Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents Over Three Decades, 1995-2017: Cross-Sectional Analysis

Abstract

Objective: To evaluate whether characteristics of pivotal efficacy trials supporting US Food and Drug Administration (FDA) approval of novel therapeutic agents have changed over the past three decades.\nDesign: Cross-sectional study.\nSetting and population: Publicly available data on novel therapeutics approved by the FDA between 1995-1997, 2005-2007, and 2015-2017.\nMain outcome measures: Use of randomization, blinding, types of comparators and primary endpoints, number of treated patients, and trial duration in pivotal trials supporting novel therapeutic approval, both individually and aggregated by each indication approval. Analyses were repeated stratifying by use of orphan designation and use of special regulatory programs.\nResults: There were 273 novel therapeutics approved by the FDA in these 3 periods (107 in 1995-1997, 57 in 2005-2007, 109 in 2015-2017), representing 339 indications (157, 64, and 118, respectively). Overall, the proportion of indication approvals supported by at least 2 pivotal trials decreased (80.6% in 1995-1997, 60.3% in 2005-2007, 52.8% in 2015-2017; p<0.001). The proportion supported by only single-arm pivotal trials increased (4.0% in 1995-1997, 12.7% in 2005-2007, 17.0% in 2015-2017; p=0.001), as did the proportion supported by at least one pivotal trial of 6 months duration (25.8% in 1995-1997, 34.9% in 2005-2007, 46.2% in 2015-2017; p=0.001). When stratified by use of special regulatory programs, pivotal trial characteristics changed over time in divergent ways, both individually and when aggregated by indication approvals. \nConclusion: More recent FDA approvals of novel therapeutics were based on fewer pivotal trials, with less rigorous designs but longer trial durations. These findings reinforce the importance of the FDA9s strategy for requiring ongoing evaluation of therapeutic safety and efficacy after approval.