How Safe Are New Drugs? Analysis of US FDA Safety Regulatory Actions, 1980-2021

OBJECTIVES: The USFDA's expedited pathways for drug development and review have enabled the rapid introduction of new drugs to the market, but have also reduced the available evidence on their safety and efficacy. This study assessed trends in USFDA safety actions, including market discontinuations, risk evaluation and mitigation strategies (REMS), boxed warnings, medication guides, and patient information, for new drugs approved by the USFDA between 1980 and 2021. It also evaluated the association between expedited review pathways and USFDA safety regulatory actions, and assessed the effect of the Prescription Drug User Fee Act (PDUFA) and the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) on USFDA safety regulatory actions.

METHODS: Data on new molecular entities, new therapeutic biologics, and gene and cell therapies approved between 1980 and 2021 were extracted from the USFDA website. Descriptive analysis, restricted cubic spline non-parametric linear regression, and logistic regression were performed.

RESULTS: From 1980 to 2021, the USFDA approved 1,310 new drugs. A total of 343 (31.8%) new molecular entities, 87 (39.7%) biologics, and 6 (50.0%) cell and gene therapies had boxed warnings. Market discontinuation affected 198 (15.1%) products, including 39 (3.0%) that were withdrawn for safety reasons. PDUFA increased patient information by 30% per year, while FDASIA increased patient safety information by more than 50% per year, medication guides by 15% per year, and REMS by 4%. Boxed warnings decreased by 11% per year after FDASIA.

CONCLUSIONS: Safety withdrawals and REMS affected a relatively low number of drugs. Safety-related boxed warnings, medication guides, and patient information were included in the labels of one-fourth of the new drugs. The safety information directed to health care professionals decreased, while the safety information directed to patients increased during the study period.