The FDA and Accutane

Author: HLI

HLI Reports November 1991


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 of Accutane.

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 category X.

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.