‘Substantial uncertainty’ about clinical value of most accelerated approval cancer drugs
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Key takeaways:
- Most oncology accelerated approvals failed to improve OS in confirmatory studies.
- Approximately one-fifth of accelerated approvals had been withdrawn from U.S. market after lack of confirmed benefits.
Less than half of the cancer therapies granted FDA accelerated approval showed meaningful improvement in survival or quality-of-life, study results presented at American Association for Cancer Research Annual Meeting showed.
The findings, simultaneously published in Journal of the American Medical Association, showed that despite a lack of proven clinical benefit in confirmatory trials for the majority of accelerated approvals, 63% of these indications transitioned to regular approval from 2013 to 2023.
“More than 5 years after accelerated approval, more than half of drugs had yet to demonstrate clinical benefit, leaving patients and physicians with substantial uncertainty,” Edward R.S. Cliff, MBBS, MPH, a postdoctoral research fellow for the Program on Regulation, Therapeutics and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School, said during a presentation. “Some of these therapies have not been shown to extend life, and patients should know that, whether they elect to use these therapies in a clinical trial or standard-of-care setting.”
Background
In place for more than 3 decades, the FDA’s accelerated approval pathway is most frequently used for the approval of oncology treatments, with about one-third of all anticancer agents using the expedited method, according to Cliff.
A previous analysis showed that only 14% of indications receiving accelerated approval between 2008 and 2012 resulted in an OS benefit, he added.
Many accelerated approvals are based on the results of trials that use surrogate endpoints the FDA believes are “reasonably likely” to be predictive of clinical benefit, Cliff said. He added that these endpoints are derived from imaging studies or laboratory tests that “reflect disease activity but are not necessarily felt by patient.”
Methodology
Cliff and colleagues conducted two separate analyses to investigate how the FDA’s accelerated approval program has evolved since earlier studies.
They first evaluated all oncology agents granted accelerated approval between 2013 and 2017, which allowed at least 5 years to evaluate each indication via a confirmatory trial. The researchers then looked at the reasons FDA cited for conversion of the accelerated approval into a regular approval between 2013 and 2023.
Researchers culled data for each portion of the study from publicly available sources, including published peer-reviewed studies, the FDA website, commercial press releases and information from ClincalTrials.gov.
Key findings
Results showed 129 anticancer agents received accelerated approval from 2013 to 2023, of which 46 had more than 5 years of follow-up (2013-2017) for confirmatory trials and became the study sample for first portion of the analysis.
Of the 46 accelerated approvals, 43% provided some form of clinically meaningful benefit in confirmatory studies. Meanwhile, 63% of accelerated approvals from this sample set transitioned to regular approval.
FDA withdrew indications for 22% of the agents given accelerated approval over the 5-year period.
Additional findings revealed an increase from 1.6 to 3.6 years for converting from accelerated to regular approval, with an accompanying marked decrease from 9.9 to 3.6 years for drug withdrawal from the market.
As part of the second leg of the study analysis, researchers reported that 48 agents given accelerated approval from 2013 to 2023 transitioned to regular approval. FDA based full approval on improvement in OS for 40% of the indications. Other rationales for regular approval include improvement of PFS for 44%, response rate plus duration of response for 10%, and response rate for 4% of therapies.
Study investigators reported one agent received conversion to regular approval after a negative confirmatory trial. They also noted that 63% of agents converted to regular approval had an indication that differed from the accelerated approval, with most being broader indications or for earlier lines of therapy.
Study limitations identified by the researchers included seven ongoing confirmatory trials for accelerated approvals lacking available efficacy results during the study period. They also used only confirmatory trial data, which may not include additional findings about clinical benefits shown from other large studies with longer follow-up.
Clinical implications
“The FDA should ensure that manufacturers run confirmatory trials powered to robustly assess clinically meaningful endpoints,” Cliff said. “Clinicians should consider and inform patients about the uncertainty of clinical benefit when offering novel therapies.”
References:
- Liu ITT, et al. Abstract 918. Presented at: American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
- Liu ITT, et al. J Am Med Assoc. 2024;doi:10.1001/jama.2024.2396.
For more information:
Edward R.S. Cliff, MBBS, MPH, can be reached at eddie.cliff@petermac.org.
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Liu ITT, et al. Abstract 918. Presented at: American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
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