1. 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

2. Funded by the Centers for Disease Control and Prevention in partnership with the Association of American Medical Colleges Funded by the Centers for Disease Control and Prevention in partnership with the Association of American Medical Colleges OTIS Survey Team: 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

3. Non-profit, North American network of 19 state or regional Teratology Information Services (TIS) 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 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 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

4. OTIS is organized exclusively 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

5. Increased regulatory safeguards using the thalidomide S.T.E.P.S. program as a template to include: 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

6. Availability strictly limited to women who meet the clinical criteria for severe recalcitrant cystic acne 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 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 More effective and comprehensive contraceptive counseling Toll–free number and website on all packaging for direct access to risk assessment and 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 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

7. Previous Accutane Research OTIS 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).

8. 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 200337291182 200232241682 2001392420152 North American Isotretinoin Information & Survey Line

9. 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 200337291182 200232241682 2001392420152 North American Isotretinoin Information & Survey Line

10. Enrollment Enrollment Women who called a TIS about an isotretinoin exposure during pregnancy; enrolling through Sept. 2004 Methods Methods Detailed, structured interview by a research specialist; participant followed until the outcome is known Detailed, structured interview by a research specialist; participant followed until the outcome is known Study Objective 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

11. Goals of the S.M.A.R.T. Program 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 Case histories from the OTIS survey OTIS Isotretinoin Survey: Assessing the Goals North American Isotretinoin Information & Survey Line

12. Goal: To prevent pregnancy in women who are taking isotretinoin Goal: To prevent pregnancy in women who are taking isotretinoin Ms. A., 30’s, reported taking isotretinoin samples 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

13. Goal: To prevent embryonic exposure to isotretinoin in women who are already pregnant Goal: To prevent embryonic exposure to isotretinoin in women who are already pregnant Ms. Z., teenager, reported taking isotretinoin 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

14. Case histories illustrate several missed opportunities for prevention of exposure to isotretinoin during pregnancy 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 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 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

15. Enrollment Enrollment –United States11 women (Apr. 2003 - Feb. 2004) –Canada12 women (Feb. 2001 - Feb. 2004) Key differences in isotretinoin risk management programs in the United States and Canada Key differences in isotretinoin risk management programs in the United States and Canada –United StatesS.M.A.R.T. program begun Apr. 2002 –CanadaP.P.P. continued OTIS Isotretinoin Survey Interim Results North American Isotretinoin Information & Survey Line

16. In response to several questions about use of isotretinoin, survey participants: 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%) 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%) 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%) S.M.A.R.T. (82%)P.P.P. (57%) Use of Isotretinoin Interim Results North American Isotretinoin Information & Survey Line

17. Women must have two negative pregnancy tests before receiving a prescription 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 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 Women must receive a pregnancy test each month before refilling their prescription Pharmacists must only fill prescriptions that bear a yellow qualification sticker Pharmacists must only fill prescriptions that bear a yellow qualification sticker S.M.A.R.T. Elements North American Isotretinoin Information & Survey Line

18. Women must have two negative pregnancy tests before receiving a prescription 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%) 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 Interim Results North American Isotretinoin Information & Survey Line

19. Women must use two forms of birth control simultaneously, starting one month before receiving a prescription 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%) 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 Interim Results

20. Women must receive a pregnancy test each month before refilling their prescription 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%) 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 Interim Results

21. Pharmacists must only fill prescriptions that bear a 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 Interim Results

22. In response to participation in any of the manufacturers’ surveys, for the U.S. and Canada combined 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 Interim Results

23. Strengths 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 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

24. Consistent with U.S. data reported prior to institution of the S.M.A.R.T. program 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. 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 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 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

25. 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

26. 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

27. Organization of Teratology Information Services (OTIS) North American Isotretinoin Information & Survey Line