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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

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
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
human gonadotropins endocrinology
Human Gonadotropins - Endocrinology
  • Link between hypothalamic-pituitary axis and the ovary
  • Required at threshold levels for follicular development
human gonadotropins
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.
types of gonadotropins
Types of Gonadotropins
  • In females, the reproductive axis is responsive to two main gonadotropin types:
    • Follicle Stimulating Hormone (FSH)
    • Luteinizing Hormone (LH)
follicle stimulating hormone fsh
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
luteinizing hormone lh
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
exogenous gonadotropin therapy10
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
exogenous gonadotropin therapy11
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
a typical u s gonadotropin treatment protocol
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)
gonadotropin drugs development history
Gonadotropin Drugs - Development History
  • 1926-1927: Discovery of pituitary hormones
  • 1955: Clinical use of urinary hormone assays (steroids and gonadotropins)
gonadotropin drug development continued
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
types of gonadotropin therapy marketed
Types of Gonadotropin Therapy Marketed
  • Urinary derived human gonadotropins - menotropins, urofolitropin,

chorionic gonadotropin

  • Recombinant human gonadotropins

- follitropin alfa and follitropin beta,

chorionic gonadotropin alfa

urinary derived human gonadotropins
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
manufacture recombinant human gonadotropins
Manufacture: Recombinant Human Gonadotropins

and

FSH or LH

sequence

CHOCells

CHO Cells

Transfected

with FSH/LH

manufacture recombinant human gonadotropins18
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
pergonal
Pergonal®
  • Generic Name: menotropins for injection, USP
  • Active Ingredients: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH)
  • Derived: Post-menopausal human urine
pergonal20
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)
pergonal21
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
pergonal22
Pergonal®
  • Primary Efficacy Endpoints:
    • Mean number of oocytes retrieved at time of laparoscopy – 3.82
pergonal23
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 %
metrodin
Metrodin®
  • Generic name: urofollitropin for injection
  • Active ingredient: FSH
  • Derived: Post-menopausal human urine
  • Approved: September 18, 1986
metrodin25
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”
metrodin26
Metrodin®
  • Efficacy and safety data :
    • Literature review of retrospective data from five open-label, non-comparative, clinical studies of ovulation induction (n=80 patients)
metrodin27
Metrodin®
  • Efficacy:
    • Observational reports of ovulation and pregnancy
metrodin28
Metrodin®
  • Safety Endpoints :
    • Ovarian hyperstimulation syndrome rate – 6%
    • Multiple birth rate – 17%
gonal f
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
gonal f30
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”
gonal f31
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
gonal f32
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
gonal f35
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%
follistim
Follistim®
  • Generic name: follitropin beta for injection
  • Active Ingredient: Follicle Stimulating Hormone
  • Derived: Chinese Hamster Ovary Cells (Recombinant)
  • Approved: September 29, 1997
follistim37
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”
follistim38
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
follistim39
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
follistim40
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).
follistim43
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%
study population
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?
study population46
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
study design
Study Design
  • What study designs should be used?
    • Blinding
      • double or assessor blind
    • Comparators
      • active or placebo
primary efficacy endpoint
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)
primary efficacy endpoint49
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?
study analysis
Study Analysis
  • How should success be defined?
    • Superiority to comparator (placebo; active control)
    • Equivalence to active comparator
    • Non-inferiority to active comparator
safety endpoint questions
Safety Endpoint Questions
  • Discuss the advantages and disadvantages of evaluating the following safety endpoint(s):
    • Rate of ovarian hyperstimulation syndrome
    • Rate of miscarriages
    • Rate of multiple pregnancies
    • Rate of ectopic pregnancies
acknowledgements
Acknowledgements
  • Audrey Gassman, M.D.
  • Ridgely Bennett, M.D.
  • Barbara Wesley, M.D., M.P.H.
  • Phill Price, M.D.
  • Dornette Spell-Lesane, C.N.P.
  • Donna Griebel, M.D.
  • Dan Shames, M.D.
  • Florence Houn, M.D.