Analysis Finds 2020 Drug Approvals Based on Smaller, Less Rigorous Trials


While regulatory flexibility is important for drugs for rare diseases, investigators are concerned the trend toward surrogate endpoints decreases confidence that new drugs can improve patient outcomes.

Nearly half of the trials used to support novel drugs approved by the FDA in 2020 used a surrogate measure of outcomes, according to a new review published in JAMA Network Open.

The 49 novel drugs approved in 2020 were supported by 75 pivotal trials. More than half of these drug approvals were supported by a single pivotal trial, and nearly half of the trials used surrogate measures as endpoints.

Mayookha Mitra-Majumdar, MPH

Mayookha Mitra-Majumdar, MPH

Investigators, led by Mayookha Mitra-Majumdar, MPH, a research specialist at Brigham and Women’s Hospital in Boston, noted that drugs for rare diseases require regulatory flexibility. Of the novel new drugs approved in 2020, 19 were first in class, and pivotal trials of oncology drugs had more flexible trial designs than approvals overall. In fact, pivotal trials supporting oncology approvals were much more likely to have historical controls and to use at least one surrogate measure as a primary endpoint.

The use of historical controls instead of placebo or active controls, investigators said, raised questions about the strength of the evidence. Investigators found that postmarket requirements were common and “take on increased importance in cases in which they are intended to fill gaps in efficacy and safety left by preapproval evidence limited in amount and/or quality,” the wrote.

This analysis of trials to support 2020 drug approvals follows a trend in the use of surrogate endpoints, especially in trials for oncology therapies. Between 1992 and 2019, the FDA issued 194 unique oncology drug authorizations for 132 drugs that were based on surrogate endpoints, according to a report last year from IQVIA.

Progression-free survival is frequently used as a surrogate marker for regular and accelerated approvals, which requires limited patient numbers and shorter follow-up compared with overall survival, which IQVIA said is considered the gold standard for demonstrating clinical benefit.

investigators in the JAMA Network Open analysis noted that reduced requirements raise concerns about the impact on patient outcomes, and these surrogate endpoints may not accurately predict the benefit of a therapy.

“Without a reasonable likelihood that these drugs provide substantial clinical benefits, the argument for more rapid entry becomes less compelling,” investigators wrote. “The FDA and consumers may benefit from a reexamination of how the agency balances time to market with ensuring that approved drugs are sufficiently safe and effective.”

Once confirmatory trials are conducted, therapies may be found to not provide survival benefit. Last year, for example, several manufacturers withdrew indications that had received accelerated approval, including Genentech who withdrew the indication of Tecentriq (atezolizumab) to treat metastatic breast cancer, and Merck who withdrew gastric cancer indication for Keytruda (pembrolizumab).

Investigators pointed that a limitation of their assessment is that the analysis was too recent to assess outcomes of the postmarket requirements, and whether the FDA takes appropriate action based on these confirmatory studies.

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