By John Carruthers, staff writer, May 01, 2012
The use and regulation of isotretinoin has been a significant issue in dermatology since the strong link between the drug and birth defects came to light, and ramped up further when the media took to the issue in the early 2000s. Women of childbearing age taking oral isotretinoin were said to have a fetal exposure risk of up to one in every 300-450 courses of therapy, according to the CDC. After a 250 percent increase in isotretinoin prescriptions from 1992 to 2000, widespread fear of perceived risks led to a decline in prescriptions of 23 percent between 2002 and 2003.
As a result, the FDA began efforts to ensure safe use in patients of childbearing age while still protecting patient access to the vital drug. Following the widely perceived failure of the FDA’s original System to Manage Accutane-Related Teratogenicity (SMART) program, the FDA instituted the iPLEDGE program in March 2006. Under the program, patients and their physicians and pharmacists were required to register on the FDA’s iPLEDGE website and follow a set of regulations designed to minimize the risk of fetal exposure. More than six years after the program’s implementation, dermatologists say the program has set a number of good prescribing practices while paradoxically failing to significantly decrease the annual number of fetal exposures.
iPledge and patient registration
Controversial at the outset, the iPLEDGE program, with its strict prescribing windows, blackout periods, and mandatory registration for both female and male patients, has been called “a logistical nightmare,” with loopholes “sealed with a wall of bureaucratic red tape,” by Danbury, Conn., physician Graeme Lipper, MD, in an isotretinoin column published on MedScape. Yet over the years, some of the program’s rougher edges have been smoothed away thanks to physician and patient advocacy.
According to dermatologist Mary Maloney, MD, who chairs the American Academy of Dermatology Association’s Regulatory Policy Committee, there is still room for the program to improve, becoming more consumer-friendly, though it’s doubtful that this will happen soon.[pagebreak]
“One of the things that I question is the validity of continuing to register men. And I think that there is absolutely no question about the fact that there’s no indication for the registration of men. It doesn’t provide us any detail on the epidemiology of the use of istotretinoin, they’re at no risk of getting pregnant, and whether or not we register them, they can still give their medicine away if they want to,” Dr. Maloney said. “Some of the logic was letting men know that they couldn’t give their medicine to their girlfriend, for example. But it has significant costs to the health care system to register men, so I think that’s an area where we should continue to work and see if we can somehow eliminate some of those costs.”
Former Academy President Stephen P. Stone, MD, who co-authored an editorial on iPLEDGE with Dr. Maloney in the Journal of the American Academy of Dermatology (2011;65:418-9), said that at present, the iPLEDGE program is running with relative smoothness, especially compared to the furor that met its launch during his presidential year. From the perspective of those in charge of the program, he said, it may not prove worthwhile to significantly alter it at present.
“I think there are still some dermatologists who feel it should be changed and liberalized a great deal,” Dr. Stone said. “But I’m not sure that it will be done. There is certainly a vested interest on the part of people who participate in the program to maintain it running smoothly. And I think that quite frankly there is a concern if we change too much, it will increase the risk of pregnancies. Another question is how much it will cost to make these changes. Still, it makes no sense to include males in the program at this point.”
While many aspects of iPLEDGE and isotretinoin are hotly debated, one fact that remains at the center of the debate is that the program has not been able to significantly decrease the number of fetal exposures per year. This, according to Dr. Maloney, implies that the program has reached something approaching a baseline minimum.
“The failures are failures of compliance, either with taking birth control pills, or with using two barrier methods,” Dr. Maloney said. “We just haven’t seen that number budge significantly through all of the FDA’s programs. It’s always been 120 plus or minus five, seven, two and we can’t seem to break that number.”
While the fetal exposure numbers may not have changed, Dr. Stone said, there is a visible difference in physician attitudes toward exposure and risk management.[pagebreak]
“People who continued to prescribe the drug have developed a significant understanding of the rationale for the REMS [Risk Evaluation and Mitigation Strategies]. It clearly is important that these drugs that can cause such terrible, avoidable side effects be carefully handled,” Dr. Stone said. “I remember years ago I was talking to a dermatologist who said that he wasn’t going to do pregnancy tests on his patients back before it was compulsory. He said I’m from a small town, I know these kids, I know they’re not sexually active.’ Well lo and behold, that’s exactly the kind of patient that risks exposure. So I think we’ve developed a healthier awareness that you really do have to at least follow some rules and take more than a common sense approach to the issue.”
