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The US Food and Drug Administration (FDA) may need to re-evaluate how confirmatory testing is conducted after only one-fifth of these FDA-approved cancer drug trials have demonstrated improved overall survival (OS), researchers reported Tuesday in JAMA Internal Medicine research.
The researchers examined 93 anti-cancer drug indications that received FDA accelerated approval from 1992 to May 2017, and found confirmatory tests indicating that 20% had improved overall survival, 21% improved 39, a different substitution measure and 20% an improvement of the same substitute. measurement used in confirmatory testing and pre-approval testing.
"The proper use of surrogates for expedited approval requires an appreciation of how the validity of a surrogate may vary from one indication to another." One strategy to capture this variability would be to have a constantly updated database of surrogate validation forces for different types of tumors as the results of new trials become available, "said the researchers. Regulatory, Therapeutic and Legal Program (PORTAL), Division of Pharmacoepidemiology. and Pharmacoeconomics at Brigham and Women's Hospital and Harvard Medical School.
They also called for the adaptation of the FDA's recently published list of surrogate measures to include the strengths of surrogacy validation. "Confirmation of the clinical benefit of an anti-cancer drug using the same surrogate measure as that used in its prior approval trial should be reserved at the time when the surrogate measure for a given indication has been validated", they added.
In addition, the researchers addressed potential critics who might not agree on the importance of demonstrating the benefit of the operating system for verifying the clinical benefit. They use the example of imatinib for chronic myeloid leukemia (CML), which has been approved without it being necessary to report the benefits badociated with the SE during trials.
"However, imatinib for CML is an atypical example of a drug with such important benefits that it is seen as a way to save life rather than prolong it," they wrote. "Most of the approved anti-cancer drugs belong to the latter category and therefore even impressive effects on surrogate measures may not translate into prolonged survival benefits. Thus, although an improvement in surrogate measures alone may be acceptable for accelerated approval, confirmatory testing should verify the clinical benefits in terms of OS benefits, quality of life or a valid substitute for both.
"A rebadessment of the requirements for confirmatory testing may be needed to obtain more clinically meaningful information," they added. "The FDA should take a consistent approach to the results of confirmatory testing to help physicians and patients better understand what constitutes benefit verification."
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In a commentary accompanying the study and a second study of anti-cancer drugs approved based on response rates, professors at the Perelman School of Medicine at the University of Pennsylvania blame the FDA for having qualified the accelerated approval process for success, as only 5% of confirmation tests failed.
"The FDA welcomes itself, using its own surrogate criteria, which it can modify to demonstrate that its policies are successful. This low withdrawal rate is not a valid measure of success. There is no good reason for the FDA to rely as much on accelerated approval using response rates or other unreliable surrogate parameters, "they write.
They also point to three necessary policy changes: "First, the criterion for evaluating confirmatory trials should never be the same substitute badessment criterion used in the original study, and a new one. Alternative evaluation criteria should only be used if there is a proven correlation between this endpoint and the overall outcome. survival or improvement of the quality of life. Most confirmatory tests must use the global survival and / or quality of life parameters.
"Second, drug approvals must be promptly withdrawn when confirmatory tests report serious toxic effects or do not report significant clinical improvements. Finally, confirmatory testing must be conducted quickly, with credible threats of reverse approval. Having more than a quarter of incomplete testing years after accelerated approval is unacceptable, "they add.
Another comment from a professor from the Yale School of Medicine and from a professor from the University of Birmingham in the UK explains how the results of the two studies "s' rely on a number growing work that, overall, demonstrate a post-market evaluation process neither patients nor society well. "
Evaluation of Clinical Benefits of Anticancer Drugs with Expedited Approval
An overview of cancer drugs approved by the US Food and Drug Administration based on the final response rate of the surrogate
Accelerated Approval of Anti-Cancer Drugs: Straightening the Bar of the US Food and Drug Administration
An international perspective on anticancer drugs
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