Trends in the Quality of Evidence Supporting FDA Drug Approvals: Results from a Literature Review

Abstract

Context: New drug approvals in the US must be supported by substantial evidence from “adequate and well-controlled” trials. The Food and Drug Administration (FDA) has flexibility in how it applies this standard. Methods: We conducted a systematic literature review of PubMed for studies between 2005-2020 evaluating the design and outcomes of the key trials supporting new drug approvals in the US. We extracted data on the trial characteristics, endpoint types, and expedited regulatory pathways. Findings: Among 48 publications eligible for inclusion, 30 covered trial characteristics, 23 covered surrogate measures, and 30 covered regulatory pathways. Trends point towards less frequent randomization, double-blinding, and active controls, with variation by drug type and indication. Surrogate measures are becoming more common but are not consistently well-correlated with clinical outcomes. Drugs approved through expedited regulatory pathways often have less rigorous trial design characteristics. Conclusions: The characteristics of trials used to approve new drugs have evolved over the past two decades, along with greater use of expedited regulatory pathways and changes in the nature of drugs being evaluated. While flexibility in regulatory standards is important, policy changes can emphasize high quality data collection before or after FDA approval.

Review of Evidence Supporting 2022 US Food and Drug Administration Drug Approvals

“…In 2016, 55% of products were approved based on 3 or more studies, in comparison with 11% in 2022. 1 Our results are consistent with other reports. Zhang and associates 3 also reported systematic decreases in the number of trials used for approvals.…”

“…In contrast to 2016, when 4 of 20 products (20%) were approved based on a single trial, single studies justified 65% of the 2022 approvals. In 2016, 55% of products were approved based on 3 or more studies, in comparison with 11% in 2022 …”

“…Our results highlight a trend toward less rigorous standards for novel drug approvals that has evolved over the past few decades. 1 In contrast to 2016, when 4 of 20 products (20%) were approved based on a single trial, single studies justified 65% of the 2022 approvals. In 2016, 55% of products were approved based on 3 or more studies, in comparison with 11% in 2022.…”

“…The 21st Century Cures Act, enacted in 2017, gave the US Food and Drug Administration (FDA) greater flexibility to apply evidence-based standards for novel drug approvals. 1 To evaluate current practice, we summarize evidence supporting the 37 drugs approved in 2022.…”

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016

“…Preapproval trials of investigational drugs have limited duration and size and often exclude certain populations. Furthermore, the US Food and Drug Administration (FDA) has recently approved drugs based on fewer clinical trials or less rigorous study designs than in previous years through increased use of expedited pathways and often instructs manufacturers to conduct postapproval studies, which may be delayed or incomplete . Because data are lacking about the timeliness of postapproval studies for new drugs approved after 2012, we studied 2013-2016 approvals with follow-up through the end of 2020.…”