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Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration.
JAMA. 2017 Aug 15; 318(7):626-636.JAMA

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.

Authors+Show Affiliations

LSE Health, Department of Health Policy, London School of Economics and Political Science, London, England.LSE Health, Department of Health Policy, London School of Economics and Political Science, London, England.Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28810023

Citation

Naci, Huseyin, et al. "Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval By the US Food and Drug Administration." JAMA, vol. 318, no. 7, 2017, pp. 626-636.
Naci H, Smalley KR, Kesselheim AS. Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.
Naci, H., Smalley, K. R., & Kesselheim, A. S. (2017). Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. JAMA, 318(7), 626-636. https://doi.org/10.1001/jama.2017.9415
Naci H, Smalley KR, Kesselheim AS. Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval By the US Food and Drug Administration. JAMA. 2017 Aug 15;318(7):626-636. PubMed PMID: 28810023.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. AU - Naci,Huseyin, AU - Smalley,Katelyn R, AU - Kesselheim,Aaron S, PY - 2017/8/16/entrez PY - 2017/8/16/pubmed PY - 2017/8/23/medline SP - 626 EP - 636 JF - JAMA JO - JAMA VL - 318 IS - 7 N2 - 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. SN - 1538-3598 UR - https://neuro.unboundmedicine.com/medline/citation/28810023/Characteristics_of_Preapproval_and_Postapproval_Studies_for_Drugs_Granted_Accelerated_Approval_by_the_US_Food_and_Drug_Administration_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2017.9415 DB - PRIME DP - Unbound Medicine ER -