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BMJ. 2017 May 3;357:j1680. doi: 10.1136/bmj.j1680.

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review.

Author information

1
State University of New York Downstate College of Medicine, Brooklyn, NY, USA.
2
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
3
Robert Wood Johnson Foundation Clinical Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
4
Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
5
Center for Outcomes Research and Evaluation, Yale-New Haven Health, New Haven, CT, USA.
6
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
7
Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
8
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.

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.

PMID:
28468750
PMCID:
PMC5421452
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: HMK and JSR receive support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Centers of Medicare and Medicaid Services to develop and maintain performance measures that are used for public reporting, from Medtronic and the FDA to develop methods for postmarket surveillance of medical devices, from the Blue Cross Blue Shield Association to better understand medical technology evaluation, and from the Laura and John Arnold Foundation to support the Collaboration on Research Integrity and Transparency at Yale. HMK reports that he chairs a scientific advisory board for UnitedHealthcare. NDS and JSR receive support from the FDA to establish the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation. AMP, NSD, and JAA declareno support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.”

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