1. Luveris ® New Drug Application (21-322 ) Kate Meaker, M.S. Statistical Reviewer Division of Biometrics II Kate Meaker, M.S. Statistical Reviewer Division of Biometrics II Center for Drug Evaluation and Research

2. Title of Advisory Committee Meeting Date 2 Objectives Present FDA analyses of three main studies Discuss lack of sufficient evidence of efficacy Present FDA analyses of three main studies Discuss lack of sufficient evidence of efficacy

3. Title of Advisory Committee Meeting Date 3 Main Issue FDA believes that patients whose cycles were cancelled due to risk of OHSS should be classified as treatment failures.

4. Title of Advisory Committee Meeting Date 4 Studies Reviewed Study 6905 – Dose-finding Phase II Study 6253 – Dose-finding Phase II Study 21008 – Phase III Study 6905 – Dose-finding Phase II Study 6253 – Dose-finding Phase II Study 21008 – Phase III

5. Title of Advisory Committee Meeting Date 5 Phase II Studies Planned Analysis = Trend Test Appropriate for dose-finding Weights are assigned to each dose group Typically weights reflect a linear dose response or other dose relationship Appropriate for dose-finding Weights are assigned to each dose group Typically weights reflect a linear dose response or other dose relationship

6. Title of Advisory Committee Meeting Date 6 Phase II Studies Planned Analyses = Trend test In these Phase II protocols the weights were not pre-specified Sponsor selected weights after unblinding data Sponsor applied equal weight to 75 and 225 IU groups In these Phase II protocols the weights were not pre-specified Sponsor selected weights after unblinding data Sponsor applied equal weight to 75 and 225 IU groups

7. Title of Advisory Committee Meeting Date 7 Phase II Studies Planned Analyses = Trend test Selected weights: placebo-2 25 IU0 75 IU1 225 IU1

8. Title of Advisory Committee Meeting Date 8 % Success – Follicular Development Study 6905 (Phase II)

9. Title of Advisory Committee Meeting Date 9 Study 6905 (Phase II) FDA analysis classified OHSS risk as treatment failure Conclusion: The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.670). FDA analysis classified OHSS risk as treatment failure Conclusion: The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.670).

10. Title of Advisory Committee Meeting Date 10 % Success – Follicular Development Study 6253 (Phase II)

11. Title of Advisory Committee Meeting Date 11 Study 6253 (Phase II) FDA analysis classified OHSS risk as treatment failure Conclusion: The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.157) FDA analysis classified OHSS risk as treatment failure Conclusion: The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.157)

12. Title of Advisory Committee Meeting Date 12 % Success – Follicular Development Study 21008 (Phase III)

13. Title of Advisory Committee Meeting Date 13 Study 21008 (Phase III) FDA analysis classified OHSS risk as treatment failure Conclusion: The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.063). FDA analysis classified OHSS risk as treatment failure Conclusion: The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.063).

14. Title of Advisory Committee Meeting Date 14 % Success – Follicular Development Risk of OHSS = Failure

15. Title of Advisory Committee Meeting Date 15 Secondary Endpoint: Ovulation Rate Desired indication was ovulation induction FDA requested sponsor use ovulation rate (determined by P 4 level) as primary endpoint Sponsor included ovulation rate as secondary endpoint Desired indication was ovulation induction FDA requested sponsor use ovulation rate (determined by P 4 level) as primary endpoint Sponsor included ovulation rate as secondary endpoint

16. Title of Advisory Committee Meeting Date 16 Secondary Endpoint Ovulation Rate (determined by P 4 level)

17. Title of Advisory Committee Meeting Date 17 Summary of Individual Studies None of the placebo-controlled studies provides sufficient evidence to support the efficacy of Luveris 75 IU

18. Title of Advisory Committee Meeting Date 18 Post hoc Pooled Analyses FDA does not typically consider unplanned pooling of studies, particularly when the individual studies do not meet statistical significance on their own.

19. Title of Advisory Committee Meeting Date 19 Post hoc Pooled Analyses ICH E9: Statistical Principles for Clinical Trials “ Only results from analyses envisaged in the protocol (including amendments) can be regarded as confirmatory.”

20. Title of Advisory Committee Meeting Date 20 Post hoc Pooled Analyses If pooled analyses were to be considered, a more stringent level of statistical significance would be required than alpha = 0.05. Need to adjust alpha for all possible ways studies could be picked to combine (multiplicity issue) If pooled analyses were to be considered, a more stringent level of statistical significance would be required than alpha = 0.05. Need to adjust alpha for all possible ways studies could be picked to combine (multiplicity issue)

21. Title of Advisory Committee Meeting Date 21 Post hoc Pooled Analyses Combine two studies which have same endpoint definition and patient population (21008 + 6253) Combine all 3 gives largest sample size (Note: 6905 has design differences) Neither of these combination achieves statistical significance Combine two studies which have same endpoint definition and patient population (21008 + 6253) Combine all 3 gives largest sample size (Note: 6905 has design differences) Neither of these combination achieves statistical significance

22. Title of Advisory Committee Meeting Date 22 Post hoc Pooled Analyses Conclusions Pooled analyses were not prospectively planned FDA would generally not consider for confirmatory evidence Analyses of the combined studies do not show sufficient evidence of efficacy of Luveris 75 IU vs. placebo Pooled analyses were not prospectively planned FDA would generally not consider for confirmatory evidence Analyses of the combined studies do not show sufficient evidence of efficacy of Luveris 75 IU vs. placebo

23. Title of Advisory Committee Meeting Date 23 SummarySummary Compare Luveris 75 IU to placebo FDA endpoint classifies patients whose cycles were cancelled due to risk of OHSS as treatment failures Compare Luveris 75 IU to placebo FDA endpoint classifies patients whose cycles were cancelled due to risk of OHSS as treatment failures

24. Title of Advisory Committee Meeting Date 24 SummarySummary The three studies do not provide sufficient evidence to conclude the differences between Luveris 75 IU and placebo are statistically significantly. Post hoc pooled analyses do not show Luveris 75 IU is statistically significantly different from placebo. The three studies do not provide sufficient evidence to conclude the differences between Luveris 75 IU and placebo are statistically significantly. Post hoc pooled analyses do not show Luveris 75 IU is statistically significantly different from placebo.