New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence.

INTRODUCTION

After the approval of a new drug, the Food and Drug Administration (FDA) may issue postmarketing requirements (PMRs), studies that the law requires manufacturers to conduct for drugs approved under certain conditions, and postmarketing commitments (PMCs), studies that the FDA and manufacturers agree should be conducted as a condition of approval.

OBJECTIVE

With regulators' increasing reliance on gathering important evidence after initial product approval, we sought to assess the track record of PMRs and PMCs by synthesizing information about postmarketing study completion rates, timeliness, study types, and results reporting.

METHODS

A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. Studies published in academic journals or government reports that reported original data about the characteristics of PMRs or PMCs were included. Studies of post-approval trial mandates issued by regulators outside the USA were excluded, as were those that addressed post-approval research without mentioning either PMCs or PMRs or a specific approval pathway associated with statutorily required PMRs. Two investigators independently screened and extracted data from studies and reports. Data sources included the Federal Register from 2003 to 2020, FDA backlog reviews from 2008 to 2020, PubMed from January 2006 to April 2021, and the US Government Accountability Office (GAO) database for reports from January 2006 to April 2021. PMR/PMC characteristics (e.g., completion rates, timeliness, results reporting, outcomes) were not meta-analyzed due to the heterogeneity in study designs.

RESULTS

Twenty-seven peer-reviewed articles from PubMed, five GAO reports, 17 annual Federal Register notices, and 12 annual backlog reviews were included. Among the 27 studies, 13 reviewed PMRs and PMCs, one reviewed only PMCs, and 13 reviewed only PMRs. A majority of new drugs were approved with at least one PMR or PMC. PMCs were completed at higher rates than PMRs, although delays were common and neither was found to be completed more than two-thirds of the time. Over two-thirds of PMRs and PMCs reported their findings in publications and trial registries. Over half of PMCs and PMRs produced novel information for clinical practice or leading to regulatory action, such as confirmation of benefit or a labeling change.

CONCLUSION

PMRs and PMCs are common for new drugs and can lead to worthwhile outcomes, but are often delayed or incomplete. Greater attention is needed to timely completion, improving transparency of findings, and ensuring that PMRs and PMCs produce optimally useful information for prescribers and patients.