Luveris ® New Drug Application (21-322 )

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

2. Objectives • Present FDA analyses of three main studies • Discuss lack of sufficient evidence of efficacy

3. Main Issue • FDA believes that patients whose cycles were cancelled due to risk of OHSS should be classified as treatment failures.

4. Studies Reviewed • Study 6905 – Dose-finding Phase II • Study 6253 – Dose-finding Phase II • Study 21008 – Phase III

5. Phase II StudiesPlanned 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

6. Phase II StudiesPlanned 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

7. Phase II StudiesPlanned Analyses = Trend test • Selected weights:placebo -2 25 IU 0 75 IU 1 225 IU 1

8. % Success – Follicular DevelopmentStudy 6905 (Phase II)

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).

10. % Success – Follicular DevelopmentStudy 6253 (Phase II)

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)

12. % Success – Follicular DevelopmentStudy 21008 (Phase III)

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).

14. % Success – Follicular DevelopmentRisk of OHSS = Failure

15. Secondary Endpoint:Ovulation Rate • Desired indication was ovulation induction • FDA requested sponsor use ovulation rate (determined by P4 level) as primary endpoint • Sponsor included ovulation rate as secondary endpoint

16. Secondary EndpointOvulation Rate(determined by P4 level)

17. Summary of Individual Studies • None of the placebo-controlled studies provides sufficient evidence to support the efficacy of Luveris 75 IU

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. 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. 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)

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

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

23. Summary • Compare Luveris 75 IU to placebo • FDA endpoint classifies patients whose cycles were cancelled due to risk of OHSS as treatment failures

24. Summary • 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.