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.
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.
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.
The approval of a drug by the US Food and Drug Administration (FDA) conveys that the product is safe and effective. An Internet-based survey of a national probability sample of 4316 US adults (2944 respondents [68% response rate]) found that 39% report believing that the FDA approves only “extremely effective” drugs and 25% only drugs without serious adverse effects. Some physicians make similar assumptions about effectiveness and safety, expecting that patients are likely to benefit from newly approved therapies.
FDA review of new drug applications is guided by the Federal Food, Drug, and Cosmetic Act, which requires “adequate and well controlled investigations” to determine efficacy. FDA guidance suggests that drug manufacturers submit at least 2 trials, each providing independent evidence of efficacy—such studies are known as “pivotal” efficacy trials—but also implies flexibility, describing circumstances in which a single efficacy trial might be sufficient to support approval. Moreover, for certain applications, the FDA provides written guidance on the design of pivotal efficacy trials, including features of trial design, such as sample selection and choice of comparator, and may provide further guidance in meetings with individual sponsors. As an example, for therapeutic agents evaluated through the accelerated approval pathway, which aims to speed approval of therapeutic agents that treat life-threatening diseases, the FDA permits pivotal efficacy trials to use surrogate end points that are “reasonably likely” to predict clinical benefit.
The clinical research findings available at the time of a drug’s approval have important implications: if made public, these findings represent the only source of information available to patients and their physicians as they decide whether to use a newly approved drug. However, flexible approval standards may lead to some therapeutic agents being approved by the FDA on the basis of numerous rigorously designed clinical trials and others on the basis of fewer or less robust studies, leading to differing levels of certainty about the risks and benefits of newly approved drugs. Accordingly, we sought to systematically examine this issue, evaluating the strength of the clinical trial evidence supporting FDA approval decisions for novel therapeutic agents—pharmacologics and biologics—between 2005 and 2012 by characterizing key features of pivotal efficacy trials, such as trial size, design, duration, and end points.