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Original Investigation
August 15, 2017

Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration

Author Affiliations
  • 1LSE Health, Department of Health Policy, London School of Economics and Political Science, London, England
  • 2Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. 2017;318(7):626-636. doi:10.1001/jama.2017.9415
Key Points

Question  What are the characteristics and findings of preapproval and mandated postapproval trials of drugs granted US Food and Drug Administration (FDA) accelerated approval between 2009 and 2013?

Findings  The FDA granted accelerated approval to 22 drugs for 24 indications. Clinical trials conducted before (n=30) and after (n=18) approval had similar design characteristics, such as lack of blinding, randomization, and comparator groups. Of the required postapproval confirmatory studies, half were completed a minimum of 3 years after approval, and of these, most showed some benefit but relied on surrogate measures rather than clinical outcomes.

Meaning  Among 24 indications granted accelerated approval by the FDA in 2009-2013, 42% had efficacy confirmed in postapproval trials a minimum of 3 years after approval, although both preapproval and postapproval trials had limitations in the study designs and end points used.

Abstract

Importance  Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements.

Objective  To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval.

Design and Setting  Publicly available FDA documents were reviewed to identify the preapproval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA’s database of postmarketing requirements and commitments, ClinicalTrials.gov, and matched peer-reviewed publications. Follow-up ended on April 7, 2017.

Exposures  Granting of accelerated approval.

Main Outcomes and Measures  Characteristics of preapproval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized.

Results  The FDA granted accelerated approval to 22 drugs for 24 indications (19 for indications involving cancer treatment) between 2009 and 2013. A total of 30 preapproval studies supported the 24 indications. The median number of participants enrolled in the preapproval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, −15% to 46%; P = .31). Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior.

Conclusions and Relevance  Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval, although confirmatory trials and preapproval trials had similar design elements, including reliance on surrogate measures as outcomes.

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