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Clinical trial evidence supporting FDA approvals varies widely
The quality and scope of clinical trial evidence utilized by the FDA as the grounds for drug approvals is highly variable across indications, with more than one-third of indications approved on the strength of a single pivotal efficacy trial, according to new study findings.
Researchers for the cross-sectional study evaluated publicly accessible FDA documents relating to all novel therapeutic agents approved between 2005 and 2012.
For each of the new drugs evaluated, an investigator determined the pivotal efficacy trials used as grounds for approval. Each of these trials was classified based on its use of randomization and blinding, primary endpoints, type of comparator, number of treated patients, trial duration and completion rates. The investigators noted the use of “surrogate” outcomes, defined as any endpoint using a biomarker to predict clinical utility.
The researchers found that during the study period, the FDA approved 188 new drugs for 206 indications, on the strength of 448 pivotal efficacy trials. Although for each indication the median number of pivotal trials was two, 74 indications (36.8%) were approved on the grounds of a single pivotal trial. Most trials were randomized (89.3%; 95% CI, 86.4-92.2), double blind (79.5%; 95% CI, 75.7-83.2) and used either an active or inactive comparator (87.1%; 95% CI, 83.9-90.2). Among all pivotal trials, the median number of patients enrolled per indication was 760. The approval of 68 indications was backed by at least one pivotal trial with a duration of at least 6 months (33.8%; 95% CI, 27.2-40.4). For 91 indications, pivotal trials using surrogate endpoints as the primary outcome constituted the sole basis of approval (45.3%; 95% CI, 38.3-52.2). Trials using clinical outcomes and clinical scales served as the exclusive grounds for approval for 67 (33.3%; 95% CI, 26.8-39.9) and 36 indications (17.9%; 95% CI, 12.6-23.3), respectively. The features of the trials differed based on therapeutic and indication variables, including therapeutic area, anticipated duration of treatment, orphan status and accelerated approval.
The researchers said although the FDA’s regulatory flexibility allows valuable customization in approving new agents, it should be considered when making therapeutic decisions.
“This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents, and has the potential to inform current FDA regulatory approval standards and postmarket surveillance initiatives,” the researchers wrote.
Disclosure: See the study for a full list of all researchers’ relevant financial disclosures.