HLI Reports November 1991
THE FACE, THE FETUS, AND THE FDA
Special to HLI
Accutane (isotretinoin) is produced by Hoffman-LaRoche. It was approved by
FDA in 1982 for use in cases of severe recalcitrant cystic acne
unresponsive to other therapies including systemic antibiotics.
At the time of approval, it received an FDA pregnancy category X rating,
because it had been shown to cause birth defects in animals. Category X
designation means that because of the dangers posed by this drug in
pregnancy, Accutane should not be used by women who are pregnant or are at
risk of becoming pregnant. Patient benefit never outweighs fetal risk.
Soon after market introduction in September of 1982, reports of children
born with birth defects due to in utero Accutane exposure began to appear
in the literature and to be received by FDA.
In 1984, FDA convened its Dermatologic Drugs Adviso~r Committee to discuss
the problem of Accutane and pregnancy exposure. The Committee recommended
that product labeling be "strengthened" to warn physicians and patients of
the risks to the fetus posed by first trimester exposure to Accutane.
In 1985, an article appeared in the New England Journal of Medicine
describing "isotretinoin embryopathy," the constellation of birth defects
attributable to Accutane. From this report, it was estimated that in about
33% of the cases, the danger arose because women were being started on
Accutane after they had become pregnant. Up to 25% of pregnancies with
first trimester exposure which came to delivery had a birth defect, with
severity ranging from mild to severe. Birth defects could involve the head,
face, brain, or heart.
In 1988, an FDA report found evidence that Accutane was being used on women
of childbearing age, far in excess of the labeled indication. It was being
used on women with milder or no acne. Although the incidence of severe
cystic acne was roughly two and a half times higher in men than in women,
Accutane usage was nearly equal. Dermatologists prescribed 80-90% of the
drug. The report also estimated that up to 5% of women of childbearing
potential treated with Accutane between 1982 and 1986 had experienced first
trimester pregnancy exposure to it. Of these, at least 60% had undergone
induced abortion (a two-fold increase above the baseline national rate).
This report recommended that FDA consider removing Accutane from the market
as an "imminent hazard."
FDA's Dermatologic Drugs Advisory Committee, which didn't want to accept
the implication that dermatologists were prescribing Accutane outside its
labeled indication, and didn't want to accept the evidence that large
numbers of pregnancy exposures, birth defects and abortions had occurred.
This Committee recommended that the product label for Accutane be
strengthened, that a program be started to educate physicians and patients
on the use of this drug and its risks, and that women be required to sign
an informed consent prior to treatment with it.
FDA and Hoffman-La Roche rewrote the product label for Accutane. The new
label implied that the risk of severe birth defect was virtually 100% and
that this risk applied to all trimesters of pregnancy. The professional
labeling (that intended for physicians) also included a line drawing of the
head of a child with a composite of numerous defects. Further down on the
label was a statement instructing women who become pregnant while using
Accutane to discuss with their physicians the "desirability of continuing
the pregnancy." At a May 1989 Advisory Committee meeting, Dr. Sidney Wolfe
of the Health Research Group told FDA and the Committee that this labeling
would "coerce women" into abortion.
Hoffman-La Roche implemented its "Pregnancy Prevention Program," which
included physician educational mailings, educational advertising, and
visits to physician offices by company representatives to deliver a
"Pregnancy Prevention Kit." This kit included various forms for the
physician to use in determining if female patients met the labeled
indication for the drug and to assist in educating them about the
teratogenic risk and the need to practice contraception while on Accutane.
In a letter to Hoffman-La Roche, FDA stated that the purpose of the
"Pregnancy Prevention Program" was not simply a reduction in birth defects
but the elimination of pregnancy exposure. At three open public Advisory
Committee meetings on the subject of Accutane held in 1989 and 1990,
officials of FDA publicly stated that the goal of the Program was to limit
the use of Accutane to those women with the labeled indication and to
eliminate pregnancy exposure.
