1. Epidemiology Center Isotretinoin Survey Allen A. Mitchell, MD Carla M. Van Bennekom, RN, MPH Slone Epidemiology Center At Boston University For presentation at FDA Advisory Committee Meeting February 26,-27, 2004

2. Epidemiology Center Isotretinoin Survey Survey extends design SEC developed in 1989 for SEC’s Accutane Survey under Roche sponsorship. Survey extends design SEC developed in 1989 for SEC’s Accutane Survey under Roche sponsorship. SEC conducted the Accutane Survey until 7/03 (n=591,936). SEC conducted the Accutane Survey until 7/03 (n=591,936). SEC has conducted the Isotretinoin Survey since 12/02 (n=8,625). SEC has conducted the Isotretinoin Survey since 12/02 (n=8,625).

3. Epidemiology Center Objectives Assess compliance with pregnancy prevention efforts:  Awareness of the teratogenic risk  Patient and physician behaviors  Pregnancy rate  Pregnancy outcome  Risk factors for pregnancy

4. Epidemiology Center Pregnancy Rate/1000 Person Courses by Enrollment Year

5. Epidemiology Center Isotretinoin Survey Background In 2001, in anticipation of SMART, SEC modified the Survey design and questionnaires with input from Roche and FDA. In 2001, in anticipation of SMART, SEC modified the Survey design and questionnaires with input from Roche and FDA. The data that follow were collected for the generic sponsors, post-SMART, using the modified design and questionnaires. The data that follow were collected for the generic sponsors, post-SMART, using the modified design and questionnaires.

6. Epidemiology Center Isotretinoin Survey Enrollments December 10, 2002 – December 31, 2003

7. Epidemiology Center Isotretinoin Survey

8. Epidemiology Center Isotretinoin Survey Pregnancy Risk Category: DAT1* (n=4,665) Hysterectomy or postmenopausal 5% Not sexually active, using birth control 31% Not sexually active, not using birth control 23% Sexually active, using birth control 39% Sexually active, not using birth control 1% Unknown<1% *Excludes women who had not yet started isotretinoin.

9. Epidemiology Center

10. Isotretinoin Survey R eported Source of Informational Materials Received: DAT1 (n=4,669) Claravis (Barr) 1% Amnesteem (Bertek) 18% Sotret (Ranbaxy) 4% Accutane (Roche) 58% Other Materials 3% >1 of above 6% None9%

11. Epidemiology Center Isotretinoin Survey Report of Receipt of Medication Guide with Most Recent Prescription Filled: DAT1* (n=4,632) Yes92% No2% Not sure 6% *Excludes 37 women with missing information.

12. Epidemiology Center Isotretinoin Survey Information Received on Pregnancy Prevention: DAT1 (n=4,669) % Told to avoid pregnancy 99 Read guide to contraception 80 Read contraceptive knowledge self-assessment 75 Read emergency contraception information 68 Watched video about pregnancy prevention 7

13. Epidemiology Center Isotretinoin Survey Information Received on Isotretinoin/Pregnancy Prevention: DAT1 (n=4,669) % Knew about isotretinoin information telephone line 44 Knew about contraception counseling telephone line 38 Doctor discussed contraception 82 Doctor mentioned emergency contraception 19

14. Epidemiology Center Isotretinoin Survey Report of Consent Forms Signed: DAT1* (n=4,657) Signed 2 consent forms 79% Signed 1 consent form 6% Didn’t sign any consent forms 7% Not sure 8% *Excludes 12 women with missing information.

15. Epidemiology Center Isotretinoin Survey Start of Isotretinoin Treatment Relative to Most Recent Prescription Received We anticipated that many women would switch from Accutane to generic once generic became available. We anticipated that many women would switch from Accutane to generic once generic became available. We also expected that many of these women would enroll in Isotretinoin Survey during treatment prompted by the enrollment form in generic package. We also expected that many of these women would enroll in Isotretinoin Survey during treatment prompted by the enrollment form in generic package. DAT1 Questionnaire was designed to assess compliance at onset of treatment, not during treatment. DAT1 Questionnaire was designed to assess compliance at onset of treatment, not during treatment. Therefore, some questions may be confusing to those enrolling during treatment, and some of their responses may be inaccurate. Therefore, some questions may be confusing to those enrolling during treatment, and some of their responses may be inaccurate.

