Labels and guidelines include cancer drugs that have failed confirmatory trials

05 October 2021

2 minutes to read

Source / Disclosures

Disclosures: Arnold Ventures funded this study. Gyawali reports Vivio Health consultant fees outside of submitted work and Ontario Institute for Cancer Research salary support. Please see the study for relevant financial information from all other authors.

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Indications for which cancer drugs receive expedited approval often remain on drug labeling after confirmatory trials show no improvement in primary endpoint of efficacy, study results show retrospective observational.

Clinical guidelines – including those published by the National Comprehensive Cancer Network (see accompanying perspective) – frequently continue to recommend these agents, the researchers added.

List of main conclusions.

The results suggest that regulatory management and treatment guidelines for some therapies do not match the results of post-approval trials, Bishal Gyawali, MD, PhD, Associate Professor in the Departments of Oncology and Public Health Services at Queen’s University in Canada, as well as Adjunct Professor in the Regulatory, Therapeutics and Law Program and Harvard University, and colleagues concluded.

Bishal Gyawali

“That the system is a little broken is no surprise to me, but seeing how broken the system is was a surprise,” Gyawali told Healio. “Converting an accelerated approval to a regular approval based on negative data is hard to understand. The NCCN giving Category 1 recommendations to such failed drugs is also difficult to understand. “

Gyawali and his colleagues systematically searched the Drugs @ FDA database for all anti-cancer drugs that had achieved FDA fast-track approval until December 2020.

The researchers used the FDA’s Post-Market Requirements and Commitments Database to verify the status of post-approval trials required by law for these drugs for indications that received expedited approval.

Researchers also searched PubMed and Google Scholar for published post-approval trials and used Google News to identify updates on the status of post-approval trials.

The analysis focused on cancer drugs that received accelerated approval but ultimately failed to show benefit, either because a post-approval trial failed to show improvement in endpoint principal, or because the post-approval trials were not completed or conducted, resulting in the withdrawal of the indication. .

“Our impression of working on a previous article told us that the second half of the expedited approval package – the withdrawal of approval when confirmatory tests are negative – may not have been met,” said Gyawali to Healio. “So we wanted to do a formal analysis of what happens to these fast-track cancer drugs when they fail in post-approval trials.

“It is important to note that when we say ‘fail’ it is not our subjective judgment,” Gyawali added. “The trials actually failed to improve their own primary endpoint. We took it a step further and asked, “Do the guidelines also change when these negative trials are announced?” “”

Gyawali and colleagues identified 18 indications for 10 anticancer drugs that received accelerated approval, but for which post-approval trials did not show improvement in the primary endpoint.

Manufacturers voluntarily withdrew 11 (61%) of these indications, and the FDA revoked another – bevacizumab (Avastin, Genentech) for breast cancer. The other six indications for which the FDA granted fast-track approval remained on drug labels.

“The NCCN guidelines provide a high level of approval (Category 1 approval for one and Category 2A approval for seven) for fast-track drugs that have failed post-approval trials, sometimes even after approval has passed. been withdrawn or revoked, “Gyawali and colleagues wrote.

Further clarification from the FDA is needed as to why indications for certain anticancer drugs that do not show benefit in post-approval trials are being withdrawn while others are not, the researchers wrote. .

Gyawali provided two key take-home messages for doctors.

“No. 1, don’t trust the FDA or clinical guidelines. Analyze the data yourself for the drug you are using,” Gyawali told Healio. 2, the rapid de-adoption of failed drugs is as important as the rapid adoption [of a therapy after a] positive test.


Gyawali B, et al. BMJ. 2021; doi: 10.1136 / bmj.n1959.
Gyawali B, et al. JAMA Med Intern. 2019; doi: 10.1001 / jamainternmed.2019.0462.

For more information:

Bishal Gyawali, MD, Doctorate, can be reached at [email protected]

About Mark A. Tomlin

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