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Subcommittee on Oversight and Investigations
December 11, 2002
09:30 AM
2123 Rayburn House Office Building
Summary
March of Dimes Testimony
Issues Relating to the Safety of Accutane
In brief, oral isotretinoin
is widely used in women of reproductive age and is a known potent teratogen
(an agent with a high risk of causing birth defects), on the same scale as
thalidomide. No pregnant
women should take isotretinoin, and no women taking isotretinoin should get
pregnant. Despite current voluntary safety measures taken by the
manufacturer, many pregnant women and their developing fetuses are continuing
to be unnecessarily exposed to this drug and major birth defects have
developed in their babies.
The voluntary registration
and survey program (SMART), introduced earlier in this year, was designed to
improve the system by applying pressure to join on providers and women
consumers of Accutane. Making the monitoring system even more difficult is the
release of generic forms of isotretinoin. Roche is no longer using the BUAS,
though the generic manufacturers are; thus there will be two separate
isotretinoin surveys: one for the Roche formulation and another for the
generic products. The March of Dimes firmly believes this system is inadequate
to ensure 100% participation. Furthermore, we are concerned that the
complexity of the SMART program's expansion will further erode
participation. The March of Dimes
strongly recommends FDA-mandated implementation of a single program that is
designed to put in place a more stringent system that would reduce exposure to
developing fetuses from Accutane/isotretinoin.
We further recommend using as a model the highly effective program that
is already in place for thalidomide.
Statement of the March of Dimes
Subcommittee on Oversight and Investigations
U.S. House Committee on Energy and Commerce
December 11, 2002
Issues Relating to the Safety of Accutane
Good morning, Mr. Chairman
and Members of the Subcommittee. I
am Dr. Nancy Green, medical director of the March of Dimes Birth Defects
Foundation. I am also Associate Professor of Pediatrics and Cell Biology at the
Albert Einstein College of Medicine. As
you know, the March of Dimes is a national voluntary health agency founded in
1938 by President Franklin D. Roosevelt to find a scientific prevention of the
threat of polio to the public. Today,
the Foundation works to improve the health of mothers, infants and children by
preventing birth defects and infant mortality through research, community
services, education and advocacy. The
March of Dimes is a unique partnership of scientists, clinicians, parents,
members of the business community, and other volunteers in every state, the
District of Columbia and Puerto Rico.
I am pleased to have the
opportunity to testify this morning on behalf of the over 3 million volunteers
and 1500 staff of the March of Dimes, and to share with you the Foundation's
views on issues relating to the safety of Accutane and generic forms of
isotretinoin. Specifically, I will
provide recommendations intended to minimize the risk for causing serious birth
defects or fetal death via exposure to developing fetuses. As you know, one of
the major difficulties with preventing fetal exposure to isotretinoin is that
the target clients of this drug are people with acne, a sometimes serious but
certainly not life-threatening condition, occurring primarily in young adults
- of whom half are women of reproductive age.
The March of Dimes has reviewed
the current medical literature on the pregnancy-related risks of oral
isotretinoin and would like to make several points and recommendations for
consideration by this committee.
In brief, oral isotretinoin is
widely used in women of reproductive age and is a known potent teratogen (an
agent with a high risk of causing birth defects), on the same scale as
thalidomide. No pregnant
women should take isotretinoin, and no women taking isotretinoin should get
pregnant. Despite current voluntary
safety measures taken by the manufacturer, many pregnant women and their
developing fetuses are continuing to be unnecessarily exposed to this drug and
major birth defects have developed in their babies. We recommend a single, stringently monitored and restricted
system for clinical use of Accutane, such as the system currently in place for
thalidomide.
Accutane (isotretinoin) is an
oral medication approved by the Food and Drug Administration (FDA) for treatment
of recalcitrant nodular acne, an important but not a life-threatening disorder.
FDA reports that retail pharmacies dispensed 19.8 million outpatient
prescriptions for isotretinoin from 1982 through 2000. The Centers for Disease
Control and Prevention (CDC) reports that Roche Laboratories began
direct-to-consumer print advertisements in 1996, and added television and radio
advertisements in 1997. Data
published by FDA indicate that the number of prescriptions for Accutane has
increased dramatically and has been accelerating over the past 5-6 years. In
2000, nearly 2 million prescriptions for Accutane were filled.
There are well-documented data
pertaining to prescribed use of Accutane for less severe acne. In 2000, an FDA
survey found that the proportion of treatment for mild and moderate acne was
half of all treated cases. Half of these patients were female, and half of these
female patients were 15 to 24 years old. Increasing numbers of prescriptions
pose a risk to a greater number of women who have the potential for inadvertent
fetal exposure.
The CDC and others have
collected an overwhelming amount of data demonstrating that oral use of
isotretinoin during pregnancy causes major birth defects and miscarriage.