Despite appearing to reach something of a plateau, Dr. Maloney said that as the chair of the Academy’s relevant committee, she has not received any feedback from the FDA indicating that a more strict REMS system is in the works.
“I can’t speak for the FDA, but personally, I haven’t felt pressure from them that we need to have a stricter program,” she said. “I haven’t felt that as a practitioner or as part of the Regulatory Policy Committee, which I think is reasonable. I think that we have a very tough REMS program at present.”
To truly decrease the number to zero, Dr. Maloney said, isotretinoin would likely have to be completely withdrawn, which she does not advocate.
“I think it’s a great drug. We need to have it available for the patients that need it, and a lot of them do. I think that because we deal with human beings, we have a program that we probably can’t make a lot better,” Dr. Maloney said.
In terms of issue visibility, Dr. Stone said, patients and physicians are much more aware of the risks associated with isotretinoin and the proper precautions for treatment than before the media, Congress, and the FDA took up the issue.
“I think that we’ve also learned that in spite of the best we can do, there are a small number of patients who, even when we play the game exactly as we should, will get pregnant,” Dr. Stone said. “But certainly it seems that something like iPLEDGE — involving the compulsory regulation of the patient, the forced reminding with each prescription refill of the serious risk of pregnancy — gets the point across that would not be gotten across if we just had to put a sticker on the prescription pad.”
Isotretinoin and IBD
During isotretinoin’s prolonged term in the public eye, some in medicine and the media began to question whether there was a link between the drug and the development or exacerbation of inflammatory bowel disease (IBD). After Roche Holding ceased production of Accutane in 2009, a Los Angeles Times headline read “New study may deal final blow to acne drug Accutane.” Yet a number of dermatologists and researchers found no link with IBD following population-based case control studies.
Researchers at the University of Manitoba found that isotretinoin use was neither more nor less prevalent in patients suffering from IBD than in the general population. A June 2011 article by Catalin Mihai Popescu, MD, PhD, and Raluca Popescu, MD, PhD, in Archives of Dermatology (2011:147(6);724-729) concluded that there was insufficient evidence to confirm or refute a causal association between isotretinoin and IBD.
Dermatologist Elliot Mostow, MD, who prescribes isotretinoin to patients, and who offered comment on the Archives article (2011:147(6);729-730), said that he makes patients aware of all the issues linked to the drug, and stresses that the benefits outweigh the potential side effects.
“I have a discussion with my patients who are contemplating isotretinoin that goes beyond iPLEDGE to try to include as many potential areas of side effects that they might read about elsewhere as possible,” Dr. Mostow said. “I want them to know that I am aware of the issues, some that can be proven, some that cannot, and am still willing to prescribe the medication because I believe that the benefits outweigh the risks.”
Dr. Mostow acknowledges that especially in patients with a family history of IBD, it can be an especially difficult decision to accept isotretinoin treatment.
“I reference the article by Popescu in the Archives of Dermatology (and my own comment there), that a critical number is the number needed to treat’ of 2977 (I say 2900 generally), meaning we need to treat 2977 people to get one case of ulcerative colitis,” Dr. Mostow said. “I use a line I borrowed from the epidemiologist David Savitz, PhD, stating that the one thing we know for sure is that this product will not prevent or cure any of the side effects that are reported in the literature. It can be a tough decision, and I acknowledge that with parents and patients. All of this being said, most people appreciate the honest approach and many decide to proceed.”
Aware of the litigious nature of isotretinoin treatment, Dr. Mostow has patients or their parents sign an additional form outlining each of the potential side effects that he discusses with patients, and takes extra time to address each of the concerns that patients may have. In all, Dr. Mostow said, the vast majority of patients are thankful that isotretinoin is available as a means of treatment. That, he said, is the most consistent side effect of isotretinoin in his office.