(14) A Comprehensive Review on The Teratogenic Risks for Twelve Drugs with Risk Evaluation and Mitigation Strategy (REMS) to Prevent Prenatal Exposure

Publication Number: 345

Background: Risk Evaluation and Mitigation Strategies (REMS) are programs required by the US Food and Drug Administration (FDA) to minimize treatment risks beyond warnings in drug labeling. REMS requirement for drugs with teratogenic risk is a complex regulatory decision, and evidence on the teratogenicity risk is a crucial determinant.

Objectives: To evaluate the available evidence on teratogenic risks of twelve drugs with a current or former REMS for teratogenicity.

Methods: We conducted a comprehensive literature search using PubMed, Drugs@FDA, REMS@FDA, and FDA Advisory Committee documents to identify publications and reports on teratogenic evidence of the twelve drugs. We included evidence from controlled and uncontrolled studies in humans (e.g., registry analyses), case series, case reports, and controlled animal studies. Among the selected clinical studies, we extracted data on teratogenic outcomes (i.e., pregnancy loss and major congenital malformations) and magnitude of risk if available.

Results: Controlled and uncontrolled human studies were identified for five drugs: thalidomide (1 controlled/5 uncontrolled), isotretinoin (7/18), topiramate (24/2), mycophenolate (6/2), and fingolimod (4/3). The magnitude of risk detail was available for both congenital malformations and pregnancy loss outcomes for each of these drugs. We identified only case reports and case series for bosentan, ambrisentan, macitentan, and telavancin. Animal studies were the only available evidence for riociguat, lenalidomide, and pomalidomide. The REMS programs for fingolimod and telavancin were retired because the risk communication plans were completed as planned, but no new evidence on teratogenicity risk was cited in the FDA decision letters.

Conclusions: The level of evidence detailing the type and magnitude of teratogenic risk in human pregnancy for drugs with a current or former REMS program varied widely. Several drugs received a REMS program despite little or no evidence in humans; however, animal data or concerns about drug class effects informed decisions. Further assessment of the teratogenic risk using real-world data of these drugs could inform regulatory and clinical decision-making in assessing the risk-benefit of treatment and treatment prevention with REMS requirements.