Luveris™: The FDA Perspective

1. Luveris™: The FDA Perspective Shelley R. Slaughter, M.D., Ph. D. Reproductive Team Leader Division of Reproductive and Urologic Drug Products Food and Drug Administration

2. Luveris™ -Lutropin Alfa for Injection Indicated for concomitant administration with r-hFSH for the induction of ovulation in infertile women with severe LH and FSH deficiency

3. Luveris™ LH and FSH Deficiency • Hypogonadotropic Hypogonadism • Hypothalamic Pituitary Failure • Criteria for enrollment in the NDA studies defined Subpopulations (requiring therapy) based on serum LH, FSH and estradiol levels with or without functional evidence of endogenous estrogen

4. Luveris™ • October 7, 1994 –granted Orphan Drug designation

5. Orphan Drug Act of 1983 • A rare disease or conditions • affecting less than 200,000 person in the United States • Marketing exclusivity • Orphan products receive no preferential treatment in terms of testing and submission requirements, and face the same safety and effectiveness criteria and review processes as undesignated products

6. New Drug Application (NDA) Review Issues • Presentation will discuss efficacy only • Population • Endpoint(s) • Power (Number of Subjects Enrolled) of Phase 3 Study • Dose • FDA had no concerns with the safety profile

7. Overview of Efficacy Issues • Primary studies proposed to establish efficacy • FDA Requirements to establish efficacy • Examine the regulatory evaluation of Luveris™ • The strength of the evidence • Summarize the concerns of the FDA • Questions for the Committee

8. Proposed Studies to Establish Efficacy • Two identical Phase 2 dose-finding studies proposed to the FDA • One Phase 2 Study (U.S. -6905) submitted to the FDA • Proposed as primary–1996 • European Phase 2 (6253) not submitted to the FDA – • Proposed as primary–1998

9. U.S. Phase 2 Study (6905) Open Label U.S. Phase 2 Study (6905) - Amended Open Label European Phase 2 Study (6253) Open Label Patient Population FSH LH P challenge E2 <5 IU/L < 5 IU/L Not required Negative < 10.85 IU/L < 13.3 IU/L < 60 pg/mL Not required < 5 IU/L < 1.2 IU/L Not required Negative Efficacy Criteria 1. Follicle size 2. E2 day of hCG 3. Mid-luteal P4 >16mm >200pg/mL >10 ng/mL > 17mm >160 pg/mL >7.9 ng/mL > 17mm >109 pg/mL >7.9 ng/mL NDA REVIEW

10. Proposed Studies to Establish EfficacyProposed NDA (1998- 1999 ) • Proposed Studies to Establish Efficacy • Two non-identical Phase 2 Studies – 6905 and 6253 • no statistical hypothesis was set for these studies at the outset • not powered for efficacy • limited size of the patient population • trend tests used as confirmatory statistical tools for efficacy assessment; FDAconsiders these to be exploratory • The results of the European study (6253) are significantly different from that of the U.S. Study (6905)

11. Proposed Studies to Establish EfficacyChange of NDA Focus Serono proposed Study 6253 as primary as opposed to Study 6905

12. Proposed Studies to Establish EfficacyFDA Conclusion Database was insufficientfor filing an NDA (11 patients - 75 IU Luveris™ vs. 9 patients - placebo)

13. Proposed Studies to Establish EfficacyOptions Presented Discuss with an Advisory Committee whether the database for Luveris™ was sufficient to support an NDA

14. Proposed Studies to Establish EfficacyOptions Presented Conduct a Phase 3 study • Enroll patients with LH levels < 5IU/L • A significant subset with LH < 1.2 IU/L could also be included; however, product labeling would reflect both the population showing efficacy and that for which the product was ineffective • If the study could not be powered to demonstrate a difference in the pregnancy rate, then ovulation rate (the proposed label indication) should be the primary clinical outcomemeasure • A single treatment cycle would be adequate to demonstrate efficacy regarding ovulation rate

15. Proposed Studies to Establish Efficacy Phase 3 Protocol 21008 • 1999 –submitted • Population - • LH < 1.2IU/L, FSH< 5.0 IU/L (same as Study 6253) • E2< 60 pg/ml • Single dose (75 IU) • Follicular development (primary clinical outcome) • Serono’s cover letter stated “a review of Serono data indicates that the use of ovulation rates as a primary endpoint would be burdensome since some patients will be cancelled for the risk of OHSS and will not reach ovulation”

16. Phase 3 ProtocolComments • Dose-responsiveness had not been demonstrated • Single 75 IU/L dose was proposed • Population studied different from previous FDA recommendation (LH < 5 IU with subset LH < 1.2 IU)

17. Phase 3 Protocol Recommendations • FDA recommendations • Demonstrate Dose Responsiveness • Determine the lowest effective dose (25 IU?) in Phase 3 or conduct a separate Phase 2 trial • A single dose study may be an issue that affects the outcome of the review recommendation • Use a placebo arm, not historical data

