Perspective: FDA’s accelerated approval guidance doesn’t go far enough
Health policy researchers are calling on the US Food and Drug Administration (FDA) to do more to strengthen its accelerated approval program for cancer drugs, including no longer approving drugs based on progression-free survival or overall response endpoints, as well as establishing standards for automatic withdrawal of drugs that lack evidence of clinical benefit.The perspective article, published in the New England Journal of Medicine, calls FDA’s recent draft guidance on accelerated approval a “step in the right direction” but calls out remaining issues related to trial design and endpoints. FDA published draft guidance in March 2023 that identified randomized controlled trials, not single-arm studies, as the “preferred approach” for supporting accelerated approval for cancer drugs (RELATED: FDA encourages RCTS in accelerated approval guidance for oncology, Regulatory Focus 26 March 2023).
“Additional measures could promote an appropriate balance among supporting early access to potentially effective cancer drugs, confirming that drugs improve patient outcomes for the accelerated approval indications, and ensuring that patients aren’t unnecessarily exposed to drugs that have unconfirmed benefits but often carry substantial risks,” wrote Bishal Gyawali, MD, PhD, associate professor of oncology and public health sciences at Queen’s University in Ontario, Canada, and colleagues at Yale School of Medicine and the Program on Regulation, Therapeutics, and Law (PORTAL) at Harvard Medical School and Brigham & Women’s Hospital.
FDA’s accelerated approval program has been under scrutiny in recent years as some studies have shown that drugs that are approved via the pathway don’t offer high therapeutic value and remain on the market without demonstrating a clinically meaningful benefit (RELATED: Study: Most accelerated approval indications don’t add high therapeutic value, Regulatory Focus 19 August 2022; OIG raises concerns about accelerated approval pathway, Regulatory Focus 30 September 2022).
In their perspective, Gyawali and colleagues wrote that single-arm trials should be the basis for accelerated approvals only in “exceptional cases” involving “dramatic effects” in ultra-rare cancers where there are no other treatment options. Even in those cases, the authors argued, FDA should base approval on complete response rate rather than overall response rate since partial responses are “unreliable markers of drug activity.”
The authors also called on FDA not to allow the use of progression free survival as a long-term endpoint to confirm clinical benefit, noting that it is not a validated surrogate for overall survival or quality of life. “Under a single-trial approach, if a drug has already been granted accelerated approval and is on the market, we believe only overall survival or quality of life – measured with the use of validated tools – should be acceptable long-term clinical endpoints, and the trial should be powered to assess these endpoints,” the authtors wrote.
The researchers also proposed changes in trial design for studies used in accelerated approval. For example, they suggested that control group interventions should use the “best available treatment,” rather than appropriate available therapy, which they said can be subjective. They also urged FDA to establish “parameters” for the automatic withdrawal of drug indications when the confirmatory trials do not find evidence of clinical benefit.
In an interview with Focus, Gyawali said that the FDA has the power to act on all the proposals in the perspective without any new legislative authority and that their proposals would not delay patients’ access to cancer medicines.
“The drug will have already been on the market under accelerated approval so our suggestions will only protect the patients from receiving unhelpful and harmful drugs for a long time without any evidence of clinical benefit,” he said.
NEJM Perspective
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