Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019 | Oncology | JAMA Network Open | JAMA Network
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    Original Investigation
    Health Policy
    June 10, 2021

    Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019

    Author Affiliations
    • 1Yale School of Medicine, Yale University, New Haven, Connecticut
    • 2Department of Medicine, Duke University School of Medicine, Durham, North Carolina
    • 3Bain Capital Life Sciences, Boston, Massachusetts
    • 4Division of Health Care Policy and Research, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
    • 5Section of General Medicine and the National Clinical Scholars Program, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • 6Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut
    • 7Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, Connecticut
    JAMA Netw Open. 2021;4(6):e2113224. doi:10.1001/jamanetworkopen.2021.13224
    Key Points

    Question  What is the strength of evidence supporting supplemental new indication approvals for drugs and biologics and how does it compare with the evidence that supported their original approval?

    Findings  In this cross-sectional study of 107 therapeutics approved for 146 supplemental indications by the US Food and Drug Administration between 2017 and 2019, supplemental approvals for oncology drugs were based on fewer pivotal efficacy trials with less rigorous designs than supplemental approvals for other therapeutic areas. Supplemental approvals were based on fewer pivotal trials than their original indication approvals, but their designs were similar.

    Meaning  These findings suggest that there was little difference in the evidence supporting supplemental and original indication approvals, but the number and design of pivotal trials supporting supplemental indication approvals varied according to therapeutic area.

    Abstract

    Importance  After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications.

    Objective  To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics’ original indication approvals.

    Design, Setting, and Participants  This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics’ original indication approvals. Data analysis was performed from August to October 2020.

    Main Outcomes and Measures  Number and design of pivotal trials supporting both supplemental and original indication approvals.

    Results  From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months’ duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different.

    Conclusions and Relevance  These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

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