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

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Abstract

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.

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Acknowledgements

Mr. Moneer affirms that the article is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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Authors and Affiliations

  1. Yale School of Medicine, New Haven, CT, USA

    Osman Moneer

  2. Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA

    Osman Moneer, Beatrice L. Brown, Jerry Avorn, Jonathan J. Darrow, Mayookha Mitra-Majumdar & Aaron S. Kesselheim

  3. Kaiser Permanente Institute for Health Policy, Oakland, CA, USA

    Krysten W. Joyce & Murray Ross

  4. Kaiser Permanente National Pharmacy, Downey, CA, USA

    Catherine Pham

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Correspondence to Aaron S. Kesselheim.

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Funding

Kaiser Permanente Institute for Health Policy. Aaron S. Kesselheim also receives funding from Arnold Ventures.

Conflict of interest

Murray Ross and Krysten W. Joyce receive support from Kaiser Foundation Health Plan as salaried employees. Jonathan J. Darrow and Aaron S. Kesselheim receive grants/contracts from Commonwealth Fund, Greenwall Foundation, Health Action International’s ACCISS program, National Institutes of Health, West Health, Novo Nordisk Foundation, and Massachusetts Health Policy Commission. Jonathan J. Darrow has royalties/licenses from Wolters Kluwer. Jonathan J. Darrow has received payments from National Cooperative Rx. Jonathan J. Darrow is involved with CURE Drug Repurposing Collaboratory (NIH-FDA) and the Swiss non-profit Molecule in an unpaid capacity. Murray Ross is a board chair for the Institute for Clinical and Economic Review and a board chair for the Network for Excellence in Health Innovation. Osman Moneer, Beatrice L. Brown, Jerry Avorn, Mayookha Mitra-Majumdar, and Catherine Pham have no interests to disclose.

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OM had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. OM, BLB, and ASK were responsible for the data acquisition and analyses. All authors contributed to interpretation of the findings. OM drafted the manuscript. All the authors contributed to critical revision of the manuscript for important intellectual content. ASK supervised the study. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors have read and approved the final version of the manuscript.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Moneer, O., Brown, B.L., Avorn, J. et al. New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence. Drug Saf 45, 305–318 (2022). https://doi.org/10.1007/s40264-022-01152-9

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