On February 26 and 27, 2004, the Food and Drug Administration (FDA) convened a joint Advisory Committee meeting of the Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee to discuss the "Effectiveness of the Isotretinoin Risk Management Program for the Prevention of Fetal Exposure to Accutane and its Generic Equivalents and Consideration of whether Changes to Isotretinoin Risk Management Program would be Appropriate."

Dr. Steve Galson, acting director of CDER, set the stage for the meeting and restated the goals of the 2001 risk management program, S.M.A.R.T.- that no person should begin isotretinoin therapy if pregnant and that no pregnancy should occur while a woman is taking isotretinoin - but at the same time pointed out that a goal of zero pregnancy was not practical.

Dr. Jill Lindstrom summarized the regulatory history of isotretinoin in its 22 years on the market in the US. There were two speakers in the open public hearing -Drs. Robert Silverman and Sidney Wolfe. Dr. Silverman, a pediatric dermatologist at Georgetown University spoke in favor of keeping the drug on the market for use in a responsible fashion as it was the only really effective drug for severe acne. Dr. Wolfe of the Public Citizen's Health Research Group, argued for restricted distribution to curb off-label use of the drug and reduce exposure during pregnancy in this way. This was followed by presentations from the sponsors, Hoffman-La Roche, Inc., and a representative of the generic firms, outlining their proposal for a new, more robust risk management plan. Dr. Allen Mitchell of Boston University’s Slone Epidemiology Center then followed with a report on the isotretinoin survey conducted by his unit. This survey assessed aspects of the S.M.A.R.T. program.

The afternoon session saw presentations by FDA — Dr. Marilyn Pitts summarized data that showed isotretinoin exposed pregnancies were still being reported to AERS — and Dr. Allen Brinker critically reviewed the evaluation of the S.M.A.R.T. program, pointing out areas of weakness. Dr. Richard Wagner of Kaiser Permanente, California, presented his organization’s experience with a different approach than the SMART program, but with the same goals. Two more presentations from the agency completed the afternoon’s session: Dr. Kathleen Uhl presented an overview of drug related teratogenic risk during pregnancy and risk management options for pregnancy prevention. Dr Anne Trontell presented a discussion of various risk management tools generally available for use.

The early part of the second day was dominated by dramatic testimony in the open public hearing. Congressman Bart Stupak, who indicated that his son committed suicide while on isotretinoin, was the first presenter. He outlined the history of recommendations made at isotretinoin advisory committee meetings over the years. He pointed out that there was probably substantial off label use, as it was estimated that there were 6000 women with severe nodulocystic acne, but 1.5 million prescriptions were written in 2001, and exposed pregnancies were still being reported to the FDA. He was skeptical that anything less than a mandatory registry would be helpful in reducing the risk of exposed pregnancies and resulting congenital malformations. The committee then heard from 3 representatives of dermatology healthcare providers associations, all of whom expressed a desire to see isotretinoin remain on the market to be available for patients who needed it, as it is a very effective drug. The committee also heard from a lawyer who represented families with claims of harm due to isotretinoin use, and from several parents and patients who had experienced birth defects or depression associated with isotretinoin exposure. This latter group was in favor of a registry for patients, healthcare provider and pharmacists. The final speaker was an industry consultant representative, who discussed issues in design of a pregnancy registry. The committee members deliberated and discussed the questions posed by the FDA. At the end of the day, there was general agreement that the goals were not being met by the current program and that a more comprehensive risk management program with registration of all prescribers, patients and dispensing pharmacies should be adopted.

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