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Original Investigation |

Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012

Nicholas S. Downing, AB1; Jenerius A. Aminawung, MD, MPH2; Nilay D. Shah, PhD7; Harlan M. Krumholz, MD, SM3,4,5,6; Joseph S. Ross, MD, MHS2,4,5,6
[+] Author Affiliations
1Yale University School of Medicine, New Haven, Connecticut
2Section of General Internal Medicine, Department of Internal Medicine, Yale University School of Medicine
3Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine
4Robert Wood Johnson Clinical Scholars Program, Department of Internal Medicine, Yale University School of Medicine
5Section of Health Policy and Administration, Department of Epidemiology and Public Health, Yale University School of Medicine
6Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Connecticut
7Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota
JAMA. 2014;311(4):368-377. doi:10.1001/jama.2013.282034.
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Importance  Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated.

Objectives  To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents.

Design and Setting  Cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012.

Main Outcomes and Measures  Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined.

Results  Between 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval.

Conclusions and Relevance  The quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.

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Sample Construction of Novel Therapeutic Agents Approved by the US Food and Drug Administration (FDA) Between 2005 and 2012
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