Study: Accelerated approvals leave lingering uncertainty about cancer drugs’ benefits

Cancer drugs that get to market via accelerated approval often have uncertain clinical benefits and increasingly are supported by less robust evidence when converted to full approval, according to a study published 7 April in JAMA.

Accelerated approval has been on the rise in the field of oncology treatment.

“Despite its origins in HIV treatment, accelerated approval is now most common in oncology, with approximately one-third of all oncology drug approvals using the pathway and more than 80% of all accelerated approvals being granted for cancer therapies,” noted researchers affiliated with the Program on Regulation, Therapeutics and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School in JAMA.

Accelerated approvals are typically supported by trials that use surrogate endpoints like tumor response rates and progression-free survival, rather than overall survival. Confirmatory trials are subsequently done to support conversion from accelerated to regular approval.

PORTAL researchers examined the accelerated approvals and conversions to full approvals in oncology by the US Food and Drug Administration (FDA) between 2013 and 2023. Most cancer drugs that got accelerated approval did not demonstrate a benefit in overall survival or quality of life within five years, they reported.

The accelerated approval program is successful with giving access to drugs for patients who have unmet medical needs and that’s a good thing, said Ian Liu, MD, post-doctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, in an interview with Focus.

“What I think is a bad thing is that after confirmatory trials have ended, oftentimes it has been a long time since the accelerated approvals are granted. So that's one problem,” Liu added. “But secondly, there's often still a significant amount of residual uncertainty as to whether a drug works and for which indication.”

Double-checking value of today’s oncology drugs

The PORTAL group is an independent research body that conducts research across the spectrum of drug development, from basic science, to funding, all the way through approvals, reimbursement, and value to patients. This month, they also published research in JAMA Oncology about the quality of evidence behind molecularly-targeted cancer drugs. (RELATED: Few FDA-approved targeted cancer drugs meet ESMO benefit benchmarks, Regulatory Focus 4 April 2024)

For the latest JAMA study, researchers analyzed the FDA Accelerated Approval list and the Drugs@FDA database to identify 129 cancer drug–indication pairs that were granted accelerated approval between January 2013 and July 2023. Out of 46 indications approved between 2013 and 2017 and with more than five years of follow-up available, 29 were converted to regulatory approval, ten were withdrawn, and seven were ongoing after 6.3 years. Of the 29 that converted, researchers reported the following:

Seven (24%) demonstrated an improvement in overall survival and quality of life.
Seven (24%) improved overall survival but not qualify of life.
Six (21%) improved quality of life.
Nine (31%) were converted to regular approval without showing a benefit for overall survival or quality of life.

“Despite more than 5 years of follow-up, most cancer drug indications granted accelerated approval between 2013 and 2017 did not demonstrate a benefit in overall survival or quality of life to patients in confirmatory trials by mid-2023,” the PORTAL investigators wrote. “Among this cohort of accelerated approvals for cancer drugs, some improved overall survival, several ineffective drugs were withdrawn, multiple drugs had ongoing confirmatory studies, and others were converted to regular approval based on surrogate measures.”

Researchers also analyzed evidence supporting conversion decisions for regular approval before August 2023 and found what Liu described as a trend in favor of using surrogate measures instead of overall survival for endpoints in confirmatory trials. Whereas none of 28 conversions from accelerated approvals relied on response rates from 2013 to 2020, seven of 19 conversions from 2021 to 2023 were based on response rates.

“Because many surrogate measures in oncology correlate poorly with survival, even after confirmatory trials, substantial uncertainty can remain as to the clinical benefit of accelerated approval drugs,” the authors wrote. “Many confirmatory trials have been delayed, with some products being used for more than a decade without confirming clinical benefit.”

Take-home messages for stakeholders

Manufacturers discuss endpoints with FDA and the PORTAL study results underscore the importance of using endpoints that matter to patients and prescribers in confirmatory trials, Liu commented. (RELATED: FDA expands types of acceptable confirmatory evidence, Regulatory Focus 19 September 2023)

Some aspects of the accelerated approval program have changed through recent federal action. The agency used its new amended authorities under the 2022 Food and Drug Omnibus Report Act (FDORA) in February for the withdrawal of Oncopeptides’ multiple myeloma drug Pepaxto (melphalan flufenamide).

Lateness of confirmatory studies has been a concern (RELATED: Study: Half of confirmatory studies for accelerated approvals are late, Regulatory Focus 4 April 2023).

Through the Consolidated Appropriations Act of 2023, the FDA can impose requirements for the timing of confirmatory trials. In the PORTAL study, researchers found that the time from accelerated approval to withdrawal declined from 9.9 years to 3.6 years between 2013 and 2023, while the time between projected trial completion and withdrawal or conversion narrowed.

As for patients, considering the risk that some drugs cleared through the accelerated approval program might not wind up showing a clinical benefit, they should be having nuanced conversations with their providers about the pros and cons of treatment, Liu suggested.

“Together, patients and clinicians are able to make informed decisions as to what therapies may or may not be right for that patient,” he said.

JAMA

Study: Accelerated approvals leave lingering uncertainty about cancer drugs’ benefits

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