1. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 Isotretinoin Pregnancy Prevention Program Evaluation Prescription Compliance Survey and Patient Surveys Allen Brinker, MD, MS February 26, 2004 Prescription Compliance Survey and Patient Surveys Allen Brinker, MD, MS February 26, 2004

2. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 Isotretinoin Pregnancy Prevention Program Evaluation Collaborators - Cynthia Kornegay, Ph.D. Primary reviewer for prescription compliance survey Parivash Nourjah, Ph.D. Primary analyst for a patient survey dataset supplied by Hoffmann-LaRoche Collaborators - Cynthia Kornegay, Ph.D. Primary reviewer for prescription compliance survey Parivash Nourjah, Ph.D. Primary analyst for a patient survey dataset supplied by Hoffmann-LaRoche

3. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 Isotretinoin Pregnancy Prevention Program Evaluation Order of topics: Prescription Compliance Program (PCS) Patient Survey Order of topics: Prescription Compliance Program (PCS) Patient Survey

4. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 4 Prescription Compliance Survey (PCS) Overview Survey Design Survey Results Methodological Issues –Response Rate –Number of Prescriptions Captured –Participation by Stores Survey Audit –Recruiting Strategy/Response Rate Conclusions Survey Design Survey Results Methodological Issues –Response Rate –Number of Prescriptions Captured –Participation by Stores Survey Audit –Recruiting Strategy/Response Rate Conclusions

5. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 5 PCS Goals Primary Outcome: Compliance with Qualification sticker use Secondary Outcomes: Completeness and correctness of Qualification stickers Inference –presence of a Qualification sticker does not imply adherence to all parts of the current RMP Primary Outcome: Compliance with Qualification sticker use Secondary Outcomes: Completeness and correctness of Qualification stickers Inference –presence of a Qualification sticker does not imply adherence to all parts of the current RMP

6. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 6 PCS Design Retrospective, repeated-measures survey 6,000 selected U.S. pharmacies Stratified, random sample Data collected in March, June, September, and December for 2 years 750 Stores selected for each collection period Stores can only be included once Retrospective, repeated-measures survey 6,000 selected U.S. pharmacies Stratified, random sample Data collected in March, June, September, and December for 2 years 750 Stores selected for each collection period Stores can only be included once

7. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 7 PCS Results High rate of compliance (>90%) across all survey waves for both PCS and audit Results consistent across age, gender, and payer type Some differences across prescription volume and population density –both high volume and rural pharmacies more likely to receive prescriptions with incomplete stickers High rate of compliance (>90%) across all survey waves for both PCS and audit Results consistent across age, gender, and payer type Some differences across prescription volume and population density –both high volume and rural pharmacies more likely to receive prescriptions with incomplete stickers

8. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 8 Methodological Issues Minimum necessary response rate for each wave was 60% of the sample, or 450 stores –response rates ranged from 25% to 59% In December 2002, CVS, Eckerd, Rite Aid, Walgreens and Wal-Mart asked and were removed from the survey pool –33% of stores, or 15,200 –probably represented more than 33% of Rxs Minimum necessary response rate for each wave was 60% of the sample, or 450 stores –response rates ranged from 25% to 59% In December 2002, CVS, Eckerd, Rite Aid, Walgreens and Wal-Mart asked and were removed from the survey pool –33% of stores, or 15,200 –probably represented more than 33% of Rxs

9. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 9 Methodological Issues PCS Prescriptions Captured Number of Prescriptions:EstimatedActual Average no. per QTR2.550.84 Total per QTR1,150268

10. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 10 PCS Audit Recruiting Proposed strategy: random sample of 15% of PCS respondents –does not appear to have been implemented as proposed –consistently high response rates (>20%) recruiting strategy may not be random –utility and/or applicability of audit results is questionable Proposed strategy: random sample of 15% of PCS respondents –does not appear to have been implemented as proposed –consistently high response rates (>20%) recruiting strategy may not be random –utility and/or applicability of audit results is questionable

11. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 11 PCS Overall Conclusions High rate of compliance with Qualification stickers –not the same as high rate of compliance with SMART program in total High rate of compliance with Qualification stickers –not the same as high rate of compliance with SMART program in total

12. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 12 PCS Overall Conclusions Insufficient pharmacy sample size Generalizability compromised –low pharmacy response rate –23% of expected prescriptions captured –five largest U.S. chains dropped out Alternate study designs should be considered for future studies with similar goals Insufficient pharmacy sample size Generalizability compromised –low pharmacy response rate –23% of expected prescriptions captured –five largest U.S. chains dropped out Alternate study designs should be considered for future studies with similar goals

13. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 13 Patient Surveys Overview Purpose of Patient Survey Methods –Limitations Survey Population –Representativeness / Generalizability Results Summary Conclusions Purpose of Patient Survey Methods –Limitations Survey Population –Representativeness / Generalizability Results Summary Conclusions

14. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 14 Patient Survey - Purpose Isotretinoin Patient Surveys –Implemented in 1989 to “assess the compliance of physicians and patients with the Accutane Pregnancy Prevention Program and to identify the rate of pregnancy during treatment with isotretinoin.” Isotretinoin Patient Surveys –Implemented in 1989 to “assess the compliance of physicians and patients with the Accutane Pregnancy Prevention Program and to identify the rate of pregnancy during treatment with isotretinoin.”

15. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 15 Patient Survey - Reports and Analysis Overview FDA data include: –Slone Epidemiology Group Quarterly Reports year prior and continuing in year following –Primary FDA analysis of an Accutane- brand patient survey started in 3 rd QTR following implementation of the current RMP FDA data include: –Slone Epidemiology Group Quarterly Reports year prior and continuing in year following –Primary FDA analysis of an Accutane- brand patient survey started in 3 rd QTR following implementation of the current RMP

16. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 16 Patient Survey - Methods Two versions of survey instrument: –Old survey instrument –no questions on Qualification sticker –no questions related to MedGuide –pregnancy test question limited to whether a pregnancy test was performed Two versions of survey instrument: –Old survey instrument –no questions on Qualification sticker –no questions related to MedGuide –pregnancy test question limited to whether a pregnancy test was performed

17. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 17 Patient Survey - Methods New survey instrument Current RMP-specific questions –Qualification sticker present on Rx ? –date and number of pregnancy tests performed Not introduced until 3 rd QTR following implementation of the current RMP –enrolled ~6,000 participants through the end of first year New survey instrument Current RMP-specific questions –Qualification sticker present on Rx ? –date and number of pregnancy tests performed Not introduced until 3 rd QTR following implementation of the current RMP –enrolled ~6,000 participants through the end of first year

18. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 18 Patient Survey - Methods Selected Limitations Mailed survey –some are surveyed by telephone Follow-up survey –cannot be anonymous Generalizability limited due to –low enrollment rate –voluntary survey participation Mailed survey –some are surveyed by telephone Follow-up survey –cannot be anonymous Generalizability limited due to –low enrollment rate –voluntary survey participation

19. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 19 Patient Survey - Methods Selected Limitations Important issues - continued Measurement errors Recall bias Social desirability bias Poor questionnaire design –complex questions and question skip patterns to be followed Important issues - continued Measurement errors Recall bias Social desirability bias Poor questionnaire design –complex questions and question skip patterns to be followed

20. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 20 Results Survey Population Absolute participation in Isotretinoin Patient Surveys based on FDA models: –16% to 19% in year before current RMP –22% to 26% in the first year current RMP Absolute participation in Isotretinoin Patient Surveys based on FDA models: –16% to 19% in year before current RMP –22% to 26% in the first year current RMP

21. Trends in Enrollment in Isotretinoin Patient Surveys Arrow separates the 4 QTR’s before implementation of the current RMP and the 4 QTR's following its implementation

22. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 22 Results Survey Population

23. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 23 Results Survey Population Prescriber –94% of isotretinoin recipients within Degge/SI cohort indicated prescriber was a dermatologist –80% of recent isotretinoin prescriptions* associated with a dermatologist * Source: IMS Health National Prescription Audit Plus TM (3 Dec 2003) Prescriber –94% of isotretinoin recipients within Degge/SI cohort indicated prescriber was a dermatologist –80% of recent isotretinoin prescriptions* associated with a dermatologist * Source: IMS Health National Prescription Audit Plus TM (3 Dec 2003)

24. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 24 Results - Initiation of Therapy Consent form Analyses of Degge/SI cohort: –76% signed two consent forms (as required) –4% signed only one form –9% reported signing no consent forms –11% were uncertain / did not answer Analyses of Degge/SI cohort: –76% signed two consent forms (as required) –4% signed only one form –9% reported signing no consent forms –11% were uncertain / did not answer

25. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 25 Results - Initiation of Therapy Qualification sticker Analyses of Degge/SI cohort: –92% reported Rx with Qualification Sticker Consistent with findings from the PCS –2.5% reported no sticker –5.5% did not know / did not answer Analyses of Degge/SI cohort: –92% reported Rx with Qualification Sticker Consistent with findings from the PCS –2.5% reported no sticker –5.5% did not know / did not answer

26. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 26 Results - Initiation of Therapy Pregnancy Testing Analyses of apparently fertile, 15-45 year-old participants in Degge/SI cohort: 91% reported at least one pregnancy test 66% reported two tests Performance increased only slightly with restriction to sexually active Performance decreased only slightly with restriction to sexually INactive

27. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 27 Results - Initiation of Therapy Trends in Pregnancy Testing Slone Epi Group Quarterly reports ANY pregnancy testing 77%-85% for year prior to the current RMP 91%-92% in first year of current RMP

28. Results - Initiation of Therapy Trends in ANY Pregnancy Testing in Slone Survey Arrow separates the 4 QTRs before implementation of the current RMP and the 4 QTRs following its implementation

29. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 29 Results - Initiation of Therapy Contraception Practices Analyses of apparently fertile and sexually active women among the Degge/SI cohort: –95.4% reported use of some form of birth control –48.9% reported use of appropriate birth control per the revised RMP one primary and one secondary birth control method Analyses of apparently fertile and sexually active women among the Degge/SI cohort: –95.4% reported use of some form of birth control –48.9% reported use of appropriate birth control per the revised RMP one primary and one secondary birth control method

30. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 30 Results - Initiation of Therapy Sexual Activity - Univariate Focus N Total4596 Sexually active since starting Accutane therapy 1806 Sexually active before but not during Accutane therapy 993 Not sexually active before or during Accutane therapy 1797

31. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 31 Results - Initiation of Therapy Bivariate Analyses Conducted to address the relationship between the presence or absence of a Qualification sticker and any pregnancy testing any birth control

32. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 32 Results - Initiation of Therapy Qualification Sticker and Pregnancy Testing n=4400 NoYes Pregnancy Test Qualification Sticker 90 (90%) 3908 (91%) Yes 10 (10%) 392 (9%) No

33. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 33 Results - Initiation of Therapy Qualification Sticker and Birth Control (any) n=1788 NoYes Any Birth Control Use Qualification Sticker 70 (96%) 1671 (97%) Yes 3 (4%) 44 (3%) No

34. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 34 Results During Therapy Analyses of Degge/SI participants during therapy: –95% report use of a Qualification sticker –81% report monthly pregnancy testing Analyses of Degge/SI participants during therapy: –95% report use of a Qualification sticker –81% report monthly pregnancy testing

35. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 35 Results - During Therapy Trends in Report of Pregnancy Testing Slone Epi Group Quarterly reports ANY pregnancy testing during therapy with isotretinoin ~70% in year prior to revised RMP ~85% in first year of revised RMP Slone Epi Group Quarterly reports ANY pregnancy testing during therapy with isotretinoin ~70% in year prior to revised RMP ~85% in first year of revised RMP

36. Results - During Therapy Trends in ANY Pregnancy Testing in Slone Survey Arrow separates the 4 QTRs before implementation of the current RMP and the 4 QTRs following its implementation

37. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 37 Pregnancy Rate 15 pregnancies were identified among 4277 first-time users within the Degge/Si cohort –pregnancy rate: 3.5/1000 women –the rate is likely an underestimate as it is censored as of the data lock date Similar to that reported for participants in the Slone Survey of Accutane recipients 15 pregnancies were identified among 4277 first-time users within the Degge/Si cohort –pregnancy rate: 3.5/1000 women –the rate is likely an underestimate as it is censored as of the data lock date Similar to that reported for participants in the Slone Survey of Accutane recipients

38. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 38 Addendum Generic Isotretinoin Data Any pregnancy testing prior to initiation: ~90% Two pregnancy tests prior to initiation: ~65% NO birth control among apparently fertile, sexually active respondents: ~3% Any pregnancy testing during therapy: ~82% Any pregnancy testing prior to initiation: ~90% Two pregnancy tests prior to initiation: ~65% NO birth control among apparently fertile, sexually active respondents: ~3% Any pregnancy testing during therapy: ~82%

39. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 39 Overall Summary Isotretinoin-exposed pregnancies continue to occur after implementation of the current RMP Enrollment in isotretinoin patient surveys increased only modestly after implementation of the current RMP Isotretinoin-exposed pregnancies continue to occur after implementation of the current RMP Enrollment in isotretinoin patient surveys increased only modestly after implementation of the current RMP

40. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 40 Overall Summary Despite their wide utilization, Qualification stickers have been issued to patients who have not undergone pregnancy testing

41. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 41 Overall Summary The observed pregnancy rate for the Degge/SI cohort recruited following implementation of the current RMP appears similar to that reported for cohorts recruited before implementation of the current RMP