Assessment of Clinical Trials Supporting US Food and Drug Administration Approval of Novel Therapeutic Agents, 1995-2017.

Importance: Since the introduction of the Fast Track designation in 1988, the number of special regulatory programs available for the approval of new drugs and biologics by the US Food and Drug Administration (FDA) has increased, offering the agency flexibility with respect to evidentiary requirements.

Objective: To characterize pivotal efficacy trials supporting the approval of new drugs and biologics during the past 3 decades.

Design, Setting, And Participants: This cross-sectional study included 273 new drugs and biologics approved by the FDA for 339 indications from 1995 to 1997, from 2005 to 2007, and from 2015 to 2017.

Main Outcomes And Measures: Therapeutics were classified by product type and therapeutic area as well as orphan designation and use of special regulatory programs, such as Priority Review and Accelerated Approval. Pivotal trials were characterized by use of randomization, blinding, types of comparators, primary end points, number of treated patients, and trial duration, both individually and aggregated by each indication approval.

Results: A total of 273 new drugs and biologics were approved by the FDA in these 3 periods (107 [39.2%] in 1995-1997; 57 [20.9%] in 2005-2007; and 109 [39.9%] in 2015-2017), representing 339 indications (157 [46.3%], 64 [18.9%], and 118 [34.8%], respectively). The proportion of therapeutic approvals using at least 1 special regulatory program increased (37 [34.6%] in 1995-1997; 33 [57.9%] in 2005-2007; and 70 [64.2%] in 2015-2017), as did indication approvals receiving an orphan designation (20 [12.7%] in 1995-1997; 17 [26.6%] in 2005-2007, and 45 [38.1%] in 2015-2017). The most common therapeutic areas differed over time (infectious disease, 53 [33.8%] in 1995-1997 vs cancer, 32 [27.1%] in 2015-2017). When considering the aggregate pivotal trials supporting each indication approval, the proportion of indications supported by at least 2 pivotal trials decreased (80.6% [95% CI, 72.6%-87.2%] in 1995-1997; 60.3% [95% CI, 47.2%-72.4%] in 2005-2007; and 52.8% [95% CI, 42.9%-62.6%] in 2015-2017; P < .001). The proportion of indications supported by only single-group pivotal trials increased (4.0% [95% CI, 1.3%-9.2%] in 1995-1997; 12.7% [95% CI, 5.6%-23.5%] in 2005-2007; and 17.0% [95% CI, 10.4%-25.5%] in 2015-2017; P = .001), whereas the proportion supported by at least 1 pivotal trial of 6 months' duration increased (25.8% [95% CI, 18.4%-34.4%] in 1995-1997; 34.9% [95% CI, 23.3%-48.0%] in 2005-2007; and 46.2% [95% CI, 36.5%-56.2%] in 2015-2017; P = .001).

Conclusions And Relevance: In this study, more recent FDA approvals of new drugs and biologics were based on fewer pivotal trials, which, when aggregated by indication, had less rigorous designs but longer trial durations, suggesting an ongoing need for continued evaluation of therapeutic safety and efficacy after approval.