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The researchers focused on the 54 cancer drugs that gained FDA approval in those years, and systematically searched for post-approval reports on the clinical endpoint of survival. They were unable to find evidence of a survival benefit for 57 percent of the approved cancer drugs.
"After nearly five years, that is probably too high," says senior author Vinay Prasad, M.D., M.P.H., a specialist in blood diseases and cancer at the OHSU Knight Cancer Institute, and an assistant professor of medicine (hematology and medical oncology) in the OHSU School of Medicine.
Prasad and co-author Chul Kim, M.D., clinical fellow in medical oncology at the National Cancer Institute, found that two-thirds of the approvals were based on a shortcut measure called a surrogate endpoint, such as tumor shrinkage or halting of tumor growth. Surrogate endpoints are used as time-saving stand-ins for clinical endpoints that directly measure how patients feel, how well they function or how long they survive.
When the FDA grants an accelerated approval based on a surrogate endpoint, the agency requires, on paper, that the sponsoring drug company completes a post-marketing study to confirm clinical benefits for patients. The FDA increasingly relies on surrogate endpoints in traditional approvals, and in those cases, the agency does not routinely require post-marketing studies.
"The FDA is under intense pressure to approve drugs more rapidly, and the FDA has been doing that," Prasad says. "The price they are paying is lowering the bar for approval."
Previous studies have found that surrogate measures often have little or no correlation with overall survival or other clinically meaningful results. The widely used surrogate endpoint of progression-free survival, for example, measures the share of patients at a given point in time with tumor growth that has not exceeded some arbitrary threshold, typically a 20 percent increase. "In and of itself, progression-free survival does not matter to people," Prasad says. "What you really want is for people to live longer or live better. Those are meaningful endpoints."
The drug bevacizumab (Avastin) is an often-cited example of the downside of surrogate endpoints. Bevacizumab gained an accelerated approval for metastatic breast cancer in 2008 based on dramatic gains in progression-free survival. But in subsequent randomized trials, the drug did not help patients live longer, even as it caused a range of severe side effects, some of them life-threatening. The FDA withdrew its approval for breast cancer in 2011.
Prasad and Kim determined that 36 cancer drugs gained approval on the basis of a surrogate endpoint from Jan. 1, 2008, to Dec. 31, 2012. Their literature search rooted up published evidence of improving patient survival for only five of the drugs. Studies on 18 of the drugs found that they failed to improve overall survival. The survival benefit of the remaining 13 drugs could not be judged because they have gone untested or drug company sponsors and investigators have not reported survival results.
Prasad says the findings highlight the need for regulators to act more forcefully to get drug companies to complete and report post-marketing studies for drugs approved on surrogate evidence. "The agency needs to insist that sponsors complete more definitive trials in a reasonably short time," he says. "And if a drug doesn't improve survival, the FDA has to withdraw its approval."
Oncologists and cancer patients, he says, should be mindful that many approved cancer drugs have not yet proved effective in trials using clinical endpoints. "People with cancer should ask their doctor if a proposed treatment has been shown to make you live longer or feel better, or is the evidence just based on a surrogate endpoint."
This work was not grant funded. Both authors were National Institutes of Health employees when this work began; Prasad is currently an employee of the OHSU Knight Cancer Institute.
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