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Human Gonadotropins: A Regulatory Perspective

Human Gonadotropins: 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. Introduction.

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Human Gonadotropins: A Regulatory Perspective

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  1. Human Gonadotropins: 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. Introduction • Review the physiology and role of gonadotropin therapy in female infertility • Overview of the regulatory history of selected approved gonadotropin drug products • Discussion: population, design, efficacy endpoints, analysis and safety endpoints for trials of these drug products

  3. Human Gonadotropins - Endocrinology • Link between hypothalamic-pituitary axis and the ovary • Required at threshold levels for follicular development

  4. Human Gonadotropins • Control of gonadotropin release occurs through pulsatile hypothalamic production of gonadotropin releasing hormone (GnRH) • Pulses vary over the course of the menstrual cycle. • The timing and amplitude of pulses determine gonadotropin release from the pituitary.

  5. Types of Gonadotropins • In females, the reproductive axis is responsive to two main gonadotropin types: • Follicle Stimulating Hormone (FSH) • Luteinizing Hormone (LH)

  6. Follicle Stimulating Hormone (FSH) • Half-life of 180 - 240 minutes • Stimulates the growth of an ovarian follicle • Increases the production of estrogen • Stimulates production of luteinizing hormone (LH) receptors and other factors (inhibin, activin) in preparation for ovulation

  7. Luteinizing Hormone (LH) • Half-life is 38-60 minutes • LH role in folliculogenesis is unclear • Induces follicular maturation and the sequence of events leading to ovulation • Responsible for steroid production by theca cells

  8. Exogenous Gonadotropin Therapy

  9. Exogenous Gonadotropin Therapy • The goal:

  10. Exogenous Gonadotropin Therapy • Patient Types • Substitution - hypogonadal women • Stimulation – women with hypothalamic dysfunction • Regulation - oligo-anovulatory women • Hyperstimulation therapy – women undergoing Assisted Reproductive Technology procedures

  11. Exogenous Gonadotropin Therapy • Objective: simulate a normal menstrual cycle • Action: override the hypothalamic-pituitary axis and direct: • the onset and duration of follicular development • the timing and number of follicles that reach maturity • the production of gonadal steroids

  12. A Typical U.S. Gonadotropin Treatment Protocol • Baseline serum estradiol (E2) level • Baseline ultrasound scan • Administer daily for 7 - 10 days • Repeat E2 level and ultrasound approximately every 2 to 3 days until follicular maturity is achieved • Administer human chorionic gonadotropin (hCG)

  13. Gonadotropin Drugs - Development History • 1926-1927: Discovery of pituitary hormones • 1955: Clinical use of urinary hormone assays (steroids and gonadotropins)

  14. Gonadotropin Drug Development (continued) • 1959: Extraction of gonadotropins from human pituitary and urine. • 1979: Initial use of ultrasound to determine human ovarian follicle size • 1985: Use of human pituitary extracts was abandoned after literature reports of patients contracting Jacob-Creutzfeldt disease

  15. Types of Gonadotropin Therapy Marketed • Urinary derived human gonadotropins - menotropins, urofolitropin, chorionic gonadotropin • Recombinant human gonadotropins - follitropin alfa and follitropin beta, chorionic gonadotropin alfa

  16. Urinary-derived Human Gonadotropins • Urine is pooled from post-menopausal women • Urine pool is processed to concentrate gonadotropins • Gonadotropins are purified by either antibody affinity column or conventional chromatography

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

  18. Manufacture: Recombinant Human Gonadotropins • DNA constructs containing coding sequences of either alfa or beta subunit of FSH or LH are prepared. • Chinese hamster ovary (CHO) cells are co-transfected with two DNA constructs • Stable CHO cell lines containing integrated FSH or LH sequence are selected. • Master and Working Cell Banks are prepared for productionin bioreactors • FSH or LH in the cell culture harvests are purified by chromatography

  19. Pergonal® • Generic Name: menotropins for injection, USP • Active Ingredients: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) • Derived: Post-menopausal human urine

  20. Pergonal® • In women: • “Pergonal and hCG given in a sequential manner are indicated for: • Induction of ovulation in anovulatory women (Approved – June 23, 1970) • Development of multiple follicles in ovulatory patients participating in an IVF program” (Approved - March 1, 1988)

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

  22. Pergonal® • Primary Efficacy Endpoints: • Mean number of oocytes retrieved at time of laparoscopy – 3.82

  23. Pergonal® • Safety Endpoints: • Rate of ovarian hyperstimulation syndrome– 1.3% • (In the retrospective analysis of the Jones Institute data, no severe ovarian hyperstimulation or other adverse reactions were noted in 192 IVF subjects) • Multiple pregnancy rate – 20 %

  24. Metrodin® • Generic name: urofollitropin for injection • Active ingredient: FSH • Derived: Post-menopausal human urine • Approved: September 18, 1986

  25. Metrodin® • Indication: • “Metrodin and human chorionic gonadotropin (hCG) given in a sequential manner are indicated for: • the induction of ovulation in patients with polycystic ovarian disease who have an elevated FSH/LH ratio and who have failed to respond to adequate clomiphene citrate therapy”

