Title: Clinical Trials Human Gonadotropin Drug Products A Regulatory Perspective
1Clinical 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
2Guidance 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
3Clinical Background
4Clinical StudiesIntroduction
- Review Gonadotropin Drug Products
- Overview of clinical studies for selected
approved gonadotropin drug products - Discussion by the Committee
5Approved urinary derived gonadotropins and
recombinant gonadotropins
6Gonadotropin Drug ProductsApproved Indications
- Ovulation Induction in Chronic Anovulatory Women
- Multiple Follicular Development in Ovulatory
Women for ART
7Gonadotropin Drug Products
8Overview 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
9Overview of Clinical Studies
- Examine clinical study information on selected
approved gonadotropin drug products historical
perspective - design
- efficacy surrogate endpoints and analysis
- safety endpoints
10Surrogate 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
11Pergonal
- Approved on
- June 23, 1970 - Induction of ovulation
- March 1, 1988 - Development of multiple follicles
in ovulatory patients participating in an IVF
program
12Pergonal
- 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)
13Pergonal
- Primary Efficacy Endpoint
- Mean number of oocytes retrieved at time of
laparoscopy
14Metrodin
- Approved
- September 18, 1986
15Metrodin
- 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
16Gonal-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
17Gonal-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
18Gonal-f - Ovulation Induction Results
19Gonal-f - IVF results
20Follistim
- Approved
- September 29, 1997
- The actual data was submitted for review to the
FDA - protocols for the studies were not submitted
21Follistim
- 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
22Follistim - Ovulation Induction Results
23Follistim
- 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
24Follistim - IVF results
25Safety
- Safety Endpoints
- Ovarian hyperstimulation syndrome rate
- Multiple birth rate
26Previous 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
27For Committee Discussion
28For Committee DiscussionIndications
- 1. Does the Committee agree with the Indications
of - Induction of Ovulation and Pregnancy?
- Multiple follicular development in ART?
29For 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?
30For 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
31Study Design
- 5. What study designs should be used
- Open or blinded?
- assessor blind
- double blind
- Comparator?
- active
- placebo
32Primary Efficacy Endpoint
- Desired outcome - Take Home Baby
- 6. Is it feasible to power studies to detect a
difference in live birth rate? Ongoing pregnancy?
33Primary 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)
34Primary Efficacy Endpoint
- 7. Can the committee come to a consensus on the
most relevant surrogate endpoint? and - the clinically meaningful difference in that
endpoint? -
35Primary 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?
36Primary Efficacy Endpoint Analysis
- 10. If not appropriate for ART, should cycles be
analyzed - Per retrieval?
- Per embryo transfer?
37Study Analysis
- 11. How should success be defined
- Superiority to
- Placebo?
- active control?
- Non-inferiority to active control?
38Safety 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?
39Pregnancy and Birth Outcome
- 13. Is a pregnancy registry feasible?
- 14. If feasible, what information should be
collected?
40Urinary-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
41Manufacture Recombinant Human Gonadotropins
and
FSH or LH sequence
CHO Cells
CHO Cells Transfected with FSH/LH