11 Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition Early Forms of Formal Risk Management: The Isotretinoin (Accutane) Example Formal systems for drug product risk management developed gradually during the two decades leading up to the creation of REMS by FDAAA. A noteworthy example was the system developed for isotretinoin (originally sold under the brand name Accutane), a vitamin A analog indicated for the treatment of severe forms of acne. It had unequivocal benefit for many patients, but it also had the potential to cause severe birth defects if used during pregnancy. The risk was compounded by the fact that female patients who use isotretinoin often are at an age when sexual activity might occur and frequently are those whose self-perception of social rejection due to severe acne also might increase the likelihood of sexual activity and pregnancy. Throughout the 1980s and 1990s, FDA wrestled with how to maintain isotretinoin’s availability for patients who needed it while trying to prevent its inadvertent use by girls and women who might become pregnant.1,2 Hoffmann-LaRoche, the original product manufacturer (before the advent of generic isotretinoin products), worked cooperatively with FDA to try to balance the drug’s avail- ability by controlling its use. Isotretinoin provided cosmetic benefits that helped end the social isolation and alienation of adolescents with severe acne. While it originally was labeled for use in cystic acne and now is labeled for severe recalcitrant nodular acne, it always was widely prescribed for any severe acne, “severe” being the prescribing physician’s judgment. At one point in the 1980s, when isotretinoin was labeled for treatment of cystic acne, the number of prescriptions written in the US exceeded the number of patients with cystic acne by a factor of two. This “overprescribing” has continued throughout the years at an FDA Advisory Committee Meeting in 2011,3 it was stated that there were more than 4,000 patients with severe recalcitrant nodular acne in the US, but about 250,000 prescriptions for isotretinoin were being written each year. This discrepancy was largely 2 Pharmaceutical Risk Management Plans Before REMS
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