AACR: Study Suggests Accelerated Approval Doesn’t Always Lead to Clinical Benefit

Accelerated Approval Study_Nicole Bean

Pictured: Arrows pointing both ways over a cancel cell/Nicole Bean for BioSpace.

A recently published study suggests that many cancer drugs greenlit under the FDA’s accelerated approval pathway were given regulatory approval even though confirmatory studies failed to demonstrate clinical benefit in terms of quality of life or overall survival.

Of the 46 cancer drugs that received accelerated approval between 2013 and 2017, 63% were converted to regular approval, despite less than half demonstrating clinical benefit based on these metrics after more than five years of follow-up, according to the study, which was presented at the American Association for Cancer Research’s annual meeting and simultaneously published in JAMA.

The FDA’s accelerated approval pathway was designed to provide early access to drugs that treat serious conditions and fill an unmet medical need, based on a surrogate endpoint. The aim is to allow patients to receive critical treatment while requiring drugmakers to prove their efficacy with confirmatory trials.

One potential consequence of this strategy is that drugs may be provided to patients and later be found to be ineffective.

“The simplest reason why more drug-indication pairs were converted to regular approval is that the confirmatory trials were powered to other endpoints––such as progression-free survival,” study co-author Ian Liu, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, told BioSpace in an email.

The study’s authors chose to look only at overall survival (OS) and quality-of-life (QOL) as constituting clinical benefit because “surrogate endpoints such as progression-free survival often correlate poorly—or not at all—with ‘hard’ clinical outcomes, though this varies based on cancer type,” Liu said.

When asked about the importance of QOL metrics in considering regular approvals, Liu said improvements seen in imaging studies and lab values are helpful tools but generally do not matter to patients. Instead, “Patients generally care about living better and living longer. We think that QOL data is an important tool to ensure that what matters to patients is measured in clinical trials,” he said.

The study also found that the conversion time from accelerated approval to regular approval increased from 1.6 to 3.6 years, and the time to a drug being withdrawn from the market decreased from 9.9 to 3.6 years.

“Faster, appropriate withdrawal decisions are a good thing for patients, as they ensure that ineffective drugs are on the market for a shorter period of time,” Liu said in an article published on the AACR website. In relation to the second statistic, Liu added, “We believe that conversion decisions should be both timely but—more importantly—supported by high-quality clinical outcomes.”

FDA Defends Record of Conversions

In an email to BioSpace, an FDA spokesperson noted that the agency does not comment on specific studies but did address some of the issues raised by the authors. “For serious and life-threatening diseases with inadequate treatment options, accelerated approval offers earlier access with some residual uncertainty regarding clinical benefit,” the spokesperson said, adding that in the vast majority of accelerated approvals, clinical benefit has been verified through the required confirmatory studies.

“Because inherent in the framework is some uncertainty, it is expected that certain products may fail to confirm clinical benefit,” the spokesperson added. “If post-marketing clinical trials fail to verify clinical benefit, the sponsor may withdraw the product, or the FDA can initiate proceedings that would withdraw a drug’s approval.” The spokesperson reiterated that “the overwhelming majority of products have shown clinical benefit in confirmatory trials.”

Earlier this year, the FDA indicated that overall survival data will play a more important role in regulatory approval decisions for cancer drugs going forward. This would dovetail with what the authors of the Brigham study deemed “high-quality clinical outcomes,” which they said were “critical” for the proper functioning of the pathway.

Liu noted that some of the drugs studied were converted to regular approvals based on surrogate endpoints, such as response rate, including tumor shrinkage. This is a logical trial endpoint for accelerated approval but leaves “considerable uncertainty” as to actual clinical efficacy when used alone in confirmatory trials, Liu said. He recommended that confirmatory trials should be powered toward clinically meaningful, patient-centered endpoints.

Ben Hargreaves is a freelance science journalist based in Tosse, France. Reach him on LinkedIn.

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