These data include a number of studies revealing that oral use of
isotretinoin, especially early in pregnancy, poses a significant risk of
multiple major birth defects in the exposed fetuses as well as a very large risk
for spontaneous miscarriage. Early exposure may even occur prior to a woman's knowledge
of her pregnancy. These major
defects include a syndrome that includes mental retardation, hydrocephalus,
microcephaly, cleft lip and palate, cardiovascular anomalies, and ear and limb
abnormalities. The data supporting
isotretinoin as causing birth defects are strengthened by findings of similar
birth defects in multiple species of experimental laboratory animals exposed to
isotretinoin in utero.
Many fetuses are at risk of
exposure to isotretinoin and its effects. According to a January 2000 Morbidity and Mortality
Weekly Report, the 1999 Boston University Accutane Survey (BUAS) enrolled over
450,000 women between 1989 and 1999; this number translates to about one million
women exposed to the drug during this period.
Despite warning labels and the availability of consumer based educational
information, the BUAS identified 900 women who became pregnant during this
period of time, a rate of 3 women becoming pregnant for each 1000 treatments of
Accutane. CDC and others have documented continued occurrences of isotretinoin-exposed
pregnancies, indicating that more needs to done to eliminate this known risk.
Major birth defects have been
reported in many babies exposed to isotretinoin in utero. In 1999, both
the BUAS and the California Teratogen Information Service reported the birth of
infants who had had fetal exposure to isotretinoin. Roche reported to FDA that,
from 1982 to 2000, there were 1,995 pregnancy exposures and 383 live births of
which 162 had congenital anomalies.
The prescription, dispensing
and consumption of another known potent teratogen, thalidomide is currently
carefully monitored. Due to the
FDA's diligence 40 years ago, thalidomide was not licensed for use in the U.S.
Nonetheless, 10,000 babies were affected worldwide. For thalidomide, a
single registration program currently exists: only physicians registered with
the program may prescribe the drug and only pharmacists registered with the
program may dispense it. Patients
must comply with mandatory education, contraception and monitoring measures. Pregnancy testing must be performed both before and during
treatment, and only one month's supply of the drug is dispensed at a time to
limit its availability. Though
based on small numbers of women this system appears to be highly effective. The
program to reduce in utero exposure to
thalidomide is a more carefully monitored approach than the System to Manage
Accutane Related Teratogenicity (SMART) program currently used to monitor
dispensing of isotretinoin.
Half of all pregnancies in the
U.S. are unintended. Even amongst
college educated women in their 30's, one third of pregnancies are unplanned.
These statistics, and their implications for the significant risk of exposure to
a potent teratogen that is widely prescribed for use in women of child-bearing
age, are a reality that should be recognized.
The voluntary registration and
survey program (SMART), introduced earlier in this year, was designed to improve
the system by applying pressure to join on providers and women consumers of
Accutane. Making the monitoring system even more difficult is the release of
generic forms of isotretinoin. Roche is no longer using the BUAS, though the
generic manufacturers are; thus there will be two separate isotretinoin surveys:
one for the Roche formulation and another for the generic products. The March of
Dimes firmly believes this system is inadequate to ensure 100% participation.
Furthermore, we are concerned that the complexity of the SMART program's
expansion will further erode participation.
We strongly recommend FDA-mandated implementation of a single program
that is designed to put in place a more stringent system that would reduce
exposure to developing fetuses from Accutane/isotretinoin.
We further recommend using as a model the highly effective program that
is already in place for thalidomide.
In conclusion, on behalf of the
March of Dimes, I want to thank you, Mr. Chairman, for holding this hearing
today. March of Dimes volunteers
and staff around the country stand ready to
work with you and the other Members of this committee to support public
policies to prevent birth defects.
References:
1) Wysowski DK, Swann J,
Vega A. Use of isotretinoin (Accutane) in the United States: rapid increase from
1992 through 2000. J Am Acad Dermatol 2002 Apr; 46 (4): 505-9.
Office of Post-Marketing Drug Risk Assessment, Division of Drug Risk
Evaluation, Food and Drug Administration.
2) Honein MA, Paulozzi LJ, Erickson JD. Continued occurrence of Accutane-exposed
pregnancies. Teratology 2001 Sep; 64 (3): 142-7. National Center on Birth
Defects and Developmental Disabilities, Centers for Disease Control and
Prevention.
3) Jones KL, Adams J, Chambers CD, Erickson JD, Lammer E, Polifka J; Teratology
Society. Isotretinoin and pregnancy. JAMA
2001 Apr 25; 285(16): 2079-81.
4) Accutane-exposed
pregnancies--California, 1999. Morbidity and Mortality Weekly Report 2000 Jan
21; 49 (2): 28-31, Centers for Disease Control and Prevention.
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