# Presentation: 751533

## Interim Report OTIS – North American Isotretinoin Information and Survey Line Toll-Free Number:  1-866-626-6847 Website:  www.otispregnancy.org

- FDA Advisory Committee Meeting
- Accutane Risk Management Program
- Gaithersburg, Maryland
- February 26, 2004

## 

Funded by the Centers for Disease Control and Prevention in partnership with the Association of American Medical Colleges
OTIS Survey Team:
	Principal Investigator:  
		John Carey (University of Utah)
	Coordinator: 
		Julia Robertson (Utah Department of Health) 
	OTIS Development and Review Teams:
		Tina Chambers (University of California San Diego)
		Gideon Koren (Toronto Hospital for Sick Children)
		Sharon Lavigne (University of Connecticut)
		Richard Miller (University of Rochester)
		Janine Polifka (University of Washington)
		Cynthia Moore (CDC, Technical Monitor)

- Funded by the Centers for Disease Control and Prevention in partnership with the Association of American Medical Colleges
- OTIS Survey Team:
- 	Principal Investigator:
- 		John Carey (University of Utah)
- 	Coordinator:
- 		Julia Robertson (Utah Department of Health)
- 	OTIS Development and Review Teams:
- 		Tina Chambers (University of California San Diego)
- 		Gideon Koren (Toronto Hospital for Sick Children)
- 		Sharon Lavigne (University of Connecticut)
- 		Richard Miller (University of Rochester)
- 		Janine Polifka (University of Washington)
- 		Cynthia Moore (CDC, Technical Monitor)
**	****	**** **

**Acknowledgements**

- North American Isotretinoin Information & Survey Line

##  
Non-profit, North American network of 19 state or regional Teratology Information Services (TIS) 
Provides up-to-date information regarding the effects of drugs and chemicals on the human embryo and fetus via free-of-charge telephone consultations 
Receives approximately 100,000 calls per year--half of the calls received initiated by patients (or the general public), half from health care professionals

- Non-profit, North American network of 19 state or regional Teratology Information Services (TIS)
- Provides up-to-date information regarding the effects of drugs and chemicals on the human embryo and fetus via free-of-charge telephone consultations
- Receives approximately 100,000 calls per year--half of the calls received initiated by patients (or the general public), half from health care professionals

**Organization of Teratology Information Services (OTIS)**

- North American Isotretinoin Information & Survey Line

## 		 
OTIS is organized exclusively 
to stimulate and encourage research, education, and the dissemination of knowledge in the field  of Teratology
to improve the abilities of TIS’s to provide accurate and timely information about prenatal exposures, with the overall objective of  preventing birth defects and improving the public health 

- OTIS is organized exclusively
- to stimulate and encourage research, education, and the dissemination of knowledge in the field  of Teratology
- to improve the abilities of TIS’s to provide accurate and timely information about prenatal exposures, with the overall objective of ** **preventing birth defects and improving the public health

**Organization of Teratology Information Services (OTIS)**

- North American Isotretinoin Information & Survey Line

## 			

Increased regulatory safeguards using the thalidomide S.T.E.P.S. program as a template to include:
Mandatory enrollment and compliance of physicians, pharmacists and patients in the program 
Mandatory participation of patients, prescribing physicians, and pharmacies in a single, independent and uniform registry 
Increased patient accessibility to the use of two reliable forms of contraception
Continued educational activities provided for physicians, pharmacists and patients

**	**
- Increased regulatory safeguards using the thalidomide S.T.E.P.S. program as a template to include:
- Mandatory enrollment and compliance of physicians, pharmacists and patients in the program
- Mandatory participation of patients, prescribing physicians, and pharmacies in a single, independent and uniform registry
- Increased patient accessibility to the use of two reliable forms of contraception
- Continued educational activities provided for physicians, pharmacists and patients

**OTIS Recommendations       for Use of Isotretinoin, 2002**

- North American Isotretinoin Information & Survey Line

## 	
Availability strictly limited to women who meet the clinical criteria for severe recalcitrant cystic acne
Prescribing strictly limited to dermatologists who have enrolled in and agreed to comply with the S.M.A.R.T. program 
More effective and comprehensive contraceptive counseling   
Toll–free number and website on all packaging for direct access to risk assessment and counseling  
Continued evaluation of the effectiveness of this program and modification if necessary 

- Availability strictly limited to women who meet the clinical criteria for severe recalcitrant cystic acne
- Prescribing strictly limited to dermatologists who have enrolled in and agreed to comply with the S.M.A.R.T. program
- More effective and comprehensive contraceptive counseling
- Toll–free number and website on all packaging for direct access to risk assessment and counseling
- Continued evaluation of the effectiveness of this program and modification if necessary

- The Subcommittee on Oversight and Investigations,
- The Committee on Energy and Commerce,
- United States House of Representative, 12/11/02

**OTIS Recommendations       for Use of Isotretinoin, 2002**

- North American Isotretinoin Information & Survey Line

- http://energycommerce.house.gov/107/hearings/12112002Hearing755

## 	In 2000, the California TIS contributed to a study of 14 women whose pregnancy was inadvertently exposed to isotretinoin, reflecting a failure of the pregnancy prevention program 

- North American Isotretinoin Information & Survey Line

- 	In 2000, the California TIS contributed to a study of 14 women whose pregnancy was inadvertently exposed to isotretinoin, reflecting a failure of the pregnancy prevention program

- (Chambers, C., et al., Accutane-Exposed Pregnancies  – California, 1999.  MMWR 49: 28-31, 2000).

## 		
OTIS Experience with Isotretinoin Exposures 
during Pregnancy, 2001 - 2003

**OTIS Experience with Isotretinoin Exposures **
**during Pregnancy, 2001 - 2003**

| Year | Total # of Isotretinoin Callers | Isotretinoin Exposed Callers   (US) | # of TIS Reporting | Isotretinoin Exposed Callers (Canada) | # of TIS Reporting |
| --- | --- | --- | --- | --- | --- |
| 2003 | 37 | 29 | 11 | 8 | 2 |
| 2002 | 32 | 24 | 16 | 8 | 2 |
| 2001 | 39 | 24 | 20 | 15 | 2 |

- North American Isotretinoin Information & Survey Line

## 				
OTIS Experience with Isotretinoin Exposures 
during Pregnancy, 2001 - 2003

**OTIS Experience with Isotretinoin Exposures **
**during Pregnancy, 2001 - 2003**

| Year | Total # of Isotretinoin Callers | Isotretinoin Exposed Callers   (US) | # of TIS Reporting | Isotretinoin Exposed Callers (Canada) | # of TIS Reporting |
| --- | --- | --- | --- | --- | --- |
| 2003 | 37 | 29 | 11 | 8 | 2 |
| 2002 | 32 | 24 | 16 | 8 | 2 |
| 2001 | 39 | 24 | 20 | 15 | 2 |

- North American Isotretinoin Information & Survey Line

##  
Enrollment 
	Women who called a TIS about an isotretinoin exposure during pregnancy; enrolling through Sept. 2004
Methods
  	Detailed, structured interview by a research specialist; participant followed until the outcome is known
Study Objective
	To identify barriers to the successful implementation of the components of the  pregnancy risk management  program

- Enrollment
- 	Women who called a TIS about an isotretinoin exposure during pregnancy; enrolling through Sept. 2004
- Methods
-   	Detailed, structured interview by a research specialist; participant followed until the outcome is known
- Study Objective
- 	To identify barriers to the successful implementation of the components of the  pregnancy risk management  program

**OTIS Isotretinoin Survey**

- North American Isotretinoin Information & Survey Line

## 		
Goals of the S.M.A.R.T. Program 
To prevent pregnancy in women who are taking isotretinoin
To prevent embryonic exposure to isotretinoin in women who are already pregnant
Case histories from the OTIS survey

- Goals of the S.M.A.R.T. Program
- To prevent pregnancy in women who are taking isotretinoin
- To prevent embryonic exposure to isotretinoin in women who are already pregnant
- Case histories from the OTIS survey

