Study points to weaknesses in FDA accelerated approval path

Less than half of the cancer therapies that were granted accelerated approval by the FDA between 2013 and 2017 showed a clinical benefit in a confirmatory trial within the next five years.

That is the conclusion of a study presented at the American Association of Cancer Research (AACR) in San Diego and simultaneously published in the Journal of the American Medical Association (JAMA), looking at 46 cancer drugs given accelerated approvals over that period.

According to the authors, nearly two-thirds of them (63%) were converted to full approval by the FDA, even though only 43% showed a clinical benefit on overall survival (OS) or an increase in quality-of-life in confirmatory trials completed within the next five years. Another 15% had no results available within that period.

Those findings come from a period before the FDA launched an effort to tighten up the accelerated approval system, including pulling the accelerated approvals of various cancer drugs that failed to show a benefit in a subsequent study and also insisting that these studies be well underway before clearance can be granted. An example of the latter was its recent refusal to approve Regeneron’s lymphoma therapy odronextamab.

“Accelerated approvals make up a large percentage of new cancer drug approvals, but we knew that oncology accelerated approvals are often not subsequently confirmed as having an effect on ‘hard’ clinical endpoints,” said Ian Liu of Brigham and Women’s Hospital and Harvard Medical School, one of the researchers behind the analysis.

The team also looked at the evidence used to support the full range of accelerated approvals between 2013 and 2023, including those with less than five years for follow-up trials. That data found that 37% of approvals had been converted, 40% of them based on OS and 44% based on progression-free survival (PFS).

Surrogate endpoint concern

One key trend latterly is an increasing willingness by the FDA to accept surrogate measures to support conversions, which were used in 60% of them. For example, over the period 14% of new drugs were given full approval on the strength of response rates based on tumour shrinkage, in some cases with duration of response data, which the authors say “cannot by itself determine whether a drug offers patients a clinical benefit.”

They also have concerns about confirmatory trials that extend the use of a drug into new areas, such as earlier lines of therapy, and may not resolve uncertainty about the originally approved indication.

Lead author Edward Cliff, a haematology fellow and postdoctoral fellow at the Programme on Regulation, Therapeutics, and Law (PORTAL), said: “The FDA relinquishes significant leverage once it converts accelerated approvals to regular approval – it is harder to ensure timely completion of further trials, and harder to withdraw drugs – so the evidence used to justify these decisions is important.”

Liu acknowledged that the accelerated approval pathway can be a good thing for patients where drugs are subsequently shown to be effective, but he also said that “faster appropriate withdrawal decisions” that remove ineffective drugs from the market are also in their interests.

“While our study showed an increase in the time between accelerated approval and conversion to regular approval, we believe that conversion decisions should be both timely but – more importantly – supported by high-quality clinical outcomes, and that this is critical to the proper functioning of the accelerated approval pathway.”