Cancer drugs that receive accelerated approval from the FDA, but fail to show improvement in the primary endpoint are still being prescribed and included in clinical treatment guidelines, according to a recent study published in the BMJ. 

“Patients with cancer need timely access to drugs that meaningfully improve how they feel, function, or survive. However, measuring clinical endpoints such as improvement in overall survival can take time, and patients may be willing to tolerate uncertainty about such benefits in exchange for early access to promising cancer drugs, particularly for cancers that lack other treatment options. The accelerated approval pathway of the US Food and Drug Administration (FDA) covers this situation,” explains Bishal Gyawali, MD, PhD, medical oncologist at Queen’s University in Kingston, Canada, and colleagues.

However, post-approval trials are needed to show that clinically meaningful endpoints have been satisfied. Drug approval will be withdrawn if the risks are shown to outweigh the clinical benefit. Most post-approval trials are delayed, with some still ongoing at 3 years after the initial accelerated approval.

In this retrospective observational study, Gyawali and colleagues, “investigated the regulatory consequences for cancer drugs that were previously granted accelerated approval by the FDA but failed to show improvement in the primary efficacy endpoint in post-approval trials. [They] also investigated the extent to which negative post-approval trials affected recommendations in clinical practice guidelines.”

Gyawali and colleagues found 18 indications for 10 different cancer drugs that had initially received an accelerated approval from the FDA from 1992 through December 2020, but then either failed to show primary endpoint benefit in post-approval trials (n=16) or never had their post-approval trials completed (n=2).

When cancer drugs that received accelerated approval fail to show improvement in their primary endpoint in post-approval trials, usually there is a voluntary withdrawal of the indiciation. This happened in 50% of the indications Gyawali and his colleagues studied. However, most of the drugs withdrawn remain on the market for other treatment indications. 

When looking at the National Comprehensive Cancer Network treatment guidelines, “in seven other cases, the category of recommendation remained 2A (the second highest level of recommendation) despite the drugs not improving the primary endpoint in post-approval trials. In one case (atezolizumab in triple negative breast cancer), the drug continues to hold a category 1 recommendation despite the failure to improve outcomes in the post-approval trial,” says Gyawali and colleagues.

Additionally, Gyawali and colleagues argued that there is a “need for mandating overall survival as the primary endpoint in post-approval trials for cancer drugs,” because most drugs that fail to show improvements in overall survival instead “use surrogate measures as the primary endpoint,” in post-approval trials. They note that this practice could “have the unintended consequence of serving as a further disincentive for manufacturers to choose overall survival as the primary endpoint in confirmatory trials, as the likelihood of failing to meet the primary endpoint is higher when the primary endpoint is overall survival.”

While this is the most comprehensive study of the FDA post-approval process for cancer drugs, it should also be noted that since the study relied solely on publicly available information; direct comments from sources such as the FDA, drug companies, and the NCCN, were not taken into account.

Gyawali and colleagues conclude that, “the FDA’s accelerated approval [program] is intended to balance speed of access and quality of evidence for promising new drugs. A fundamental premise of this balance is withdrawal of the approved indication if the drug does not show clinical benefit in the post-approval trial, but we found that this often does not occur. A recent flurry of regulatory action suggests that the FDA has paid greater attention to these situations in the past two years, although additional guidance and reforms of the accelerated approval pathway are needed to assure that all FDA approved drugs are shown to be safe and effective for patients.”