Infertility is a common
disorder that affects 12% of married women in the U.S1.
Approximately one-third of infertility can be attributed to the male, one-third
to the female, and the remainder a combination of problems in both partners or
unexplained.
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The most common
female fertility factor is an ovulation disorder (the ovaries’ inability to
produce mature eggs or “ovulate” [release] an egg. Another common cause
includes tubal infertility (blocked fallopian tubes preventing the egg and
sperm from meeting).
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The most common
male infertility factors include azoospermia (no sperm cells are produced) and
oligospermia (few sperm cells are produced). The diagnosis of male factors is performed
using a semen analysis. Severe male factor is usually treated using intracytoplasmic
sperm injection (ICSI ). Donor sperm is available commercially, if the couple
can accept that the male partner will not be the “biologic father”.
In infertile women who have
blocked or absent fallopian tubes or whose partners have low sperm counts, in
vitro fertilization (IVF) offers a chance at having a baby. In IVF, eggs are
removed from the ovary under the guidance of ultrasound and mixed with sperm
outside the body in a laboratory dish. These eggs fertilize in the dish and are
transferred to the woman’s uterus when they have become embryos [embryo
transfer (ET)].
The hypothalamus and
pituitary gland orchestrate the events leading to ovulation. The hypothalamus
releases gonadotropin releasing hormone (GnRH), a messenger that tells the
pituitary gland to release follicle stimulating hormone (FSH) and luteinizing
hormone (LH). FSH primarily makes the follicle grow and produce increasing
amounts of estrogen, which then signals the pituitary to shut down FSH production.
A surge of LH triggers ovulation.
There are two classes of
ovulation drug treatments available in the
Gonadotropin therapy usually
follows clomiphene citrate therapy but can be the initial therapy in certain
patients. This therapy stimulates eggs
to mature and be released. Gonadotropins are either purified FSH or FSH/LH
combinations. Since the 1980’s, IVF programs have used gonadotropin stimulation
to increase the number of oocytes and subsequently improve the pregnancy rate. Several
side effects including ovarian hyperstimulation syndrome (OHSS), thromboembolic
disease and multiple gestation are associated with these drugs used to induce
ovulation.
The Division of Reproductive
and Urologic Drug Products is assessing the current approval process for
gonadotropin therapy. Previous clinical studies have used various clinical
populations, methodologies and efficacy endpoints. However, the technology used
in the treatment of infertility and the resulting clinical pregnancy rates have
improved over the past 30 years as evidenced by the current statistics.2
The Division is developing a guidance for industry that addresses clinical
trial design and analysis for drug products that are seeking the indication of
ovulation induction and multiple follicular development in assisted
reproductive technology (ART). The Division would like to receive the
Committee’s input in this process.
Enclosed is a briefing package for your consideration.
The briefing package
includes:
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Background
Information
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Bibliography
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Labels for
Approved Gonadotropin Drug Products
The Division wishes the
Committee to discuss the following:
- The
following populations are enrolled for ovulation induction:
WHO Group I
(hypogonadotropic hypogonadism)
WHO Group
II (chronic anovulation)
Does the committee have any advice on these?
- The
following populations are enrolled for ART:
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
- What study designs should be used?
Blinding
double or assessor blind
Comparators
active or placebo
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)
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?
How should success be defined?
Superiority to comparator (placebo; active control)
Equivalence to active comparator
Non-inferiority to active comparator
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
References: