‘Broken’ system: Labels, guidelines include cancer drugs that failed confirmatory trials
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Indications for which cancer drugs receive accelerated approval often remain on drug labeling after confirmatory trials show no improvement in the primary efficacy endpoint, results of a retrospective, observational study showed.
Clinical guidelines — including those issued by National Comprehensive Cancer Network (see accompanying perspective) — frequently continue to recommend these agents, researchers added.
The findings suggest the regulatory handling of and treatment guidelines for some therapies do not align with 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 faculty with the program on regulation, therapeutics and law at Harvard University, and colleagues concluded.
“That the system was a little broken is not a surprise to me, but seeing the extent to which the system is broken was a surprise,” Gyawali told Healio. “Converting accelerated approval to regular approval based on negative data is difficult to understand. NCCN giving category 1 recommendations to such failed drugs is also difficult to understand.”
Gyawali and colleagues systematically searched the Drugs@FDA database for all cancer drugs granted accelerated approval by the FDA through December 2020.
Researchers utilized the FDA Database of Postmarketing Requirements and Commitments to verify the status of statutorily required post-approval trials for these drugs for the indications that received accelerated approval.
Investigators 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 demonstrate benefit, either because a post-approval trial failed to show improvement in the primary endpoint or because post-approval trials were not completed or conducted, leading to withdrawal of the indication.
“Our impression from working on a previous paper told us that the second half of the accelerated approval package — withdrawing approval when confirmatory trials are negative — may not have been respected,” Gyawali told Healio. “Thus, we wanted to do a formal analysis of what happens to these accelerated-approval cancer drugs when they fail in post-approval trials.
“It is important to note that when we say ‘fail,’ this is not our subjective judgment,” Gyawali added. “The trials actually failed to improve their own stated primary endpoint. We took it a step further and asked, ‘Do guidelines also change when these negative trials are announced?’”
Gyawali and colleagues identified 18 indications for 10 cancer drugs that received accelerated approval, but for which post-approval trials failed to 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 accelerated approval remained on drug labels.
“The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated-approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked,” Gyawali and colleagues wrote.
Further clarity from the FDA is needed as to why indications for some cancer drugs that do not demonstrate benefit in post-approval trials are withdrawn whereas others are not, researchers wrote.
Gyawali provided two key take-home messages for physicians.
“No. 1, don’t trust the FDA or the clinical guidelines. Analyze the data by yourself for the drug you use,” Gyawali told Healio. “No. 2, quick de-adoption of failed drugs is as important as quick adoption [of a therapy after a] positive trial.”
References:
Gyawali B, et al. BMJ. 2021;doi:10.1136/bmj.n1959.
Gyawali B, et al. JAMA Intern Med. 2019;doi:10.1001/jamainternmed.2019.0462.
For more information:
Bishal Gyawali, MD, PhD, can be reached at gyawali.bishal@queensu.ca.
Perspective
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Robert W. Carlson, MD
The NCCN is committed to empowering health care providers, patients and caregivers to make informed decisions about their cancer care through resources like the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines); NCCN Evidence Blocks, which provide a measurement of things like cost, evidence and efficacy; and NCCN Guidelines for Patients, which present clinical guidelines in lay terms.
Health care providers make individualized treatment recommendations based on a variety of factors, including the evidence supporting a given treatment, regulatory approval, clinical practice guidelines and pathways, patient-specific factors and patient preference.
The recommendations within NCCN’s resources are developed by NCCN’s 1,600-plus expert panel members who review all available evidence and make evidence-based consensus recommendations so patients can live better lives.
FDA’s accelerated approval status provides early access to potential breakthrough or novel treatments in areas where few — if any — good treatment options exist. NCCN expert panels consider the totality of the evidence, including regulatory approval status and associated Oncologic Drugs Advisory Committee proceedings, to make recommendations regarding inclusion or exclusion of an agent in the guidelines on a continuous basis. This expert review is made publicly available to help the health care community and patients understand the basis for guideline recommendations and make personalized treatment decisions.
Science is a dynamic process of testing a hypothesis (eg, a drug effect), collecting information and making the best conclusions possible from the available information. As new information becomes available, the conclusions are re-examined and modified as necessary based upon the new information. When we practice science-based medicine, we should expect the conclusions and therapies to change over time.
The processes used by the FDA and NCCN in making recommendations are fundamentally different. NCCN’s recommendations are multidisciplinary, patient centered, evidence-based and expert consensus-driven, assessing individual treatments in the context of the larger clinical landscape. Given the difference in approach and purpose, we should expect that there will be some differences between FDA approvals and NCCN recommendations.
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