Transcript 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
• 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
2
Human Gonadotropins Endocrinology
• Link between hypothalamic-pituitary axis
and the ovary
• Required at threshold levels for follicular
development
3
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.
4
Types of Gonadotropins
• In females, the reproductive axis is
responsive to two main gonadotropin types:
– Follicle Stimulating Hormone (FSH)
– Luteinizing Hormone (LH)
5
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
6
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
7
Exogenous Gonadotropin Therapy
Exogenous Gonadotropin
Therapy
• The goal:
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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
10
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
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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)
12
Gonadotropin Drugs Development History
• 1926-1927: Discovery of pituitary
hormones
• 1955: Clinical use of urinary hormone
assays (steroids and gonadotropins)
13
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
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Types of Gonadotropin
Therapy Marketed
• Urinary derived human gonadotropins
- menotropins, urofolitropin,
chorionic gonadotropin
• Recombinant human gonadotropins
- follitropin alfa and follitropin beta,
chorionic gonadotropin alfa
15
Urinary-derived Human
Gonadotropins
• Urine is pooled from postmenopausal women
• Urine pool 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
CHO Cells
FSH or LH
sequence
CHO Cells
Transfected
with FSH/LH
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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 bioreactors
• FSH or LH in the cell culture harvests are purified
by chromatography
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Pergonal®
• Generic Name: menotropins for injection,
USP
• Active Ingredients: Follicle Stimulating
Hormone (FSH) and Luteinizing Hormone
(LH)
• Derived: Post-menopausal human urine
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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)
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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
21
Pergonal®
• Primary Efficacy Endpoints:
– Mean number of oocytes retrieved at time of
laparoscopy – 3.82
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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 %
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Metrodin®
•
•
•
•
Generic name: urofollitropin for injection
Active ingredient: FSH
Derived: Post-menopausal human urine
Approved: September 18, 1986
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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”
25
Metrodin®
• Efficacy and safety data :
– Literature review of retrospective data from
five open-label, non-comparative, clinical
studies of ovulation induction (n=80 patients)
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Metrodin®
• Efficacy:
– Observational reports of ovulation and
pregnancy
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Metrodin®
• Safety Endpoints :
– Ovarian hyperstimulation syndrome rate – 6%
– Multiple birth rate – 17%
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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
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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”
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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, openlabel, active comparator, parallel group, equivalence
trial of Gonal-f® vs. Metrodin® for superovulation
in IVF
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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, openlabel, active comparator, parallel group, equivalence
trial of Gonal-f® vs. Metrodin® for ovulation
induction in WHO Type II anovulation
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Gonal-f® - IVF results
Efficacy Variable
Gonal-f®
Metrodin®
95% C.I. of difference
(N = 60)
(N = 63)
Study 5503
Mean number of follicles ≥14mm
(SD) on day hCG
7.8 (3.6)
9.2 (4.5)
(-2.9, 0.1)
Clinical Pregnancy per attempt* 20%
15.9%
N/A
(N = 50)
(N = 53)
Study 5533
Mean number of follicles ≥14mm
(SD) on day hCG
7.2 (3.3)
8.3 (4.1)
(-2.6, 0.4)
Clinical Pregnancy per attempt* 21.4%
22.4%
N/A
*Clinical Pregnancy defined as pregnancy with a fetal sac with or without cardiac activity
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Gonal-f® - Ovulation Induction Results
Efficacy Variable
Gonal-f®
Metrodin®
95% C.I. of difference
Study 5727
Cumulative Ovulation Rate
(N = 118)
81%
(N = 114)
93%
(-21%, 3.9%)
Cumulative Clinical Pregnancy *
37%
36%
N/A
(N = 110)
(N = 112)
Study 5642
Cumulative Ovulation Rate
84%
91%
(-16.1%, 1.3%)
Cumulative Clinical Pregnancy * 35%
46%
N/A
*Clinical Pregnancy defined as pregnancy with a fetal sac with or without cardiac activity
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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%
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Follistim®
• Generic name: follitropin beta for injection
• Active Ingredient: Follicle Stimulating
Hormone
• Derived: Chinese Hamster Ovary Cells
(Recombinant)
• Approved: September 29, 1997
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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”
37
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
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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
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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).
40
Follistim® - IVF results
Efficacy Variable
Follistim®
Active Comparator
(FSH)
(N=396)
95% C.I. of difference
(N=585)
Study 37608
Mean number of total
oocytes retrieved
10.9 (7.2)
9.0 (5.9)
(1.0, 2.8)
Ongoing Pregnancy per
attempt*
22.2%
18.2%
N/A
(N=54)
(N=35)
Study 37604
Mean number of total
oocytes retrieved
9.9
7.6
(-1.2, 5.8)
Ongoing Pregnancy per
attempt*
22.2%
17.1%
N/A
* A pregnancy was termed ongoing when a pregnancy, at least 12 weeks after embryo transfer, was
confirmed by the investigator
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Follistim® - Ovulation Induction Results
Efficacy Variable
Follistim®
Active Comparator
(FSH)
(N=67)
95% C.I. of difference
(N=105)
Study 37609
Cumulative Ovulation
Rate
85%
82%
(-0.10, 0.08)
Cumulative Ongoing
Pregnancy *
23%
19%
N/A
* A pregnancy was termed ongoing when a pregnancy, at least 12 weeks after embryo transfer, was
confirmed by the investigator
42
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%
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For Discussion
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?
45
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
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Study Design
• What study designs should be used?
– Blinding
• double or assessor blind
– Comparators
• active or placebo
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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)
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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?
49
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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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
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Acknowledgements
•
•
•
•
•
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•
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.
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