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Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review.
BMJ. 2017 May 03; 357:j1680.BMJ

Abstract

Objective To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence.Design Systematic review.Data sources Drugs@FDA database and PubMed.Study inclusion All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. Results Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators-67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials-and examined surrogate markers of efficacy as primary endpoints-51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.Conclusions The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.

Authors+Show Affiliations

State University of New York Downstate College of Medicine, Brooklyn, NY, USA.Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. Robert Wood Johnson Foundation Clinical Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA. Center for Outcomes Research and Evaluation, Yale-New Haven Health, New Haven, CT, USA.Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.Division of Health Care Policy and Research and Kern Center for the Science of Health Care Delivery, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.Robert Wood Johnson Foundation Clinical Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA. Center for Outcomes Research and Evaluation, Yale-New Haven Health, New Haven, CT, USA. Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Pub Type(s)

Journal Article
Review
Systematic Review

Language

eng

PubMed ID

28468750

Citation

Pease, Alison M., et al. "Postapproval Studies of Drugs Initially Approved By the FDA On the Basis of Limited Evidence: Systematic Review." BMJ (Clinical Research Ed.), vol. 357, 2017, pp. j1680.
Pease AM, Krumholz HM, Downing NS, et al. Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review. BMJ. 2017;357:j1680.
Pease, A. M., Krumholz, H. M., Downing, N. S., Aminawung, J. A., Shah, N. D., & Ross, J. S. (2017). Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review. BMJ (Clinical Research Ed.), 357, j1680. https://doi.org/10.1136/bmj.j1680
Pease AM, et al. Postapproval Studies of Drugs Initially Approved By the FDA On the Basis of Limited Evidence: Systematic Review. BMJ. 2017 May 3;357:j1680. PubMed PMID: 28468750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review. AU - Pease,Alison M, AU - Krumholz,Harlan M, AU - Downing,Nicholas S, AU - Aminawung,Jenerius A, AU - Shah,Nilay D, AU - Ross,Joseph S, Y1 - 2017/05/03/ PY - 2017/5/5/entrez PY - 2017/5/5/pubmed PY - 2017/6/6/medline SP - j1680 EP - j1680 JF - BMJ (Clinical research ed.) JO - BMJ VL - 357 N2 - Objective To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence.Design Systematic review.Data sources Drugs@FDA database and PubMed.Study inclusion All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. Results Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators-67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials-and examined surrogate markers of efficacy as primary endpoints-51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.Conclusions The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication. SN - 1756-1833 UR - https://neuro.unboundmedicine.com/medline/citation/28468750/Postapproval_studies_of_drugs_initially_approved_by_the_FDA_on_the_basis_of_limited_evidence:_systematic_review_ L2 - https://www.bmj.com/lookup/pmidlookup?view=long&pmid=28468750 DB - PRIME DP - Unbound Medicine ER -