16. Epidemiology Center Isotretinoin Survey When, in the Past 12 Months, Did Isotretinoin Treatment Begin? Total(n=4669) With most recent prescription (new user) 53% Prior to most recent prescription (prior user) 47%

17. Epidemiology Center Isotretinoin Survey Number of Pregnancy Tests in the 4 Weeks before Starting Isotretinoin* (n=2,294) 1 test 28% 2 tests 41% 3 tests 12% 4 tests 4% 5+ tests 5% No test 9% * Limited to new users

18. Epidemiology Center Isotretinoin Survey Was Pre-Tx Pregnancy Test Properly Timed Relative to Prescription Receipt?* (n=2,321) Before/on Rx receipt 82% After Rx receipt 10% No test 9% * Limited to new users

19. Epidemiology Center Isotretinoin Survey Primary Contraceptive Method among Nonsurgical Contraceptors: DAT1 (n=2,536)

20. Epidemiology Center Isotretinoin Survey Number of Contraceptive Methods Among Women Who Were Sexually Active Since Starting Isotretinoin: DAT1 (n=1,879)

21. Epidemiology Center Qualification Sticker Qualification criteria for female patients are: Must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane. The second pregnancy test (a confirmation test) should be done during the first five days of the menstrual period immediately preceding the beginning of Accutane therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using two effective forms of contraception.) Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated every month prior to the female patient receiving each prescription. Must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane. The second pregnancy test (a confirmation test) should be done during the first five days of the menstrual period immediately preceding the beginning of Accutane therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using two effective forms of contraception.) Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated every month prior to the female patient receiving each prescription. Must have selected and have committed to use of two forms of effective contraception simultaneously, at least one of which must be a primary form, unless absolute abstinence is the chosen method, or patient has undergone a hysterectomy. Patients must use two forms of effective contraception for at least one month prior to initiation of Accutane therapy, during Accutane therapy, and for one month after discontinuing Accutane therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis. Must have selected and have committed to use of two forms of effective contraception simultaneously, at least one of which must be a primary form, unless absolute abstinence is the chosen method, or patient has undergone a hysterectomy. Patients must use two forms of effective contraception for at least one month prior to initiation of Accutane therapy, during Accutane therapy, and for one month after discontinuing Accutane therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.

22. Epidemiology Center Isotretinoin Survey Report of Qualification Sticker on Most Recent Prescription: DAT1* (n=4,638) Sticker on prescription 94% No sticker on prescription 2% Don’t know because someone else obtained and filled prescription 3% Don’t know because didn’t see prescription 1% *Excludes 31 women with missing information.

23. Epidemiology Center Isotretinoin Survey Qualification Sticker vs. Patient-Reported Behaviors* Use of 2 Contraceptive Methods Qualification Sticker 2+ (%) 0-1 (%) (N) YES6832(1783) DNK6040(48) NO4951(41) (N) (1258)(614)(1872) *DAT1 – Sexually active women only; Missing values excluded

24. Epidemiology Center Isotretinoin Survey Qualification Sticker vs. Patient-Reported Behaviors* Pregnancy Testing and Timing Requirements † Qualification Sticker Compliant (%) Noncompliant (%) (N) YES2674(1826) DNK2476(90) NO2773(60) (N) (506)(1470)(1976) *DAT1 – New users who reported having a menstrual period in 4 weeks before starting; Missing values excluded Missing values excluded † Compliant = 2+ properly timed pregnancy tests before starting isotretinoin

25. Epidemiology Center Isotretinoin Survey Qualification Sticker and Medication Guide: DAT2 Qualification sticker on last prescription (n=972)* 96% Received Medication Guide with last prescription (n=975)* 86% *Missing responses excluded

26. Epidemiology Center Isotretinoin Survey Behaviors Prompted by Information in the Medication Guide (n=840 Recipients of Medication Guide, DAT2) Changed contraceptive method 12% Decided not to have sexual intercourse with a male partner while taking isotretinoin 16% Decided to have sexual intercourse with a male partner less frequently while taking isotretinoin 6% Had a pregnancy test while taking isotretinoin 22% Requested more information on isotretinoin 5% Requested more information on contraception 2%

27. Epidemiology Center Isotretinoin Survey Pregnancy Risk Category at DAT1 and DAT2 DAT1(n=4655)DAT2(n=990) Hysterectomy or postmenopausal 5%6% Not sexually active, using birth control 31%25% Not sexually active, not using birth control 23%24% Sexually active, using birth control 39%42% Sexually active, not using birth control 1%1% Unknown<1%1%

28. Epidemiology Center Isotretinoin Survey Number of Pregnancy Tests in the Past 2 Months Reported by Women Still Taking Isotretinoin at DAT2 (n=400) 1 test 12% 2 tests 50% 3 tests 5% 4 tests 10% 5+ tests 9% No test 13%

29. Epidemiology Center Isotretinoin Survey Specialty of Isotretinoin Prescriber (DAT2) (n=990) Dermatologist93% General Practitioner 2% Family Practitioner 3% Gynecologist<1% Internist<1% Pediatrician<1% Other<1% Unknown1%

30. Epidemiology Center Isotretinoin Survey Pregnancies Reported through 12/31/03 Pregnant at start of isotretinoin treatment 2 Became pregnant during treatment 4 Total pregnancies 6 Number completing DAT1 4,669 Number completing DAT2 996