But reports of Accutane-exposed pregnancies continue, and that's enough to make FDA concerned, says Peter Honig, MD, director of FDA's office of postmarketing drug risk assessment (OPDRA) in CDER.
Shortly after the Pregnancy Prevention Program began, Roche sponsored a survey of women taking Accutane to assess compliance with the program, and the company encouraged doctors to enroll patients. Run by the Slone Epidemiology Unit at Boston University's School of Public Health, the survey set out to track pregnancy rates and outcomes, patients' awareness of risks, and patient and physician behavior.
Of the 500,000 women enrolled in the Slone survey from 1989 to 1998, there have been 958 pregnancies, 834 of which were terminations (either elective, spontaneous or due to ectopic pregnancies), 110 that resulted in live births, and 14 patients that had unknown outcomes. Of the 60 infants with available medical records, eight had congenital abnormalities. Since Accutane's approval, Roche has received close to 2,000 reports of Accutane-exposed pregnancies, 70 percent of which occurred after the PPP began.
According to FDA, exactly how well the PPP has worked is unclear. Experts say the PPP is a significant program that has prevented many pregnancies and is the first of its kind initiated by a pharmaceutical company. Roche has made extraordinary efforts to educate patients that they must not become pregnant while taking Accutane, says a Roche spokesperson.
At a September 2000 meeting of FDA's Dermatologic and Ophthalmic Drugs Advisory Committee, a Roche representative reported that from the company's perspective, pregnancy rates have declined. Amarilys Vega, MD, an FDA medical officer, agreed. However, because use of the product has increased over the years, the actual number of pregnancies occurring while taking Accutane has not declined. One limitation is that the survey is voluntary and only captures about 30 to 40 percent of all patients on Accutane. So there's no way to know exactly how many pregnancy exposures there have been, according to FDA experts. Of serious concern is that women who enroll in the survey may be more likely to comply with the contraceptive requirements than those who don't enroll in the survey. This leaves open critical questions about how representative the PPP group is and about unreported pregnancies among women who don't enroll in the PPP.
Most patients in the Slone survey have reported that they understood Accutane may cause birth defects. And according to Roche, the percentage of female patients who reported they were pregnant when they began Accutane dropped from 30 percent of pregnancies reported in 1989 to 11 percent of pregnancies reported for the period of 1991 to 1997. But substantial noncompliance with the PPP continues to be reported.
For example, a 1997 report on the survey shows that 25 percent of women in the program did not report having a pregnancy test before starting Accutane, and 33 percent did not report postponing the start of Accutane until a pregnancy test result was known. It is estimated that 40 percent of women taking Accutane are sexually active.
The only patients exempt from Accutane's contraceptive requirements are men, and women who have had a hysterectomy or who say they will abstain from sex during treatment. But the challenge is that going from sexually inactive to active can happen overnight.
