1. Clinical Trials – Human Gonadotropin Drug Products A Regulatory Perspective Shelley R. Slaughter, M.D., Ph. D. Reproductive Medical Officer Team Leader Division of Reproductive and Urologic Drug Products Food and Drug Administration

2. 2 Guidance Document for Industry “Represents the Agency’s current thinking on a particular subject. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations or both”

3. 3 Clinical Background Drs. Keefe and Toner

4. 4 Clinical Studies Introduction Review Gonadotropin Drug Products Overview of clinical studies for selected approved gonadotropin drug products Discussion by the Committee

5. 5 Approved urinary derived gonadotropins and recombinant gonadotropins

6. 6 Gonadotropin Drug Products Approved Indications Ovulation Induction in Chronic Anovulatory Women Multiple Follicular Development in Ovulatory Women for ART

7. 7 Gonadotropin Drug Products The goal:The goal:

8. 8 Overview of Clinical Studies In the 30 years since the FDA approved the drug Pergonal , the technology used in the treatment of infertility and the resulting clinical pregnancy rates have improved Time for a re-examination of the clinical studies for gonadotropin drug products

9. 9 Overview of Clinical Studies Examine clinical study information on selected approved gonadotropin drug products –historical perspective –design –efficacy surrogate endpoints and analysis –safety endpoints

10. 10 Surrogate Endpoint direct measureDefinition: A laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions or survives and that is expected to predict the effect of the therapy

11. 11 Pergonal® Approved on: June 23, 1970 - Induction of ovulation March 1, 1988 - Development of multiple follicles in ovulatory patients participating in an IVF program

12. 12 Pergonal® Efficacy and safety data: –Literature reports: IVF data representing the clinical experience with 192 patients at the Jones Institute (1981 – 1984) IVF data from Australia and New Zealand (1979- 1984)

13. 13 Pergonal® Primary Efficacy Endpoint: oocytes retrieved laparoscopy –Mean number of oocytes retrieved at time of laparoscopy

14. 14 Metrodin® Approved: –September 18, 1986

15. 15 Metrodin® Efficacy and safety: open-label, non-comparative –Literature review of retrospective data from five open-label, non-comparative, clinical studies of ovulation induction (n=80 patients) Observational reports of ovulation and pregnancy –Discussed before Advisory Committee 1985

16. 16 Gonal-f® Approved: –September 29, 1997 First gonadotropin drug product for which the actual data was submitted for review to the FDA –protocols for the studies were not submitted

17. 17 Gonal-f® Efficacy and safety data from four controlled studies: –Ovulation Induction- open-labelTwo randomized, open-label, active comparator (Metrodin  ), Phase 3 non-inferiority studies in chronic anovulatory women –Cumulative proportion of subjects with serum progesterone > 10 ng/ml –IVF open-labelTwo randomized, open-label, active comparator Phase 3 non-inferiority studies in normal ovulatory women –Follicles –Follicles on ultrasound >14 mm

18. 18 Gonal-f® - Ovulation Induction Results

19. 19 Gonal-f® - IVF results

20. 20 Follistim® Approved: –September 29, 1997 The actual data was submitted for review to the FDA –protocols for the studies were not submitted

21. 21 Follistim® Efficacy and safety to support Follistim® was derived from four controlled studies: Ovulation induction: single-blind –One randomized, single-blind, active comparator (Metrodin®), Phase 3 non-inferiority trial of Follistim® in chronic anovulatory women

22. 22 Follistim® - Ovulation Induction Results

23. 23 Follistim® IVF assessor-blind –Three randomized, assessor-blind, active comparator (1-Humegon, 2- Metrodin), Phase 3 non-inferiority studies in normal ovulatory infertile women –Mean total oocytes retrieved

24. 24 Follistim® - IVF results

25. 25 Safety Safety Endpoints: –Ovarian hyperstimulation syndrome rate –Multiple birth rate

26. 26 Previous Gonadotropin Drug Approvals Since these selected gonadotropins were approved: –IVF technology has been broadened to include adjunct procedures (ex. donor oocyte, intracytoplasmic injection) –More IVF clinics are available, leading to a greater pool of patients for inclusion in studies

27. For Committee Discussion

28. 28 For Committee Discussion Indications 1. Does the Committee agree with the Indications of: –Induction of Ovulation and Pregnancy? –Multiple follicular development in ART?

29. 29 For Committee Discussion Study Population –The following patient populations are enrolled: Ovulation Induction –hypogonadotropic hypogonadal women –chronic anovulatory women -ART –hypogonadotropic hypogonadal women –normal ovulatory women (defined by serum progesterone) chronic anovulatory 2. Can the committee make a recommendation as to what enrollment criteria should be used to adequately capture the population to be studied?

30. 30 For Committee Discussion Study Stratification 3. Should enrollment be stratified by age? 4. How do we take into account improvements in IVF and new adjunct procedures ? Donor Oocyte ICSI

31. 31 Study Design 5. What study designs should be used: –Open or blinded? assessor blind double blind –Comparator? active placebo

32. 32 Primary Efficacy Endpoint “Take Home Baby” Desired outcome - “Take Home Baby” 6. Is it feasible to power studies to detect a difference in live birth rate? Ongoing pregnancy?

33. 33 Primary Efficacy Endpoint not If it is not feasible to power studies to detect a difference in live birth rate or ongoing pregnancy rate; surrogate Discuss the relevance, advantages /disadvantages of these surrogate endpoints: –Rate of patients with presence of a fetal heart beat –Rate of patients with presence of a gestational sac –Rate of patients with a Positive ß-hCG (biochemical pregnancy) –Ovulation rate [as defined by serum progesterone level(s)] –Follicular development rate (as defined by two or three criteria)

34. 34 Primary Efficacy Endpoint 7. Can the committee come to a consensus on the most relevant surrogate endpoint? and the clinically meaningful difference in that endpoint?the clinically meaningful difference in that endpoint?

35. 35 Primary Efficacy Endpoint Analysis The FDA typically looks at an Intent-to-Treat (per treatment initiation) analysis.The FDA typically looks at an Intent-to-Treat (per treatment initiation) analysis. 8. Is this appropriate for: Ovulation Induction ? ART? 9. If not appropriate for OI, should cycles be analyzed per subjects who were given hCG?

36. 36 Primary Efficacy Endpoint Analysis 10. If not appropriate for ART, should cycles be analyzed: –Per retrieval? –Per embryo transfer?

37. 37 Study Analysis 11. How should success be defined: –Superiority to: Placebo? active control? –Non-inferiority to active control?

38. 38 Safety Endpoint(s) The FDA has focused the product-specific safety review of Infertility drug products on: –Rate of ovarian hyperstimulation syndrome –Rate of miscarriages –Rate of multiple pregnancies –Rate of ectopic pregnancies 12. Can the committee make a recommendation as to what safety endpoint(s) should be evaluated?

39. 39 Pregnancy and Birth Outcome 13. Is a pregnancy registry feasible? 14. If feasible, what information should be collected?

40. 40 Urinary-derived Human Gonadotropins Urine (~250, 000 liters) is pooled from post-menopausal women Pooled urine is processed to concentrate gonadotropins Gonadotropins are purified by either antibody affinity column or conventional chromatography

41. 41 Manufacture: Recombinant Human Gonadotropins CHO Cells and FSH or LH sequence CHO Cells Transfected with FSH/LH