Isotretinoin prescribing: finding a balance between benefit and risk

More than 25 years have passed since Peck et al. described the dramatic effects of isotretinoin in inducing prolonged remissions of severe acne. Within a year of its 1982 approval for marketing in the Unites States, the teratogenic effects of isotretinoin exposure during pregnancy in humans were established. Starting in 1983, the first of many interventions intended to lower the number of pregnancies exposed to isotretinoin began. The early interventions included a manufacturer’s letters to physicians (Dear Doctor letters), informing them of the revised labeling and a number of publications that emphasized the teratogenic risk of isotretinoin. After a few relatively quite years, in the spring of 1988 prior to an FDA Advisory Committee meeting, a front page New York Times story suggested that hundreds of fetal malformation due to isotretinoin exposure had occurred. These assertions, made in a report authored by Dr David Graham, initiated enhanced efforts to better assess the actual number of birth defects in exposed pregnancies among isotretinoin users, the extent to which those receiving isotretinoin meet the indications for use, and to reduce pregnancy exposures. Following FDA Advisory Committee Meetings in 1988 and 1989, a comprehensive program designed to help insure that those prescribed isotretinoin would meet the labeled indications and counter-indications, was instituted. This program called the Pregnancy Prevention Program (PPP), was designed to help insure that pretreatment pregnancy testing was done, and that patients would be fully informed about the risks of isotretinoin especially those related to exposure during pregnancy, that adequate contraception was used during treatment and that all women provide written consent acknowledging both that they meet prescribing requirements and understood the risks. Additionally, the drug was dispensed in new packaging meant to enhance compliance with the pregnancy prevention program and reduce drug diversion. Further modifications to the PPP were instituted in the spring of 2002. These modifications included prequalification of prescribers and use of stickers to confirm that a negative pregnancy test had been obtained and that women had agreed to use two effective means of contraception; long standing but less well documented elements of the original PPP. The 2002 modifications of the PPP are called the System to Manage Accutane-Related Teratogenicity, SMART. Even if physicians and patients complied with all aspects of either the PPP or SMART programs, as a result of contraceptive failure exposed pregnancies will occur. Although not often explicitly stated, reducing prescriptions to women was seen as one means of reducing the number of isotretinoin exposed pregnancies. In the years following the introductions of the PPPprogram, the best available data suggests use of isotretinoin among females increased substantially. In 1989–1990, the National Ambulatory Care Survey estimated 150 000 visits annually to office based practitioners with an isotretinoin prescription. From 1993 to 1997, there were more than 400 000 such visits annually. Although some of this increase may be attributable to more visits per course of treatment, clearly the PPP did not reduce usage. The introduction of the SMART Program, with its even more rigorous requirements on prescribers and patients, followed renewed focus on isotretinoin risks in the press and at FDA Advisory Committee Meetings. In contrast to the earlier focus on the teratogenic risks of isotretinoin, the meetings and press coverage concerning isotretinoin also devoted substantial attention to the possibility of depression and suicide associated with isotretinoin use. In contrast to the clearly documented and substantial teratogenic risks of