Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents Over Three Decades, 1995-2017: Cross-Sectional Analysis
Authors: Zhang Audrey D , Puthumana Jeremy , Downing Nicholas S , Shah Nilay D , Krumholz Harlan M , Ross Joseph S 
Published: September 2019

ABSTRACTObjectiveTo 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.DesignCross-sectional study.Setting and populationPublicly available data on novel therapeutics approved by the FDA between 1995-1997, 2005-2007, and 2015-2017.Main outcome measuresUse 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.ResultsThere 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.ConclusionMore 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 FDA’s strategy for requiring ongoing evaluation of therapeutic safety and efficacy after approval.What is already known on this topic- Pivotal trial characteristics supporting US Food and Drug Administration approval of novel therapeutic agents vary widely across therapeutic characteristics.- A growing number of approvals make use of special regulatory programs that expedite the development and review of potentially transformative drugs, such as Fast Track, Priority Review, Accelerated Approval, and Breakthrough Designation.- Special regulatory programs often offer more flexible requirements for approval, such as requiring only a single pivotal trial or trials using surrogate endpoints.What this study adds- Over the past three decades, the characteristics of the aggregate pivotal trials supporting new drug approvals has changed, with more recent approvals requiring fewer trials of less rigorous design.- Differences in pivotal trial characteristics over time persist after accounting for the increasing use of special regulatory programs.- Divergent patterns are observed among approvals making use of special regulatory programs, for which more recent approvals have required fewer trials of less rigorous design, as compared to approvals using the standard pathway, for which more recent approvals have required trials of more rigorous design.