. So what it\'s saying is our managed care

19 organizations are saying don\'t use this, even more

20 than the rest of the general public is.

21 Third, Curt talked about 36 percent and

22 the concerns of 36 percent, and there was a lot of

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1 argument about 36 percent. Personally, as an

2 epidemiologist, I would consider that a shockingly

3 low number. On the other hand, I think it\'s

4 important to realize certainly no NIH grant would

5 get funded with anything less than 80 or 90

6 percent. From a marketing study, it\'s high, but

7 it\'s\--I think we heard in the Accutane situation

8 about numbers that were comparable. So I don\'t

9 fault the survey, necessarily. I think in part

10 it\'s the situation. But I think it\'s important

11 that what that means is we\'re missing two-thirds of

12 the people and we\'re missing, as Annette was

13 saying, the two-thirds that are probably most

14 likely to be the problem people. So we can\'t rely

15 on those data because they\'re giving us biased

16 information.

17 The same thing in underreporting.

18 Clearly, there\'s vast underreporting, as you

19 indicated. I don\'t blame the system because docs

20 don\'t report, you know, exactly as you\'re saying.

21 But what it does mean is the rates we\'re looking at

22 here are much lower than the real rates that are

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1 out there.

2 I want to emphasize again that part of the

3 goal here is to create a barrier, and the barrier

4 is working. And so the goal isn\'t to eliminate the

5 barrier.

6 And I\'ll conclude with just a comment. I

7 was one of those who was skeptical of the program

8 two years ago. I think it\'s working. I mean, I am

9 very encouraged in many ways by what we\'re seeing.

10 I wouldn\'t want it changed in major ways. Until we

11 have data on predictors of efficacy or predictors

12 of adverse events, then I think it should be

13 refocused accordingly.

14 DR. GROSS: I\'d like to thank Glaxo and

15 the FDA people for their presentations and input,

16 and once again thank the Advisory Committee members

17 and advisers for their comments. Thank you all.

18 Have a good trip home.

19 \[Whereupon, at 4:29 p.m., the meeting was

20 adjourned.\]

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