**OTIS Isotretinoin Survey: Assessing the Goals**

- North American Isotretinoin Information & Survey Line

##         
Goal: To prevent pregnancy in women who are taking isotretinoin 
Ms. A., 30’s, reported taking isotretinoin samples  
Exposure during weeks 3 to 7 of gestation
Birth control method discontinued one month prior to starting isotretinoin and misinterpreted OB-GYN’s statement about ability to conceive afterwards 
Prescribing dermatologist did not order pregnancy tests or confirm two forms of contraception 
Pregnancy continuing; fetal status unknown  

**Goal: **To prevent pregnancy in women who are taking isotretinoin** **
- Ms. A., 30’s, reported taking isotretinoin samples
- Exposure during weeks 3 to 7 of gestation
- Birth control method discontinued one month prior to starting isotretinoin and misinterpreted OB-GYN’s statement about ability to conceive afterwards
- Prescribing dermatologist did not order pregnancy tests or confirm two forms of contraception
- Pregnancy continuing; fetal status unknown
**	**

**Case History Pregnancy Exposure**

- North American Isotretinoin Information & Survey Line

##              
Goal: To prevent embryonic exposure to isotretinoin in women who are already pregnant
Ms. Z., teenager, reported taking isotretinoin 
Exposure during weeks 5 to 6 of gestation
Denied possibility of pregnancy to dermatologist despite positive pregnancy test
Given prescription by dermatologist without additional pregnancy testing
Pregnancy continuing; fetal status unknown   

**Goal: **To prevent embryonic exposure to isotretinoin in women who are already pregnant
- Ms. Z., teenager, reported taking isotretinoin
- Exposure during weeks 5 to 6 of gestation
- Denied possibility of pregnancy to dermatologist despite positive pregnancy test
- Given prescription by dermatologist without additional pregnancy testing
- Pregnancy continuing; fetal status unknown
**	**

- North American Isotretinoin Information & Survey Line

**Case History Pregnancy Exposure**

## 
Case histories illustrate several missed opportunities for prevention of exposure to isotretinoin during pregnancy
Errors arise from multiple sources such as  miscommunication between the  health care provider and patient, misinterpretation of information by the health care provider, and denial of risk by the patient  
Lack of adherence to required components of the risk management program removed safeguards that might have prevented these exposures

- Case histories illustrate several missed opportunities for prevention of exposure to isotretinoin during pregnancy
- Errors arise from multiple sources such as  miscommunication between the  health care provider and patient, misinterpretation of information by the health care provider, and denial of risk by the patient
- Lack of adherence to required components of the risk management program removed safeguards that might have prevented these exposures

**Case History Summary**

- North American Isotretinoin Information & Survey Line

## Enrollment
United States	11 women  (Apr. 2003 -  Feb. 2004)
Canada		12 women  (Feb. 2001 -	 Feb. 2004)			 
Key differences in isotretinoin risk management programs in the United States and Canada 
United States	S.M.A.R.T. program begun Apr. 2002
Canada		P.P.P. continued 	

- United States	11 women  (Apr. 2003 -  Feb. 2004)
- Canada		12 women  (Feb. 2001 -	 Feb. 2004)
- Key differences in isotretinoin risk management programs in the United States and Canada
- United States	S.M.A.R.T. program begun Apr. 2002
- Canada		P.P.P. continued

**OTIS Isotretinoin Survey**
**Interim Results**

- North American Isotretinoin Information & Survey Line

## 
In response to several questions about use of isotretinoin, survey participants:
Described their skin problem as cystic or nodular acne  
		  S.M.A.R.T. (36%)		P.P.P. (33%)
Recalled that their doctor had diagnosed their condition as cystic or nodular acne    
		  S.M.A.R.T. (20%)		P.P.P. (9%) 
Recalled treatment with oral antibiotics before isotretinoin was prescribed  
		  S.M.A.R.T. (82%)		P.P.P. (57%) 

