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Characteristics of pre-approval and post-approval studies for drugs granted accelerated approval by the US food and drug administration

Naci, Huseyin and Smalley, Katelyn R. and Kesselheim, Aaron S. (2017) Characteristics of pre-approval and post-approval studies for drugs granted accelerated approval by the US food and drug administration. JAMA, 318 (7). pp. 626-636. ISSN 0098-7484

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Identification Number: 10.1001/jama.2017.9415

Abstract

Importance: Drugs treating serious 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 pre-approval and confirmatory clinical trials of drugs granted Accelerated Approval. Design and Setting: Publicly available FDA documents were surveyed to evaluate the pre-approval 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 publications. End date of follow up was 7 April 2017. Exposure: Granting of Accelerated Approval. Main Outcomes and Measures: Characteristics of pre-approval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary endpoint) and indications. Subsequent regulatory decisions and estimated time between Accelerated Approval and fulfillment of regulatory requirements were reviewed. Results: FDA granted Accelerated Approval to 22 drugs for 24 indications in the study period. At a minimum 3 years of follow-up, 19 of 38 required confirmatory studies were completed (50%). The proportion of studies with randomized designs did not differ before and after Accelerated Approval (16%, 95% confidence interval [CI]: -15%-46%; P=0.31). Post-approval requirements were completed and demonstrated efficacy in 10 indications (42%) on the basis of trials that evaluated surrogate measures alone. Among the 14 indications (58%) that had not yet completed requirements, confirmatory studies failed to demonstrate clinical benefit in 2 (8%) indications; were terminated in 2 (8%); and were delayed by more than one year in 3 (13%) with no regulatory action. Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 7 indications that had been initially approved 5 or more years prior. Conclusions and Relevance: Many drugs recently granted Accelerated Approval had had their efficacy confirmed in post-approval trials, although confirmatory trials have similar design elements to pre-approval trials, including reliance on surrogate measures as outcomes. Delays in completing post-approval confirmatory trials persisted for a minority of drugs.

Item Type: Article
Official URL: http://jamanetwork.com/journals/jama
Additional Information: © 2017 American Medical Association
Subjects: R Medicine > R Medicine (General)
Sets: Departments > Social Policy
Research centres and groups > LSE Health
Date Deposited: 21 Aug 2017 13:30
Last Modified: 13 Sep 2017 14:36
Funders: Higher Education Funding Council of England, Laura and John Arnold Foundation, Harvard Program in Therapeutic Science.
URI: http://eprints.lse.ac.uk/id/eprint/84056

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