Study: Breakthrough therapies approved based on surrogate endpoints often lack postmarketing requirements

The use of surrogate markers to support drug approvals without requiring postmarketing studies can “hinder accurate and informed decision-making by patients and clinicians,” according to a recent study published in JAMA.

Drugs granted breakthrough therapy designation can go on to receive accelerated approval or traditional approval; while the US Food and Drug Administration (FDA) requires postmarketing studies for drugs granted accelerated approval, they are often not required for breakthrough drugs granted traditional approval, even when surrogate markers are used for primary endpoints.

“Nevertheless, prior studies have raised questions around the association between surrogate markers and their predicted clinical outcomes, for both oncology and nononcology therapeutics, finding that surrogate markers used to inform FDA approval for these indications are not consistently correlated with clinical outcomes such as overall survival or quality of life,” wrote Maryam Mooghali, a researcher at the Yale Center for Outcomes Research and Evaluation, and colleagues, in a study published last week in JAMA Network Open.

In conducting the study, Mooghali and colleagues evaluated the primary endpoints used in pivotal clinical trials supporting all FDA breakthrough therapy-designated approvals since the inception of the designation program in 2012 through 31 December 2023. They also examined whether FDA required or requested additional postmarketing studies to confirm clinical efficacy for drugs approved based on surrogate markers.

FDA has increasingly approved products based on surrogate markers as primary efficacy endpoints instead of clinical outcomes. While clinical outcomes measure therapeutic effects such as assessing how patients feel, function, or survive, surrogate markers use laboratory measurements or imaging findings which “serve as a proxy measure” in measuring clinical outcomes.

Between 2013 and 2023, FDA approved 157 treatments with breakthrough therapy designation, and of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval.

All accelerated approvals were based on pivotal trials using surrogate markers as primary endpoints and FDA required postmarketing studies for these drugs to confirm efficacy. More than half of the traditional approvals (58%) were based on pivotal trials that relied on surrogate endpoints, and of these, only 4 (7%) were required to complete postmarketing studies to confirm efficacy. Nearly two-thirds (64%) of the breakthrough therapies granted traditional approval relied upon surrogate markers recognized by FDA for the same indication.

“Unlike with accelerated approvals in which the FDA required postmarketing studies to confirm the expected clinical benefit for all breakthrough therapy designated indications, traditional approvals based on surrogate markers were generally not accompanied by FDA-required postmarketing efficacy studies,” the authors wrote.

While recent research shows a greater overall survival for breakthrough therapy-designated vs non-designated treatments, “concerns have also been raised that the designation may imply an exceptional magnitude of clinical benefit, creating a perception among the public as well as clinicians that these medications substantially improve patient outcomes by providing a cure for serious illnesses or improving patients’ quality of life or survival.”

The authors concluded that “evidence suggests that a substantial proportion of physicians misinterpret the meaning of the breakthrough therapy designation in terms of the evidentiary standards, including that the designation automatically confers eligibility for receiving accelerated approval,” said the study. “Thus, when breakthrough therapy–designated indications are approved based on surrogate endpoints instead of clinical outcomes, without consistent postmarketing requirements to confirm benefit, this may hinder accurate and informed decision-making by patients and clinicians.”

JAMA

Study: Breakthrough therapies approved based on surrogate endpoints often lack postmarketing requirements

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