Safety of Testosterone Transdermal System (TTS) for Treatment of HSDD in Surgically Menopausal Women on Concomitant Estr

1. Safety of Testosterone Transdermal System (TTS) for Treatment of HSDD in Surgically Menopausal Womenon Concomitant Estrogen Lisa M. Soule, MD Division of Reproductive and Urologic Drug Products December 2, 2004

2. Safety Concerns • Risks of testosterone use • Risks of long-term testosterone combined with estrogen

3. Current Recommendations on Estrogen Therapy • FDA Boxed Warning: • Prescribe estrogen and estrogen/progestins “at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman” • American College of Ob-Gyn: • “The lowest effective estrogen dose should be used for the shortest possible time to alleviate symptoms” and use “should be reassessed annually”

4. Adverse Effects of TTS • Likely: • Androgenic adverse effects • Possible: • Impact on cardiac risk factors, e.g., changes in lipids • Speculative: • Increased cardiovascular morbidity • Increased risk of breast cancer

5. Relevance of Study Population to Potential Users • African-Americans under-represented (6%) • More commonly surgically menopausal than Caucasian women • Prevalence of HSDD in this population unknown • 8% of subjects were ≥ 60 years old • Subgroups at higher risk of cardiovascular morbidity under-represented or excluded • African-Americans • Women 60 and older • Women with diabetes and cardiovascular disease

6. Clinical Trial Assessments of Interest • Adverse events related to use and duration of exposure to TTS • Lab data that reflect cardiovascular risk • Lipids • Glucose and Insulin • Fibrinogen • Blood pressure • Weight • Breast cancer

7. Free Testosterone: Percent of Subjects > Upper Limit for Women 18-49 Yrs

8. Bioavailable Testosterone: Percent of Subjects > Upper Limit for Women 18-49 Yrs

9. Study Design Double Blind0-24 Wks Extension53-78 Wks Open Label25-52 Wks TTS N = 696 6 months TTS TTSTTSTTSN = 154 18 months TTS TTS TTSN = 419 12 months TTS Placebo (P)N = 703 0 months TTS P  TTSN = 418 6 months TTS P TTS TTSN = 167 12 months TTS

10. Overall Androgenic AEs by Time on TTS

11. Alopecia by Time on TTS

12. Androgenic AEs and Quartiles of Free Testosterone

13. Androgenic AEs and Quartiles of Free Testosterone

14. Adverse Effects of TTS • Likely: • Androgenic adverse effects • Possible: • Impact on cardiac risk factors, e.g., changes in lipids • Speculative: • Increased cardiovascular morbidity • Increased risk of breast cancer

15. Risks of TTS • Impact on cardiac risk factors • Metabolic syndrome • Independent risk factor for CVD • Diagnosis is based on the following components: • Plasma fasting glucose > 110 mg/dL (or diagnosis of diabetes or hyperinsulinemia) • Dyslipidemia: TG > 151 mg/dL or HDL < 39 mg/dL • Hypertension, variously defined (US 130/85) • Central obesity (BMI, waist circumference or waist:hip ratio)

16. Abnormal LDL and Triglyceride Values by Time on TTS

17. Mean Change from Baseline in Glucose

18. Mean Change from Baseline in Insulin

19. Mean Change from Baseline in Fibrinogen

20. Shifts in Systolic Blood Pressure by Time on TTS

21. Shifts in Diastolic Blood Pressure by Time on TTS

22. Weight Change ≥ 7% from Baseline

23. Adverse Effects of TTS • Likely: • Androgenic adverse effects • Possible: • Impact on cardiac risk factors, e.g., changes in lipids • Speculative: • Increased cardiovascular morbidity • Increased risk of breast cancer

24. Breast Cancer Cases

25. Limitations of Current Data • Placebo-controlled phase only 6 months • Long-term use limited to 12 months (N=494) and 18 months (N=127) • Women with diabetes and cardiac disease not studied • Limited data on naturally menopausal women: • Endometrial safety • Risks of estrogen/progesterone

26. Ongoing Trials • Studies in surgically menopausal women • 321 subjects entered year 2 of 3 yr extension • 2 placebo controlled studies in naturally menopausal women on E+P • 6-month and 12-month trials (n~400 each) • 281 in safety extension phase • 293 paired endometrial biopsy samples • Study of TTS patch without estrogen or E+P • Projected enrollment of 750 in 3 arms

27. Overview of Pharmacovigilance Plan • Prospective cohort study in a claims database • Current and recent users matched with control subjects in a 3:1 ratio • Planned outcomes include CVD & breast cancer • Endpoints adjudicated by blinded expert panel • First analysis at 24 months post-launch • Estimated power for cardiovascular events: 85% to detect a RR of 1.5 at year 5

28. Concerns about Proposed Pharmacovigilance Plan • To answer safety questions, does a claims-based cohort study provide the same level of evidence as a randomized, placebo-controlled trial? • Projected sample size inadequate • Study powered to detect a RR of 1.5 for cardiovascular disease may miss important but lower risks • Risks in WHI E+P study were: 1.2 (total CVD), 1.3 (breast cancer), and 1.4 (stroke) • Sample size of almost 17,000 to achieve this detection • No information on power to detect breast cancer risk

29. Concerns about Proposed Pharmacovigilance Plan • Events with long latency may not be detected • In WHI E+P study, breast cancer rates did not diverge until year 4 • Average follow-up 5.2 years at time trial stopped • Recruitment goals not previously met using this database • High turnover in plan coverage • 85% retention per year → retain only 44% of original population by year 5

30. Lessons from WHI • Women’s Health Initiative (WHI) data discrepant from that of observational studies • WHI reinforces value of prospective, randomized controlled studies of adequate duration to define attributable risk • WHI indicates need for heightened scrutiny of hormone therapy in postmenopausal women

31. Summary of Safety Issues • Sample size and duration of treatment inadequate to exclude serious risks • Cardiovascular disease • Breast cancer • Population studied inadequate to identify important risks in • Naturally menopausal women using E + P • Subgroups at higher risk for cardiovascular morbidity