- In response to several questions about use of isotretinoin, survey participants:
- Described their skin problem as cystic or nodular acne
- 		  S.M.A.R.T. (36%)		P.P.P. (33%)
- Recalled that their doctor had diagnosed their condition as cystic or nodular acne
- 		  S.M.A.R.T. (20%)		P.P.P. (9%)
- Recalled treatment with oral antibiotics before isotretinoin was prescribed
- 		  S.M.A.R.T. (82%)		P.P.P. (57%)

**Use of Isotretinoin**
**Interim Results**

- North American Isotretinoin Information & Survey Line

## 
Women must have two negative pregnancy tests before receiving a prescription 
Women must use two forms of birth control simultaneously, starting one month before receiving a prescription 
Women must receive a pregnancy test each month before refilling their prescription
Pharmacists must only fill prescriptions that bear a yellow qualification sticker

- Women must have two negative pregnancy tests before receiving a prescription
- Women must use two forms of birth control simultaneously, starting one month before receiving a prescription
- Women must receive a pregnancy test each month before refilling their prescription
- Pharmacists must only fill prescriptions that bear a yellow qualification sticker

**S.M.A.R.T.  Elements**

- North American Isotretinoin Information & Survey Line

##  
Women must have two negative pregnancy tests before receiving a prescription

	RESPONSES FROM OTIS SURVEY: 
	Women reporting that they had a second pregnancy test during their menstrual period before beginning isotretinoin:
		  S.M.A.R.T. (27%)		P.P.P. (33%)

	CONCLUSION:
	For the S.M.A.R.T. program, it appears that 73% of women surveyed were not screened using two pregnancy tests as required

- Women must have two negative pregnancy tests before receiving a prescription
- 	RESPONSES FROM OTIS SURVEY:
- 	Women reporting that they had a second pregnancy test during their menstrual period before beginning isotretinoin:
- 		  S.M.A.R.T. (27%)		P.P.P. (33%)
- 	CONCLUSION:
- 	For the S.M.A.R.T. program, it appears that 73% of women surveyed were not screened using two pregnancy tests as required

**S.M.A.R.T.  Elements – 1**
** ****Interim Results**

- North American Isotretinoin Information & Survey Line

##  
Women must use two forms of birth control simultaneously, starting one month before receiving a prescription

	RESPONSES FROM OTIS SURVEY: 
	Women surveyed who said they were using two forms of birth control:

		  S.M.A.R.T. (36%)	 	P.P.P. (8%)

	CONCLUSION:
	64% of the women surveyed indicated they were not following the S.M.A.R.T. requirement to use two forms of birth control

- Women must use two forms of birth control simultaneously, starting one month before receiving a prescription
- 	RESPONSES FROM OTIS SURVEY:
- 	Women surveyed who said they were using two forms of birth control:
- 		  S.M.A.R.T. (36%)	 	P.P.P. (8%)
- 	CONCLUSION:
- 	64% of the women surveyed indicated they were not following the S.M.A.R.T. requirement to use two forms of birth control

- North American Isotretinoin Information & Survey Line

**S.M.A.R.T.  Elements – 2**
** ****Interim Results**

## 
Women must receive a pregnancy test each month before refilling their prescription

	RESPONSES FROM OTIS SURVEY: 
	Women in the study reporting that they had  monthly pregnancy testing during the course of therapy: 

		  S.M.A.R.T. (36%)		 P.P.P. (83%)

	CONCLUSION:
	For the S.M.A.R.T program, it appears that 64% of women were not screened for pregnancy monthly as required

- Women must receive a pregnancy test each month before refilling their prescription
- 	RESPONSES FROM OTIS SURVEY:
- 	Women in the study reporting that they had  monthly pregnancy testing during the course of therapy:*** ***
- 		  S.M.A.R.T. (36%)		 P.P.P. (83%)
- 	CONCLUSION:
- 	For the S.M.A.R.T program, it appears that 64% of women were not screened for pregnancy monthly as required

