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

Study Questions:

What are the characteristics of pivotal efficacy trials (clinical trials that serve as the basis of Food and Drug Administration [FDA] approval) for newly approved novel therapeutic agents?


This was a cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012. Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial endpoint. Surrogate outcomes were defined as any endpoint using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined.


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 two (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% confidence interval [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 one 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 endpoints 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.


The authors concluded that 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 study reports that the quality of clinical trial evidence used by the FDA to make approval decisions varied widely across indications. Although the vast majority of indications were supported by at least one randomized, double-blinded trial, there was wide variation in trials’ choice of comparators and endpoints, duration, size, and completion rate. In addition, more than one-third of indications were approved on the basis of a single pivotal efficacy trial. These variations may have important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents, and has the potential to inform/modify current FDA regulatory approval standards and postmarket surveillance initiatives. One option would be to follow a recent Institute of Medicine recommendation that the FDA implement a plan that would summarize the FDA’s evaluation of a drug’s risk–benefit profile in a single document that would be continuously updated during the entire market life of the product.

Keywords: Reactive Oxygen Species, Choice Behavior, Triclosan, Drug Approval, Biological Markers, United States Food and Drug Administration, Cross-Sectional Studies, Confidence Intervals, Thiazolidinediones, United States

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