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
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