- North American Isotretinoin Information & Survey Line

**S.M.A.R.T.  Elements – 3**
** ****Interim Results**

## 
Pharmacists must only fill prescriptions that bear a yellow qualification sticker

	RESPONSES FROM OTIS SURVEY: 
	U.S. women who recalled seeing a yellow sticker on the prescription they took to the pharmacy:

		S.M.A.R.T. (30%)	

	CONCLUSION:
	For more than two-thirds of the women surveyed, there is doubt about compliance with use of the S.M.A.R.T. program yellow qualification sticker

- Pharmacists must only fill prescriptions that bear a yellow qualification sticker
- 	RESPONSES FROM OTIS SURVEY:
- 	U.S. women who recalled seeing a yellow sticker on the prescription they took to the pharmacy:
- 		S.M.A.R.T. (30%)
- 	CONCLUSION:
- 	For more than two-thirds of the women surveyed, there is doubt about compliance with use of the S.M.A.R.T. program yellow qualification sticker

- North American Isotretinoin Information & Survey Line

**S.M.A.R.T.  Elements – 4**
** ****Interim Results**

## 
In response to participation in any of the manufacturers’ surveys, for the U.S. and Canada combined
13% of women surveyed reported that they had participated in the Accutane Survey
65% reported that they did not participate in any of the manufacturers’ surveys
18% did not know if they had participated

- In response to participation in any of the manufacturers’ surveys, for the U.S. and Canada combined
- 13% of women surveyed reported that they had participated in the Accutane Survey
- 65% reported that they did not participate in any of the manufacturers’ surveys
- 18% did not know if they had participated

- North American Isotretinoin Information & Survey Line

**Monitoring Compliance  **
** ****Interim Results**

## 
Strengths
OTIS has extensive experience in communicating with women about their reproductive concerns 
Survey used a detailed, structured interview instrument 
Most U.S. interviews were completed within 3 months of exposure and before the status of the fetus was known 
Limitations
Small numbers limit interpretation 
Estimates based on women’s recall of events
Women who call a TIS and agree to participate in a survey might not be representative

- Strengths
- OTIS has extensive experience in communicating with women about their reproductive concerns
- Survey used a detailed, structured interview instrument
- Most U.S. interviews were completed within 3 months of exposure and before the status of the fetus was known
- Limitations
- Small numbers limit interpretation
- Estimates based on women’s recall of events
- Women who call a TIS and agree to participate in a survey might not be representative

**Survey Strengths and Limitations**

- North American Isotretinoin Information & Survey Line

## 
Consistent with U.S. data reported prior to institution of the S.M.A.R.T. program 
Show similar rates of non-compliance in the U.S. with the S.M.A.R.T. program and in Canada with the P.P.P.
Demonstrate that preventable exposures continue to occur due to non-compliance with current  requirements of the  S.M.A.R.T. program 
Provide important qualitative data that may identify risk factors for exposure and help design more effective prevention strategies  

- Consistent with U.S. data reported prior to institution of the S.M.A.R.T. program
- Show similar rates of non-compliance in the U.S. with the S.M.A.R.T. program and in Canada with the P.P.P.
- Demonstrate that preventable exposures continue to occur due to non-compliance with current  requirements of the  S.M.A.R.T. program
- Provide important qualitative data that may identify risk factors for exposure and help design more effective prevention strategies

**Preliminary Conclusions**

- North American Isotretinoin Information & Survey Line

## Interim Report OTIS – North American Isotretinoin Information and Survey Line Toll-Free Number:  1-866-626-6847 Website:  www.otispregnancy.org

- FDA Advisory Committee Meeting
- Accutane Risk Management Program
- Gaithersburg, Maryland
- February 26, 2004

## The Subcommittee on Oversight and Investigations,

- The Committee on Energy and Commerce,
- United States House of Representative, 12/11/02

**OTIS Recommendations       for Use of Isotretinoin, 2002**

- North American Isotretinoin Information & Survey Line

- http://energycommerce.house.gov/107/hearings/12112002Hearing755

**Organization of Teratology Information Services (OTIS)**

- North American Isotretinoin Information & Survey Line