  26. Metrodin® • Efficacy and safety data : • Literature review of retrospective data from five open-label, non-comparative, clinical studies of ovulation induction (n=80 patients)

  27. Metrodin® • Efficacy: • Observational reports of ovulation and pregnancy

  28. Metrodin® • Safety Endpoints : • Ovarian hyperstimulation syndrome rate – 6% • Multiple birth rate – 17%

  29. Gonal-f® • Generic Name: follitropin alfa for injection • Active Ingredient: Follicle Stimulating Hormone (FSH) • Derived: Chinese hamster ovary (CHO) cells (Recombinant) • Approved: September 29, 1997

  30. Gonal-f® • Indications: • “Induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is not functional and not due to primary ovarian failure” • “Development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology program”

  31. Gonal-f® • Efficacy and safety data from four controlled studies : • IVF • Study 5503 -multicenter (Europe),randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for multiple follicular development in IVF • Study 5533 – multicenter (U.S.), randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for superovulation in IVF

  32. Gonal-f® • Efficacy and safety data from four controlled studies: • Ovulation Induction • Study 5642 - multicenter (Europe, Israel),randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for ovulation induction in WHO Type II anovulation • Study 5727 - multicenter (U.S.),randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for ovulation induction in WHO Type II anovulation

  33. Gonal-f® - IVF results

  34. Gonal-f® - Ovulation Induction Results

  35. Gonal-f® • Safety Endpoints: • Ovarian hyperstimulation syndrome rate • Ovulation Induction (Study 5727) – 6.8% • IVF (Study 5533) - 0% • Multiple birth rate • Ovulation Induction (Study 5727) – 13.7% • IVF (Study 5533) – 25%

  36. Follistim® • Generic name: follitropin beta for injection • Active Ingredient: Follicle Stimulating Hormone • Derived: Chinese Hamster Ovary Cells (Recombinant) • Approved: September 29, 1997

  37. Follistim® • Indications: • “Induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to ovarian failure” • “Development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology program”

  38. Follistim® • IVF • Study 37604 - single center (Netherlands),randomized, assessor blind, active comparator, equivalence trial of Follistim® vs. Humegon® for infertile women treated with IVF • Study 37608 - multicenter (Europe),randomized, assessor-blind, active comparator, equivalence trial of Follistim® vs. Metrodin® for infertile women treated with IVF

  39. Follistim® • IVF • Study 37611 - multicenter (France),randomized, assessor-blind, active comparator, equivalence trial of Follistim® vs. Metrodin® for infertile women treated with IVF • Study 37613 - multicenter (non-U.S.),randomized, open-label, active comparator, equivalence trial designed to compare the safety and efficacy of two routes of administration of Follistim® subcutaneously and intramuscular for infertile women treated with IVF

  40. Follistim® • Ovulation induction: • Study 37609 - multicenter (European),randomized, assessor-blind, active comparator, equivalence trial of Follistim® vs. Metrodin® for induction of ovulation in chronic anovulation who failed to ovulate and/or conceive during clomiphene citrate treatment (WHO Type II).

  41. Follistim® - IVF results

  42. Follistim® - Ovulation Induction Results

  43. Follistim® • Safety Endpoints: • Ovarian hyperstimulation syndrome rate • Ovulation Induction (Study 37609) - 7.6% • IVF (Study (37608) - 5.2% • Multiple birth rate • Ovulation Induction (Study 37609) - 6% • IVF (Study 37608) - 23%

  44. For Discussion

  45. Study Population • Ovulation Induction • The following populations are enrolled: • WHO Group I (hypogonadotropic hypogonadism) • WHO Group II (chronic anovulation) • Does the committee have any advice on these?

  46. Study Population • ART • The following populations are enrolled: • Normal ovulatory (defined by serum progesterone levels) women • WHO Group I (hypogonadotropic hypogonadism) • WHO Group II (chronic anovulation) • Does the committee have any advice on these? • How do we take into account differences in the procedures? • IVF • ICSI • Donor Oocyte

  47. Study Design • What study designs should be used? • Blinding • double or assessor blind • Comparators • active or placebo

  48. Primary Efficacy Endpoint • Discuss the advantages and disadvantages of the following as primary or secondary endpoints: • Live birth rate • Ongoing viable pregnancy (presence of a fetal heartbeat) rate • Gestational sac development rate • Rate of Positive ß-hCG • Ovulation rate [as defined by serum progesterone level(s)] • Follicular development rate (as defined by two or three criteria)

  49. Primary Efficacy Endpoint • How should the primary endpoint(s) be analyzed? • For Ovulation Induction • Intent-to-Treat Population • Per protocol population • For ART • Per treatment initiation? • Per retrieval? • Per embryo transfer?

  50. Study Analysis • How should success be defined? • Superiority to comparator (placebo; active control) • Equivalence to active comparator • Non-inferiority to active comparator

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