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

1. Interim Report OTIS – North American Isotretinoin Information and Survey Line Toll-Free Number: 1-866-626-6847Website: www.otispregnancy.org FDA Advisory Committee Meeting Accutane Risk Management Program Gaithersburg, Maryland February 26, 2004

2. North American Isotretinoin Information & Survey Line Acknowledgements • 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)

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

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

5. North American Isotretinoin Information & Survey Line OTIS Recommendations for Use of Isotretinoin, 2002 • 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

6. North American Isotretinoin Information & Survey Line OTIS Recommendations for Use of Isotretinoin, 2002 • 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 http://energycommerce.house.gov/107/hearings/12112002Hearing755

7. North American Isotretinoin Information & Survey Line Previous Accutane Research OTIS 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. North American Isotretinoin Information & Survey Line OTIS Experience with Isotretinoin Exposures during Pregnancy, 2001 - 2003

9. North American Isotretinoin Information & Survey Line OTIS Experience with Isotretinoin Exposures during Pregnancy, 2001 - 2003

10. North American Isotretinoin Information & Survey Line OTIS Isotretinoin Survey • 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

11. North American Isotretinoin Information & Survey Line OTIS Isotretinoin Survey: Assessing the Goals • 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

12. North American Isotretinoin Information & Survey Line Case History Pregnancy Exposure • 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

13. North American Isotretinoin Information & Survey Line Case History Pregnancy Exposure • 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

14. North American Isotretinoin Information & Survey Line Case History Summary • 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

15. North American Isotretinoin Information & Survey Line OTIS Isotretinoin Survey Interim Results • 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

16. North American Isotretinoin Information & Survey Line Use of Isotretinoin Interim Results • 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%)

17. North American Isotretinoin Information & Survey Line S.M.A.R.T. Elements • 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

18. North American Isotretinoin Information & Survey Line S.M.A.R.T. Elements – 1 Interim Results • 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

19. North American Isotretinoin Information & Survey Line S.M.A.R.T. Elements – 2 Interim Results • 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

20. North American Isotretinoin Information & Survey Line S.M.A.R.T. Elements – 3 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

21. North American Isotretinoin Information & Survey Line S.M.A.R.T. Elements – 4 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

22. North American Isotretinoin Information & Survey Line Monitoring Compliance 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

23. North American Isotretinoin Information & Survey Line Survey Strengths and Limitations • 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

24. North American Isotretinoin Information & Survey Line Preliminary Conclusions • 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

25. Interim Report OTIS – North American Isotretinoin Information and Survey Line Toll-Free Number: 1-866-626-6847Website: www.otispregnancy.org FDA Advisory Committee Meeting Accutane Risk Management Program Gaithersburg, Maryland February 26, 2004

26. North American Isotretinoin Information & Survey Line OTIS Recommendations for Use of Isotretinoin, 2002 The Subcommittee on Oversight and Investigations, The Committee on Energy and Commerce, United States House of Representative, 12/11/02 http://energycommerce.house.gov/107/hearings/12112002Hearing755

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