February 20, 2004
Professor Peter Gross
Department of Internal Medicine
Hackensack University Medical Center
30 Prospect Avenue
Hackensack, NJ 07601
Due to an unexpected family health problem, I will not be able to attend the upcoming advisory committee meeting on Accutane risk management. Based on long observation and careful study, I feel very strongly about this issue and regret that I will not be there to express my views and participate in the committee’s discussion and deliberation. As a member of the committee, I would ask that the following be read aloud at the meeting after all testimony has been presented but before the committee begins its consideration and discussion of the issue and the questions presented it by the Agency.
To be candid, the history of Accutane is an example of inadequate and ineffective risk management by the FDA and the manufacturer of Accutane, to the detriment of thousands of women. Examples are numerous. Although Accutane was a known animal teratogen and a suspected human teratogen at the time of its approval, the company did not recommend and the FDA did not insist upon labeling that emphasized the importance of contraception or abstinence while under treatment with the drug. The consequences of this omission become more apparent when one understands that five women became pregnant while taking Accutane during pre-approval clinical trials despite following the contraception requirements of the study.
In 1988, a highly publicized FDA advisory committee meeting was held to discuss the high level of pregnancy exposure to Accutane and the overuse of the product and its contribution to the pregnancy exposure problem. The Pregnancy Prevention Program (PPP) emerged following this meeting as the primary means of managing Accutane’s teratogenic risks. Several advisory committee meetings were held to monitor the progress of the PPP between 1989 and 1991. It was clear from these meetings that the majority of women taking Accutane were not volunteering to participate in the PPP, that even in the group that did volunteer, pregnancy testing was infrequently performed and that pregnancy exposure to Accutane was still occurring at a high level.
Remarkably, no advisory committee meeting on the Accutane pregnancy exposure and the performance of the PPP was convened until September 2000. At this meeting, it was shown that enrollment in the PPP was low and falling, that pregnancy testing was still often not being performed and that recommendations about contraception or abstinence were often not adhered to. Even more alarming, the use of Accutane in women had increased 3-fold during the preceding 10-year period when one would have expected it to decline substantially because of successful treatment of prevalent cases of severe nodular acne. The committee’s response to this evidence was to declare the PPP a failure and to recommend that a comprehensive risk management program that included patient and physician registration as well as mandatory pregnancy testing be established. None of these has been implemented.
Instead, the SMART program was introduced. It is an effort that added “yellow stickers” to the existing PPP, but had no means of determining if pregnancy testing was actually performed or of how many pregnancy exposures actually occurred. Unfortunately, SMART had the same basic design limitations as the PPP and this should have been recognized. Now, after almost four years and thousands more of unnecessary pregnancy exposures to Accutane, this committee is once again asked to advise the FDA.
Simply put, I believe that isotretinoin is not safe and cannot be used in a safe manner. To minimize the number of pregnancy exposures to isotretinoin, an IND-like process could be implemented that ensures universal pregnancy testing, registration of all pregnancy test results and incorporates a mechanism whereby the drug cannot be dispensed without a negative pregnancy test. This coupling of a negative pregnancy test with dispensing of the drug would be analogous to the policy that has been successfully employed with the anti-psychotic clozaril and has been summarized as “no blood, no drug.” An added benefit of such an approach would be that we would have more accurate information regarding the actual number of pregnancy exposures to the drug. The numbers we have now, coming from a relatively small and self-selected group of volunteers, is undoubtedly a gross underestimate of reality.
Other features of this IND-like approach could include limiting the number of isotretinoin-dispensing centers, mandatory pregnancy-avoidance counseling at each visit and the proviso that dispensing centers would be audited periodically. An important objective of our risk management should be to reduce the overuse of isotretinoin. Therefore, I would recommend that the IND-like process I’ve briefly described include some means of documenting the presence of severe nodular acne in patients being considered for isotretinoin treatment. In clinical trials for the approval of Accutane, only patients with severe cystic acne were enrolled, and photographs of at least some of these patients were taken and used in advertisements and at professional meetings. Perhaps a photograph, documenting the patient’s severe cystic acne, could be required prior to approval for treatment.
The STEPS program for thalidomide has been talked about as a possible model for isotretinoin risk management, but it would not be adequate. If my understanding is correct, there is actually no current coupling of a negative pregnancy test with dispensing of the drug and there is no central registry of the pregnancy test results. Under this system, thalidomide-prescribers answer several questions over the telephone in response to automated prompts in order to receive a number authorizing use of the drug for the next month. This system is very similar to the “yellow-sticker” system under SMART in that it relies on prescriber self-attestation. There is no validation that what the prescriber has answered is true and there is no comprehensive or reliable means of knowing how many pregnancy exposures have occurred.
The occurrence of pregnancy exposures within the original Accutane pre-approval clinical trials, and more recently, within a clinical trial for another formulation of isotretinoin, raises an uncomfortable question. Should this drug have ever been released on the open market? I think it was and is unethical to allow isotretinoin to be available for use outside of the protections that would be afforded by a controlled and documentable process of distribution.
Curt D. Furberg, M.D., Ph.D.
cc: Shalini Jain