In 1989, FDA presented the Accutane issue to two separate groups, the
Dermatologic Drugs Advisory Committee and the Fertility and Maternal Drugs
Advisory Committee. The composition of the Dermatologic Committee is almost
exclusively dermatologists and that of the Fertility and Maternal Drugs
Committee almost exclusively gynecologists. These meetings were intended as
progress reports to update the committees as to what had happened in the
year since the 1988 meeting. An FDA report was prepared which concluded
that there was little evidence of substantive change in the problem. It
also described for the first time the problem of contraceptive failure and
its implications for the Pregnancy Prevention Program.
In May 1990, an FDA report was prepared assessing the impact of the
Pregnancy Prevention Program during 1989. This was presented before a
combined meeting of the Dermatologic Drugs and the Fertility and Maternal
Drugs Advisory Committees. Since the start of marketing in 1982, Accutane
had been prescribed to over 600,000 women of childbearing age, representing
more than 1% of women in this age range. Based on national data relating to
the use of contraception and contraceptive failure, it was estimated that
2-3% of women treated with Accutane had had a first trimester pregnancy
exposure to the drug. Furthermore, based on data from a survey paid for by
Hoffman-La Roche, it was suggested that many physicians were not performing
serum pregnancy tests prior to starting their female patients on Accutane;
indeed, the great majority of women treated with Accutane during the first
year of the Pregnancy Prevention Program had had at least one absolute
contraindication to the use of the drug. Nevertheless, the combined
Committee decided that it was too soon to make a decision on whether the
Program had succeeded or failed.
In May l991, an FDA report was written in preparation for an advisory
meeting scheduled for the end of the month. This report concluded that the
Pregnancy Prevention Program had failed to achieve either of its primary
goals, and that in fact the two goals were inconsistent because Accutane
could not be given to women without pregnancy exposure to it occurring,
because of contraceptive failure if for no other reason. The level of
Accutane use in women of childbearing age had not changed much from the
previous year, with an estimated 57,000 new women and more than 100,000
women (new and retreatment) receiving Accutane during 1990. Of this group,
an estimated 2-5% had first trimester pregnancy exposure to the drug, with
over 75% of these ending with either spontaneous (drug-induced) or
medically induced abortion. About 30% of pregnancy exposures were due to
Accutane being prescribed and started in women after they had conceived;
that is, substantial numbers of exposures were the result of Accutane being
given to pregnant women by their physicians. Updated data from the survey
sponsored by Hoffman-La Roche was used to show that fewer than half of the
women treated with Accutane and enrolled in the survey had a serum
pregnancy test performed prior to starting the drug, and that more than 95%
of women enrolled in the survey had one or more absolute contra-indications
to the use of Accutane as defined in the drug's label. The report concluded
that Accutane could not be given to women without pregnancy exposure
occurring in 2-5% of cases, with subsequent fetal injury or death (due
either to Accutane itself or to induced abortion) in the majority of these.
This report was over-ridden by FDA officials who disagreed with the
report's conclusions and recommendations.
At the advisory meeting of the combined committees held on May 21, 1991,
the goals of the Pregnancy Prevention Program were not stated, abortion due
to Accutane was not mentioned, and the magnitude of pregnancy exposure to
the drug was hardly discussed. The Committee decided that the language
describing the indication for Accutane should be broadened, that product
labeling should 7~0t state that the estimated risk of birth defects is
about 25%, and that the Pregnancy Prevention Program was successful, with
no major changes in marketing or use of Accutane required.
Further Points and Conclusions:
1. In 1989, it was learned publicly that during the controlled clinical
trials of Accutane prior to its marketing (1982), 5% of the women enrolled
in these studies became pregnant while on Accutane, despite signed informed
consent, contraceptive counseling and use, and education about the
potential risk of birth defects. These pregnancies ended with abortion, and
the enrollment of women in the studies was reduced.
2. Product labeling has never described this fact, nor has its implication
for fetal safety (or lack thereof) been publicly discussed.
