UF study finds FDA strategy cuts fetal exposure to harmful immunosuppressive drug, but risks remain

University of Florida researchers determined an FDA-approved program deters pregnant women from starting a potentially harmful immunosuppressive drug. But for women taking the drug, the program was not effective at reducing conception.

REMS StudyMycophenolate helps prevent organ rejection after transplantation and is increasingly used for a variety of autoimmune disorders such as lupus or psoriasis. However, studies suggest mycophenolate also can increase the risk of miscarriage and birth defects, so it is not recommended for use during pregnancy.

The FDA implemented a Risk Evaluation and Mitigation Strategy, or REMS, program in 2012 because of fetal safety concerns involving mycophenolate. The REMS requires certain precautions, including mandatory prescriber trainings, a patient acknowledgment form and other measures to ensure the drug is used safely. More than 200 REMS programs have been established by the FDA to address drug safety concerns, and the University of Florida study is the first to assess the effectiveness of the mycophenolate REMS program.

Almut Winterstein Headshot_web
Almut Winterstein, R.Ph., Ph.D., FISPE

“As chair of the drug safety and risk management advisory committee for the FDA, I was oftentimes faced with the need to make REMS program recommendations for drugs with certain safety concerns,” said Almut Winterstein, R.Ph., Ph.D., FISPE, a professor and the Dr. Robert and Barbara Crisafi Chair in Pharmaceutical Outcomes and Policy in the UF College of Pharmacy and the director of the UF Center for Drug Evaluation and Safety.

“Unfortunately, there is little evidence of the effectiveness of REMS programs to mitigate risk, and we were left questioning whether provider trainings and consent forms were really moving the needle in terms of safety,” she said. “Our study shows there is value in continuing REMS programs to improve drug safety, but more needs to be done to tailor them to a specific clinical scenario to ensure they are effective.”

When the FDA approved the mycophenolate REMS, the goals were to discourage pregnant women from starting to use the drug and for others to avoid conception while they were being treated.

Researchers in the UF College of Pharmacy used a large national private insurance claims database to evaluate the rate of fetal mycophenolate exposure during REMS (2012-14) compared with prior years (2007-12) when only written information about fetal concerns was provided via the drug label and a medication guide. More than 36,000 mycophenolate treatment episodes were analyzed, and the study determined women treated during the REMS period were 58% less likely to be pregnant on the first day of treatment compared to when only written information was used.

Importantly, UF researchers also examined whether REMS helped deter women from becoming pregnant during mycophenolate treatment and found REMS was not effective in preventing conception.

“The FDA implemented several rules to ensure no fetal exposure, including a consent form which requires women to agree to use two forms of contraception if they are sexually active,” Winterstein said. “It appears the strategy has not worked to ensure patients successfully follow the strict contraception warnings.”

Winterstein and Amir Sarayani, Pharm.D., M.P.H., the study’s lead author and a graduate student in the department of pharmaceutical outcomes and policy in the UF College of Pharmacy, are calling for more research to understand the effectiveness of different REMS programs. The additional knowledge will help to inform evidence-based regulatory decision-making and improve patient safety.

The study “Comparative Effectiveness of Risk Mitigation Strategies to Prevent Fetal Exposure to Mycophenolate,” was originally published in BMJ Quality and Safety, a peer-reviewed health care journal focused on improving patient safety and quality of care.