Study: Most nononcology accelerated approval pivotal trials use surrogate endpoints

Most pivotal clinical trials supporting the accelerated approval of nononcology products reported surrogate measures as primary endpoints, according to a recent research letter published in JAMA.

Ian T. T. Liu, of the Program on Regulation, Therapeutics, And Law (PORTAL) research group at Harvard Medical School and Brigham & Women’s Hospital, and colleagues evaluated the characteristics of pivotal and confirmatory trials for 50 nononcology products granted accelerated approval between 2013 and 2024. The researchers classified each nononcology product by indication and regulatory designation and examined whether the key trials supporting accelerated approval or conversion to regular approval had clinical or surrogate endpoints.

The researchers identified 50 nononcology products for 26 diseases, which included 12 vaccines (24.0%), 11 drugs for neurologic diseases (22.0%), 10 non-malignant hematological disease drugs (20.0%), and 5 infectious disease drugs (10.0%). Of the nononcology products evaluated, 35 products (70.0%) were granted use of another US Food and Drug Administration (FDA) expedited pathway, and 30 products (60.0%) had a rare disease designation.

Overall, 22 surrogate endpoint or intermediate primary endpoints were used in 82 studies that supported the accelerated approvals of nononcology products. Researchers found there was a median of 4.64 years projected between accelerated approval and a planned submission of a confirmatory trial. There were 19 products (38.0%) that were converted from accelerated approval to regular approval, while 28 products (56.0%) retained accelerated approval status, and 3 products (6.0%) were withdrawn.

For the 19 accelerated approvals converted to regular approval, 10 products (52.6%) used surrogate measures, and 9 products (47.4%) used clinical outcomes as endpoints. Of these, 7 products had the same endpoint in the pivotal trial that supported the accelerated approval and in a confirmatory trial supporting conversion to regular approval.

Liu and colleagues identified 21 confirmatory trials that supported a conversion to regular approval or withdrawal. They noted the time between accelerated approval conversion to regular approval or withdrawal was 3.26 years, while the median time for a product that has remained an accelerated approval was 3.70 years.

Surrogate vs clinical endpoints

Surrogate endpoints are a “completely expected phenomenon” of the accelerated approval program, Liu, who is also a pediatric resident at the University of Illinois at Chicago, told Focus. However, it is notable that about one-third of pivotal trials supporting accelerated approval also reported clinical outcomes as primary efficacy endpoints.

“This is interesting because it implies that the clinical outcomes evaluated in the pivotal trials were likely not sufficient to support regular approval,” he said.

Liu said he thinks “nearly all confirmatory trials” should have a primary endpoint that assesses clinical benefit.

“This is the design of the program,” he explained. “Powering a confirmatory trial to a surrogate endpoint (even a more clinically relevant one), when the drug was already granted accelerated approval based on a surrogate endpoint does not benefit patients. If there is no clinical endpoint, then patients cannot be sure that the therapy is actually benefitting them.”

FDA also cannot ask manufacturers to conduct clinical trials once a product is converted from accelerated approval to regular approval, and manufacturers would have “limited incentives to study clinical outcomes because there is a chance that the trial could be negative,” Liu said.

“Therefore, if a drug does not have trials with clinically meaningful outcomes required by the FDA, it become increasingly unlikely that these will ever occur,” Liu added.

While most accelerated approvals are granted to oncology drugs, there is significant variation in the use of surrogate endpoints with nononcology drugs because they treat a wider variety of conditions.

“However, clinical outcomes are still important to measure for all therapies. Otherwise, patients cannot know if the medications they are taking are actually likely to benefit them in the long run,” Liu said.

JAMA Liu et al.

Study: Most nononcology accelerated approval pivotal trials use surrogate endpoints

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