3. Within FDA, abortion has been viewed as an acceptable solution to the
problem of Accutane usage and pregnancy exposure. Hoffman-La Roche has
viewed abortion as the solution since early in marketing. The reasoning
offered by the manufacturer and by officials within FDA is that the real
goal of the Pregnancy Prevention Program is the elimination of birth
defects, which can be accomplished in two ways: (1) prevent pregnancy
exposure from occurring or (2) prevent those exposed pregnancies from
coming to delivery by abortion. The thrust of product labeling and the full
awareness of contraceptive failure from even before the time of marketing
show which approach has been adopted. FDA officials have been careful to
avoid or prevent public discussion of this for fear that pro-life groups
would learn that what is occurring is "abortion for cosmetic reasons."
4. The use of advisory committees by FDA for this issue shows how the
underlying bias among committee members can be used to guarantee that
certain FDA policies or decisions will be recommended or affirmed by the
Committee. Data for 1990 show that over 90% of all Accutane was prescribed
by dermatologists, that most women receiving the drug didn't have the
disease for which the drug was approved, and that most women didn't even
have an initial serum pregnancy test performed by their physician before
starting Accutane. How likely is it that dermatologists sitting on this
committee, representing the constituency responsible for the magnitude of
the existing problem, would ever find fault with the status quo, would ever
recommend major changes in marketing? How likely is it that a committee of
gynecologists would be sensitive to the abortion issue, which lies beneath
the surface of Accutane use in women? Although one would think that
pregnancy category X designation was intended to protect fetal health as a
priority over that of the patient directly receiving the drug, FDA has
consistently chosen to champion the interests of those advocating
unblemished complexions, at a cost of thousands of fetal deaths which have
been silently swept under the rug by the FDA bureaucracy and the producer
5. In 1989, Dr. Edward Lammer presented data showing that up to 40% of
pregnancies exposed to Accutane during the first trimester ended with
spontaneous abortion (miscarriage) which is three times higher than occurs
among pregnancies where no Accutane has been used. (This should be combined
with the data showing that about 60% of remaining pregnancies end with
induced abortion; the end result being that fewer than 25% of first
trimester pregnancies exposed to Accutane reach delivery. Of those coming
to delivery, as already noted, up to 25% may have a birth defect of some
degree of severity.)
6. Since 1982, over 660,000 individual women of childbearing age have been
treated, for a total of 900, 000 courses of Accutane. Each course lasted
four to five months. Pregnancy exposures to Accutane are estimated at
30,000 to 42,000 during this time, with 22,000 to 32, 000 abortions
(roughly equal numbers of spontaneous and medically
induced). Controversy has existed over the number of children born with
birth defects. FDA estimates range between 1,700 and 2,500, but Hoffman-La
Roche maintains that the only birth defects which have occurred are those
spontaneously reported to it (about 100). For all other adverse reactions,
including birth defects due to other drugs, large-scale under-reporting has
been the rule. It has been convenient for the manufacturers and FDA policy-
makers to point to the relatively few reported birth defects and say the
problem is going away. By focusing on spontaneously reported birth defects,
FDA has surreptitiously directed attention away from the large numbers of
pregnancy exposures and from the abortion-induced deaths of thousands of
in-utero "second-hand patients/recipients" of Accutane.
7. The FDA and Hoffman-La Roche frequently talk about "benefit-risk ratio"
and say that the benefit of Accutane treatment far exceeds the risk of
fetal death, in contradiction to the words which describe pregnancy
8. At the 1991 advisory meeting, a report from the American Academy of
Dermatology was circulated and discussed, in which acne severity was re-
defined in such a fashion that moderate acne could be considered "severe"
and in which great emphasis was placed on factors such as psychic distress.
A shift of definition cannot conceal the basic fact: acne is not generally
regarded as a "life-threatening" disease, yet thousands of unborn children
have died as a direct result of Accutane use.
Editor's comment. The preceding article can be a crucial. document in the
malpractice suits which women all over America can bring against careless
dermatologists. If you have first-hand information about Accutane use by a
pregnant woman, please write to HLI Reports.