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Human Gonadotropins: A Regulatory Perspective,Shelley R. Slaughter, M.D., Ph. D.Reproductive Medical Officer Team LeaderDivision of Reproductive and Urologic Drug ProductsFood and Drug Administration,2,Introduction,Review the physiology and role of gonadotropin therapy in female infertilityOverview of the regulatory history of selected approved gonadotropin drug productsDiscussion: 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 ovaryRequired 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 minutesStimulates the growth of an ovarian follicleIncreases the production of estrogenStimulates production of luteinizing hormone (LH) receptors and other factors (inhibin, activin) in preparation for ovulation,7,Luteinizing Hormone (LH),Half-life is 38-60 minutesLH role in folliculogenesis is unclearInduces follicular maturation and the sequence of events leading to ovulationResponsible for steroid production by theca cells,Exogenous Gonadotropin Therapy,9,Exogenous Gonadotropin Therapy,The goal:,10,Exogenous Gonadotropin Therapy,Patient Types Substitution - hypogonadal womenStimulation women with hypothalamic dysfunctionRegulation - oligo-anovulatory womenHyperstimulation therapy women undergoing Assisted Reproductive Technology procedures,11,Exogenous Gonadotropin Therapy,Objective: simulate a normal menstrual cycleAction: override the hypothalamic-pituitary axis and direct:the onset and duration of follicular development the timing and number of follicles that reach maturitythe production of gonadal steroids,12,A Typical U.S. Gonadotropin Treatment Protocol,Baseline serum estradiol (E2) level Baseline ultrasound scanAdminister daily for 7 - 10 daysRepeat E2 level and ultrasound approximately every 2 to 3 days until follicular maturity is achievedAdminister human chorionic gonadotropin (hCG),13,Gonadotropin Drugs - Development History,1926-1927: Discovery of pituitary hormones1955: 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 size1985: 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 gonadotropinRecombinant human gonadotropins - follitropin alfa and follitropin beta, chorionic gonadotropin alfa,16,Urinary-derived Human Gonadotropins,Urine is pooled from post-menopausal womenUrine pool is processed to concentrate gonadotropinsGonadotropins are purified by either antibody affinity column or conventional chromatography,17,Manufacture: Recombinant Human Gonadotropins,CHO Cells,and,FSH or LH sequence,CHO CellsTransfected 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 production in bioreactorsFSH or LH in the cell culture harvests are purified by chromatography,19,Pergonal,Generic Name: menotropins for injection, USPActive 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 injectionActive ingredient: FSHDerived: Post-menopausal human urineApproved: 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 :IVFStudy 5503 - multicenter (Europe), randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f vs. Metrodin for multiple follicular development in IVFStudy 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 InductionStudy 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 anovulationStudy 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 rateOvulation Induction (Study 5727) 13.7%IVF (Study 5533) 25%,36,Follistim,Generic name: follitropin beta for injectionActive Ingredient: Follicle Stimulating HormoneDerived: 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,IVFStudy 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,IVFStudy 37611 - multicenter (France), randomized, assessor-blind, active comparator, equivalence trial of Follistim vs. Metrodin for infertile women treated with IVFStudy 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 rateOvulation Induction (Study 37609) - 7.6%IVF (Study (37608) - 5.2%Multiple birth rateOvulation Induction (Study 37609) - 6%IVF (Study 37608) - 23%,For Discussion,45,Study Population,Ovulation InductionThe 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,ARTThe following populations are enrolled:Normal ovulatory (defined by serum progesterone levels) womenWHO 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?IVFICSIDonor Oocyte,47,Study Design,What study designs should be used? Blinding double or assessor blindComparatorsactive or placebo,48,Primary Efficacy Endpoint,Discuss the advantages and disadvantages of the