1. Accutane ® Use and Epidemiology John E. La Flore, MD, MSPH Vice President, Drug Safety & Risk Management Hoffmann-La Roche Inc.

2. Topics Accutane use and severe recalcitrant nodular acne Accutane use and severe recalcitrant nodular acne Pregnancies Pregnancies

3. Objectives The increased use of Accutane does not imply increased use outside the indication The increased use of Accutane does not imply increased use outside the indication While use is increasing, pregnancy rates have been declining and numbers of pregnancy reports have remained stable While use is increasing, pregnancy rates have been declining and numbers of pregnancy reports have remained stable The overall pregnancy rate from the Accutane Survey 2.8/1000 is supported by additional data The overall pregnancy rate from the Accutane Survey 2.8/1000 is supported by additional data

4. Reporting of Accutane Use Three sources of data are summarized to generate the estimates of new patients and total prescriptions each month Three sources of data are summarized to generate the estimates of new patients and total prescriptions each month Total retails prescription in the U.S. Total retails prescription in the U.S. 3rd Party payment tracking 3rd Party payment tracking Roche factory shipments Roche factory shipments

5. Estimated Number of Total Patients Using Accutane Number of Patients

6. Accutane Use In order to be counted as an Accutane user in these data, the patient would have: In order to be counted as an Accutane user in these data, the patient would have: A. Been seen by a physician B. Been diagnosed with acne (98%) C. Been prescribed Accutane

7. Data Sources Used to Understand Accutane Use: US National Health And Nutrition Examination Survey (NHANES) 1972-1974 US National Health And Nutrition Examination Survey (NHANES) 1972-1974 –supported by similar more recent, international data Large surveys of physicians Large surveys of physicians Medical utilization data Medical utilization data

8. Accutane Use The NHANES prevalence rate provides quantitative context for the use of Accutane in the treatment of severe recalcitrant nodular acne

9. Accutane Use Daniel, et al, (2000) Daniel, et al, (2000) Kilkenny, et al, (1998) Kilkenny, et al, (1998) Lello, et al, (1995) Lello, et al, (1995) Additional studies or surveys of prevalence since Accutane has been available are consistent with the NHANES point prevalence

10. Comparison of NHANES Prevalence of Severe Acne to Accutane Utilization in 1998

11. Females Have More Visits Than Males NHAMCS Age (Years)Female ThousandsMale Thousands (%)(%) *Value corrected from Briefing Document <201273 (51)1217 (49)  202015 (78)584 (22) All ages3288 (65)1801 (35) *

12. Treatment Visits Less than 5% of female patients receive Accutane at their first visit to the dermatologist Less than 5% of female patients receive Accutane at their first visit to the dermatologist Female patients are 3.5 times more likely to receive antibiotics than Accutane at a visit Female patients are 3.5 times more likely to receive antibiotics than Accutane at a visit Female Accutane patients are on average 5 years older than male patients Female Accutane patients are on average 5 years older than male patients NHAMCS

13. Prescription Patterns for Accutane Severe acne patients are seen on average 9 times per year Severe acne patients are seen on average 9 times per year 56% of patients with severe acne are treated with Accutane by the dermatologist 56% of patients with severe acne are treated with Accutane by the dermatologist Dermatologists use variety of medications before prescribing Accutane Dermatologists use variety of medications before prescribing Accutane Physicians prescribe Accutane in small percentage of patients with less severe acne Physicians prescribe Accutane in small percentage of patients with less severe acne Market Measures Inc.

14. Accutane Use The increased use of Accutane does not imply increased use outside the indication The increased use of Accutane does not imply increased use outside the indication

15. Number of Reported Pregnancies 1982- Present by Year of Therapy (US) Accutane Survey Reported Pregnancies Year Spontaneous Reports Accutane Survey Date Unknown Note: Cumulative data cut-off date of March 31, 2000; data were submitted to FDA in the 2nd Accutane Quarterly Report for 2000.

16. Reports of Pregnancy Solicited reports of pregnancies are collected from a defined denominator from the Accutane Survey by the Slone Epidemiology Unit Solicited reports of pregnancies are collected from a defined denominator from the Accutane Survey by the Slone Epidemiology Unit –This generates the pregnancy rate Spontaneous reports of pregnancies are received by Spontaneous reports of pregnancies are received by –Roche –FDA –CDC

17. Analysis of Adverse Events and Pregnancies Associated with Accutane Therapy Per 1000 Patients

18. Does the Age of Patients in the Accutane Survey Represent the User Population? Age proportionality in Accutane Survey compared to Accutane users has remained consistent Age proportionality in Accutane Survey compared to Accutane users has remained consistent Proportional distribution of age in the Accutane Survey is similar to Accutane users except for: Proportional distribution of age in the Accutane Survey is similar to Accutane users except for: –Overrepresentation in age 20-29 years old –Underrepresentation in age > 40 years old

19. Frequency and Incidence Rate of Pregnancy Among Female Accutane Users * Rate adjusted for median of 140-day courses ** Median duration of therapy was approximately 140-day courses.

20. Frequency and Incidence Rate of Pregnancy Among Female Accutane Users ** Median duration of therapy was approximately 140-day courses.

21. Summary The overall pregnancy rate from the Accutane Survey 2.8/1000 The overall pregnancy rate from the Accutane Survey 2.8/1000 Supported by additional supporting evidence Supported by additional supporting evidence Declining since the initiation of Pregnancy Prevention Plan Declining since the initiation of Pregnancy Prevention Plan

22. Conclusion The evidence presented indicates that for every 1000 women treated with Accutane, pregnancy has not occurred in 997. The evidence presented indicates that for every 1000 women treated with Accutane, pregnancy has not occurred in 997.