Public Citizen’s Health Research Group has been warning the
FDA about the risks of birth defects and mental retardation for fetuses exposed to isotretinoin (ACCUTANE) for over 20 years.
In 1983 we sent a petition recommending patient package inserts and a black box warning describing the risks of birth defects
and life-threatening side effects of the drug. The next year we sent a letter advocating improved pregnancy surveillance and
lower dosing regimens. In 1988 we described isotretinoin as an imminent public health hazard to an FDA Advisory Committee
and we urged the FDA to remove it from the market unless tight restrictions were implemented and proved effective. Our proposed
restrictions included limiting prescribing to board-certified or eligible dermatologists who would be required to file a sworn
affidavit with the FDA attesting they will adhere to the stated indications for the drug, mandating written informed patient
consent, including pregnancy testing requirements in the black box warning, and mandating pregnancy and adverse event reporting
to the FDA. The month after the testimony, we filed a petition outlining our recommendations. The following year we testified
and again urged the FDA to remove isotretinoin from the market unless our previously proposed restrictions were immediately
adopted. The next month we testified before a different FDA Advisory Committee and made the same recommendations. The next
year, 1990, we testified again and reiterated our proposed changes. Then, in 2000 we testified and recommended a Patient Medication
Guide and again advised removal from the market unless the restrictions were implemented and shown to be effective.
In 1989, the CDC testified before an FDA Advisory Committee, stating
that, “[t]he birth of babies with defects caused by fetal exposure to Accutane is unnecessary,” and the “...FDA
decision to allow the marketing of Accutane [is] a failed regulatory experiment.” They also declared that a “...decision
to depend on better contraception alone, without active intervention to reduce the number of users, is a decision to leave
the number of affected babies at an unacceptably high level.” They suggested that “[p]erhaps a formal IND...would
be a suitable mechanism...to reduce the frequency of Accutane embryopathy.” This echoes Public Citizen’s recommendation
to remove Accutane from the market and reintroduce it only under strict Investigational New Drug (IND) restrictions.
Since there is currently no reporting requirement for pregnancies
exposed to isotretinoin, the actual numbers of affected pregnancies are unknown. There is information from surveys and spontaneous
reporting, however, and according to data presented at the 2000 FDA Advisory Committee meeting, there have been 1,995 pregnancies
exposed to Accutane between 1982 and 2000. The known outcomes of these pregnancies included 1,214 elective abortions, 383 live births, and 162 infants with birth defects. During the first year of S.M.A.R.T., the System to Manage Accutane
Related Teratogenicity, there were 156,800 “unique” women who were given the drug, and the pregnancy rate was
estimated at 0.35%. We can therefore calculate that there would be 548 total pregnancies, which is 4.6 times higher than the
120 pregnancies spontaneously reported. Of 61 pregnancies with known outcomes, 48/61 or 78.7% resulted in elective abortions.
Applied to the 548 estimated pregnancies, there would have been 431 elective abortions in that year. Of 61 pregnancies with
known outcomes, 7/61 or 11.5% resulted in deliveries. Based on the 548 estimated pregnancies, there would have been 63 deliveries.
Using estimates of 25% birth defects and 50% mental retardation, this would result in 16 infants with birth defects and 31
with mental retardation.
Proposals of S.M.A.R.T. and the new Roche, the drug’s manufacturer,
have failed to seriously address two major issues. The first is the need for at least a 95% reduction in prescribing. The
CDC estimated in 1989 that there were no more than 4,000 women of child-bearing age with severe cystic acne. Adjusting for
population growth, this number may now be 6,000. Given that there were 156,800 “unique” women of child-bearing
age who got the drug in 2002-2003, this represents a twenty-six fold excess in prescribing over the number of on-label prescriptions.
The second problem is the need for mandatory pregnancy test results (not just assurance) before starting therapy and monthly
while on therapy as a prerequisite for getting every prescription filled.
We therefore insist on the withdrawal of isotretinoin from the market.
Twenty years of failed voluntary and, more recently, mandatory restrictions have led to a total of more pregnancy exposures
because the total number of prescriptions has increased. As we recommended in 1988 and the CDC suggested the next year, a
ban on marketing with subsequent availability only under a tightly controlled investigational new drug application (IND) procedure
is the only feasible way to significantly reduce prescriptions and pregnancy exposures.
The restrictions under the IND should include the following provisions
to reduce over-prescribing of the drug and pregnancy exposures. Photographic proof of severe cystic acne confirmed by an independent
group of dermatologists should be required. A written record of adequate previous treatment and recalcitrance to it should
also be obligatory. Another portion of the IND should be a compulsory written statement of contraceptive practices and provision
of a copy of the negative pregnancy test in order for the drug to be dispensed.
The S.M.A.R.T program is clearly a failure. Without these proposed
IND restrictions, this administration and this advisory committee will continue to put its imprimatur on the reckless use
of a drug that each year causes the need for hundreds of abortions and many seriously deformed infants with birth defects
and/or mental retardation. It is time to end the more than twenty years of voluntary restrictions that have failed to reduce
its prescribing for more than ten times as many women as would be using the drug if it were limited to the approved indications.
What You Can Do
You or your children should use isotretinoin only in the case of
severe recalcitrant nodular acne after other safer acne treatments have been tried and failed. Exposure of an unborn fetus
to isotretinoin is a serious adverse event and should be reported directly to the FDA Med Watch Program along with other adverse