Sep. 18, 2000 (Washington) -- After nearly 20 years on the U.S. market, the popular acne drug Accutane may now face new restrictions on its distribution and use, due mostly to its well-documented ability to cause birth defects.
A panel of expert government advisors Monday recommended that the FDA require both prescribers and users to register with a national database. The panel also recommended that prescriptions be limited to 30 days, and that women be required to have a pregnancy test prior to receiving their monthly prescription.
The Hoffmann-La Roche drug is a treatment for severe recalcitrant nodular acne. This severe form of acne often results in disfiguring scarring and psychological trauma if left untreated.
The panel was concerned about restricting the use of Accutane in women of childbearing age. Since its approval in 1982, a total of 1,995 pregnancies have been reported by women on the drug despite the drug's well-known ability to cause birth defects. These pregnancies resulted in 383 live births, of which about 42% ended in a birth defect.
The first cases of drug-related birth defects were reported in 1983. Since then, the company has taken a number of steps to prevent pregnancies in women taking the drug, including the distribution of more than a dozen "Dear Doctor" letters to inform physicians, pharmacists, and other health care professionals about these potential adverse events.
In 1988, the company also initiated a Pregnancy Prevention Program (PPP). This first-of-its-kind risk-management program was aimed at preventing pregnant women from taking Accutane and preventing those women already on Accutane from becoming pregnant. Among other things, the program stressed the importance of preventing pregnancy, and the significance of using at least two forms of birth control while on the drug.
Despite these efforts, pregnancies continued to occur. In fact, of the 1,995 pregnancies reported since the drug's approval in 1982, about 70% occurred after the PPP was implemented, according to FDA figures.
This absolute number also does not paint the entire picture, says Amarilys Vega, MD, MPH, an epidemiologist in the FDA's office of Postmarketing Drug Risk Assessment. Under-reporting of adverse events is significant, she explains. "We need better means to enumerate pregnancy rates on Accutane. How many pregnancies occurred [among Accutane users] in 1999? No one is sure," Vega says.
Still, there are concrete figures to establish that the PPP program is insufficient, Vega says. Based upon the responses of about 500,000 women that voluntarily enrolled in a study conducted by Boston University's Slone Epidemiology Unit, an estimated 25% of women prescribed Accutane receive no pregnancy test and another 33% begin treatment without first obtaining the results of their pregnancy test, she says.
"There are unacceptable high percentages of physicians and patients not complying with the components of the PPP," Vega says.
Birth defects also are only one of several pregnancy-related problems women confront while on the drug, adds FDA consultant Ed Lammer, MD, a practicing medical geneticist from Oakland, Calif. Even children who appear normal at birth may suffer long-term effects such as learning disabilities, he says. About 40% of these pregnancies result in miscarriage, an often-overlooked side effect, Lammer observes.
"The point is that surveillance of major malformations only hits the tip of the iceberg," he says.
But further regulation over the distribution of Accutane does not enjoy universal support.
"It is education, not mandatory registration, that is the most effective tool," says Barbara Reed, MD, a dermatologist and a member of the American Academy of Dermatology. Mandatory registration disrupts the physician/patient relationship while also restricting the number of physicians able to prescribe the drug, she explains. If patients are forced to give mandatory documentation, they may also seek the drug from underground sources, she says.
Since its approval, the drug has been used by about 2.5 million women, of whom approximately 75% were of childbearing age. This demonstrates that although pregnancies continue to occur, the dimension and challenges of this undesirable outcome has at least been minimized, adds Russell Ellison, MD, vice president of medical affairs at Hoffmann-La Roche.
During the hearing, Hoffmann-La Roche also argued that no additional prescribing or dispensing conditions are needed because of recent changes made to the PPP designed to enhance its effectiveness. These changes include the development of a targeted program specifically aimed at the 3 out of every 1,000 women that truly are at risk of getting pregnant, Roche said.
But after the meeting, Hoffmann-La Roche announced that it would meet with the FDA officials to discuss its panel's recommendations. "We are committed to an optimal risk management program to assure that Accutane is not taken during pregnancy," Ellison says.
The FDA is not bound by its committee's recommendation, but the agency usually does follow its panels' advice.