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    Original Investigation
    Health Policy
    April 21, 2020

    Assessment of Clinical Trials Supporting US Food and Drug Administration Approval of Novel Therapeutic Agents, 1995-2017

    Author Affiliations
    • 1New York University School of Medicine, New York
    • 2Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Connecticut
    • 3Yale School of Medicine, New Haven, Connecticut
    • 4Brigham and Women’s Hospital, Boston, Massachusetts
    • 5now with Bain Capital Life Sciences, Boston Massachusetts
    • 6Division of Health Care Policy and Research and Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
    • 7Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut
    • 8Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut
    • 9Section of General Internal Medicine, Yale School of Medicine, New Haven, Connecticut
    • 10National Clinician Scholars Program, Yale School of Medicine, Department of Internal Medicine, New Haven, Connecticut
    JAMA Netw Open. 2020;3(4):e203284. doi:10.1001/jamanetworkopen.2020.3284
    Key Points español 中文 (chinese)

    Question  Have the number and characteristics of pivotal efficacy trials supporting US Food and Drug Administration approval of new drugs and biologics changed during the past 3 decades?

    Findings  In this cross-sectional study of 273 new drugs and biologics approved by the Food and Drug Administration for 339 indications in 3 periods (1995-1997, 2005-2007, and 2015-2017), more recent approvals increasingly used special regulatory programs and were based on fewer pivotal trials. When aggregated by indication, these trials had less rigorous designs but longer trial durations over time.

    Meaning  This study found changes in the evidence supporting Food and Drug Administration approval of new drugs and biologics that suggest an ongoing need for continued evaluation of therapeutic safety and efficacy after approval.

    Abstract

    Importance  Since the introduction of the Fast Track designation in 1988, the number of special regulatory programs available for the approval of new drugs and biologics by the US Food and Drug Administration (FDA) has increased, offering the agency flexibility with respect to evidentiary requirements.

    Objective  To characterize pivotal efficacy trials supporting the approval of new drugs and biologics during the past 3 decades.

    Design, Setting, and Participants  This cross-sectional study included 273 new drugs and biologics approved by the FDA for 339 indications from 1995 to 1997, from 2005 to 2007, and from 2015 to 2017.

    Main Outcomes and Measures  Therapeutics were classified by product type and therapeutic area as well as orphan designation and use of special regulatory programs, such as Priority Review and Accelerated Approval. Pivotal trials were characterized by use of randomization, blinding, types of comparators, primary end points, number of treated patients, and trial duration, both individually and aggregated by each indication approval.

    Results  A total of 273 new drugs and biologics were approved by the FDA in these 3 periods (107 [39.2%] in 1995-1997; 57 [20.9%] in 2005-2007; and 109 [39.9%] in 2015-2017), representing 339 indications (157 [46.3%], 64 [18.9%], and 118 [34.8%], respectively). The proportion of therapeutic approvals using at least 1 special regulatory program increased (37 [34.6%] in 1995-1997; 33 [57.9%] in 2005-2007; and 70 [64.2%] in 2015-2017), as did indication approvals receiving an orphan designation (20 [12.7%] in 1995-1997; 17 [26.6%] in 2005-2007, and 45 [38.1%] in 2015-2017). The most common therapeutic areas differed over time (infectious disease, 53 [33.8%] in 1995-1997 vs cancer, 32 [27.1%] in 2015-2017). When considering the aggregate pivotal trials supporting each indication approval, the proportion of indications supported by at least 2 pivotal trials decreased (80.6% [95% CI, 72.6%-87.2%] in 1995-1997; 60.3% [95% CI, 47.2%-72.4%] in 2005-2007; and 52.8% [95% CI, 42.9%-62.6%] in 2015-2017; P < .001). The proportion of indications supported by only single-group pivotal trials increased (4.0% [95% CI, 1.3%-9.2%] in 1995-1997; 12.7% [95% CI, 5.6%-23.5%] in 2005-2007; and 17.0% [95% CI, 10.4%-25.5%] in 2015-2017; P = .001), whereas the proportion supported by at least 1 pivotal trial of 6 months’ duration increased (25.8% [95% CI, 18.4%-34.4%] in 1995-1997; 34.9% [95% CI, 23.3%-48.0%] in 2005-2007; and 46.2% [95% CI, 36.5%-56.2%] in 2015-2017; P = .001).

    Conclusions and Relevance  In this study, more recent FDA approvals of new drugs and biologics were based on fewer pivotal trials, which, when aggregated by indication, had less rigorous designs but longer trial durations, suggesting an ongoing need for continued evaluation of therapeutic safety and efficacy after approval.

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