18. Phase 3 Protocol Recommendations • Double Blind (ultrasonographer and patient) • Criteria for combination primary endpoint (follicles on ultrasound, estradiol levels and mid-luteal progesterone levels): • Estradiol - 200 pg/ml • Progesterone - 10 ng/ml

19. Proposed Studies to Establish Efficacy NDA Submission (May 1, 2001 ) • “Luveris™ (lutropin alfa for injection) is indicated for concomitant administration with r-hFSH for the induction of ovulation in infertile women with severe LH and FSH deficiency” • Efficacy • One Phase 3 trial • Two non-identical Phase 2 (dose finding) trials

20. Proposed Studies to Establish Efficacy NDA Submission • March 1, 2002 – Non-approvable decision made by the Division of Reproductive and Urologic Drug Products

21. Proposed Studies to Establish Efficacy NDA REVIEW Four Studies 6905 (Phase 2) 6253 (Phase 2) 21008 (Phase 3) 21415 (Extension of 21008)

22. NDA REVIEW • Study Objectives • U.S. Phase 2 (6905) and European Phase 2 (6253) - “to determine the need for LH and the minimum effective dose for ovulation induction” • FDA review - lowest effective dose had not been determined • U.S. Phase 3 (21008) – “confirm the efficacy and safety of the 75 IU dose of Luveris™” • FDA review – 75 IU dose of Luveris™ was not effective

23. NDA REVIEW

24. Proposed Studies to Establish Efficacy Impact of Cycle Cancellation • Major discrepant point of view between the applicant and the Division • FDA • cycles cancelled to avert ovarian hyperstimulation syndrome (OHSS) should not be considered as treatment successes for the purpose of evaluating efficacy for ovulation induction and pregnancy • OHSS, a pharmacologic adverse event, is not a surrogate for pregnancy

25. Proposed Studies to Establish Efficacy Impact of Cycle Cancellation • The sponsor defined the risk of OHSS that would lead to cancellation as: • An ultrasound scan showing more than three follicles, each with a diameter > 15 mm and a serum E2 concentration exceeding 1,100 pg/mL. • In such a case, hCG administration must be withheld • FDA believes that the appropriate way to account for cycle cancellations is to plan for and prospectively adjust the sample size

26. NDA REVIEW • Study 21415 was a non-randomized, open-label extension of Study 21008 that included 31 patients (LH 1.2 IU/L) treated in the latter study who had not conceived. • The primary objective - provide additional data on follicular development and safety of treatment with the 75 IU dose of Luveris™.

27. FDA Requirements to Establish Efficacy Substantial Evidence

28. Congress - Statutes • Section 505 (Federal Food, Drug, and Cosmetic Act of 1962) • (e) The term “substantial evidence” means evidence consisting of adequate and well-controlled investigations • Sec 115. (FDA Modernization Act of 1997) • (a) data from one adequate and well-controlled clinical investigation and confirmatory evidence are sufficient to establish effectiveness and FDA may consider such data and evidence to constitute substantial evidence

29. FDA Guidance for IndustryProviding Clinical Evidence of Effectiveness for Human Drug and Biological Products • Reliance on a single study “whether alone or with substantiation from related trial data leaves little room for study imperfections or contradictory (nonsupportive) information” • Results of Phase 2 trials - contradictory • Results of Phase 3 trial – not robust • Limited to where confirmation would be practically or ethically impossible

30. Statistics Kate Meaker, M.S.

31. Luveris®New Drug Application (21-322) Kate Meaker, M.S. Statistical Reviewer Division of Biometrics II

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

33. Main Issues of FDA Analyses • FDA believes that patients whose cycles were cancelled due to risk of OHSS should be classified as treatment failures. • The results are not robust

34. Studies Reviewed • U.S. Study 6905 – Dose-finding Phase 2 • EU Study 6253 – Dose-finding Phase 2 • Study 21008 – Phase 3

35. Phase 2 StudiesPlanned Analysis = Trend Test • Appropriate for dose-finding • Weights are assigned to each dose group prior to unblinding • Typically weights reflect a linear dose response or other dose relationship

36. Phase 2 StudiesProblems with Sponsor’s Analyses • In these Phase 2 protocols the weights were not pre-specified • Sponsor selected weights after unblinding data • Sponsor applied equal weight to 75 and 225 IU groups

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

38. % Success – Follicular DevelopmentU.S. Phase 2 Study (6905)

39. U.S. Phase 2 Study (6905) • 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).

40. % Success – Follicular DevelopmentEU Phase 2 Study (6253)

41. EU Phase 2 Study (6253) • 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)

42. % Success – Follicular DevelopmentPhase 3 Study (21008)

43. Phase 3 Study (21008) • 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).

44. % Success – Follicular DevelopmentRisk of OHSS = Failure

45. 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

46. Secondary EndpointOvulation Rate(determined by P4 level)

47. FDA Conclusions • None of the placebo-controlled studies provides sufficient evidence to support the efficacy of Luveris 75 IU

48. 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.

49. 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.”

50. 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)