Clinical Trials Human Gonadotropin Drug Products A Regulatory Perspective

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Clinical Trials Human Gonadotropin Drug
ProductsA 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

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Guidance Document for Industry

• Represents the Agencys 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

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Clinical Background

• Drs. Keefe and Toner

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Clinical StudiesIntroduction

• Review Gonadotropin Drug Products
• Overview of clinical studies for selected
  approved gonadotropin drug products
• Discussion by the Committee

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Approved urinary derived gonadotropins and
recombinant gonadotropins
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Gonadotropin Drug ProductsApproved Indications

• Ovulation Induction in Chronic Anovulatory Women
• Multiple Follicular Development in Ovulatory
  Women for ART

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Gonadotropin Drug Products

• The goal

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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

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Overview of Clinical Studies

• Examine clinical study information on selected
  approved gonadotropin drug products historical
  perspective
• design
• efficacy surrogate endpoints and analysis
• safety endpoints

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Surrogate Endpoint

• Definition 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

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Pergonal

• Approved on
• June 23, 1970 - Induction of ovulation
• March 1, 1988 - Development of multiple follicles
  in ovulatory patients participating in an IVF
  program

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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)

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Pergonal

• Primary Efficacy Endpoint
• Mean number of oocytes retrieved at time of
  laparoscopy

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Metrodin

• Approved
• September 18, 1986

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Metrodin

• Efficacy and safety
• Literature review of retrospective data from five
  open-label, non-comparative, clinical studies of
  ovulation induction (n80 patients)
• Observational reports of ovulation and pregnancy
• Discussed before Advisory Committee 1985

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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

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Gonal-f

• Efficacy and safety data from four controlled
  studies
• Ovulation Induction-
• Two randomized, open-label, active comparator
  (Metrodin?), Phase 3 non-inferiority studies in
  chronic anovulatory women
• Cumulative proportion of subjects with serum
  progesterone gt 10 ng/ml
• IVF
• Two randomized, open-label, active comparator
  Phase 3 non-inferiority studies in normal
  ovulatory women
• Follicles on ultrasound gt14 mm

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Gonal-f - Ovulation Induction Results
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Gonal-f - IVF results
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Follistim

• Approved
• September 29, 1997
• The actual data was submitted for review to the
  FDA
• protocols for the studies were not submitted

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Follistim

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

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Follistim - Ovulation Induction Results
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Follistim

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

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Follistim - IVF results
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Safety

• Safety Endpoints
• Ovarian hyperstimulation syndrome rate
• Multiple birth rate

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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

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For Committee Discussion
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For Committee DiscussionIndications

• 1. Does the Committee agree with the Indications
  of
• Induction of Ovulation and Pregnancy?
• Multiple follicular development in ART?

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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?

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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

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Study Design

• 5. What study designs should be used
• Open or blinded?
• assessor blind
• double blind
• Comparator?
• active
• placebo

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Primary Efficacy Endpoint

• Desired outcome - Take Home Baby
• 6. Is it feasible to power studies to detect a
  difference in live birth rate? Ongoing pregnancy?

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Primary Efficacy Endpoint

• If it is not feasible to power studies to
  detect a difference in live birth rate or ongoing
  pregnancy rate
• 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)

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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?

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Primary Efficacy Endpoint 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?

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Primary Efficacy Endpoint Analysis

• 10. If not appropriate for ART, should cycles be
  analyzed
• Per retrieval?
• Per embryo transfer?

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Study Analysis

• 11. How should success be defined
• Superiority to
• Placebo?
• active control?
• Non-inferiority to active control?

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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?

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Pregnancy and Birth Outcome

• 13. Is a pregnancy registry feasible?
• 14. If feasible, what information should be
  collected?

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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

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