Many drugs granted approval under FDA's accelerated approval pathway lack sufficient, post-approval evidence demonstrating their efficacy and safety—and this lack of rigorous data is also true for many modifications for high-risk medical devices, according to a pair of new studies in JAMA.
Study: Confirmation data slow, sparse for many drugs granted accelerated approval
For the study, the researchers assessed the 22 drugs approved under the accelerated program for 24 medical conditions between 2009 and 2013 based on 30 preapproval trials.
FDA typically requires randomized controlled trials to demonstrate a drug's safety and effectiveness. But, under the agency's accelerated program, drugmakers can apply for approval using less robust findings, such as predicted symptom improvement, to facilitate drug access for patients with serious or life-threating illnesses. Drugmakers are then expected to conduct post-market studies in a timely manner to verify that the drugs provide the benefits they claimed.
Of the 24 medical conditions, the researchers identified 14 of the accelerated approvals were based exclusively on "single-intervention-group studies that enrolled a median of 132 patients, which some investigators would consider a small number." Further, the researchers found that just 19 of the 38 follow-up trials FDA required to verify the drugs' benefits for the approved 24 indications had been completed within three years of the drugs' approval—11 more were ongoing, six had been postponed for more than a year, and two had been discontinued entirely.
Moreover, according to the researchers, many of the drugs for which drugmakers completed follow-up trials did not test for outcomes such as improved patient survival rates or curbed disease symptoms. And several trials were either discontinued or failed to demonstrate a benefit. Overall, the 10 approvals that did meet FDA requirements were completed within one to five years after approval, the researchers said.
Huseyin Naci of the London School of Economics and Political Science and lead author of the study said, "[W]e have found numerous situations [for drugs granted accelerated approval] in which required confirmatory studies with rigorous designs and outcomes are not pursued or are not completed in a timely fashion, and in these cases, we are concerned that regulators appear to accept data that would not otherwise meet FDA standards."
According to Naci, the findings "suggest that expediency in drug development and approval can be successful, but that drugs approved via the shorter route to market are rarely subject to tests even in the post-approval period that use established and clinically meaningful outcomes." Naci recommended that when FDA grants an accelerated approval, the agency should specify data limitations and detail how the mandatory follow-up studies should compensate for those limitations.
Study: Few FDA-approved medical device modifications backed by rigorous evidence
In a separate study, Rita Redberg from the University of California, San Francisco, assessed the approval process for modifications to high-risk medical devices and reached similar conclusions, Boggs reports.
For the study, Redberg and colleagues evaluated 78 medical device modifications. The researchers found that 71 of the modifications were supported by just one clinical study—half of which enrolled 185 or fewer patients—and that one in 12 studies did not specify what the researchers were trying to demonstrate.
Redberg said, "We expected to find generally high-quality evidence to support these changes, because these devices are important to health, and many are implanted and are difficult and/or dangerous to remove." But in fact, "relatively few studies were randomized or blinded," Redberg continued, "which means that it is not known if the device was better than an alternative treatment (or better than no treatment), and whether any purported beneficial effect was actually due to the well-documented placebo effect of procedures and devices."
Redberg said, "I think the public assumes that medical devices currently on the market, particularly high-risk devices, have been approved based on a high standard to show safety and effectiveness before doctors can recommend and implant them," adding, "Our findings show that this assumption is often incorrect."
Editorial urges patients to check with their physicians
In an editorial accompanying both studies, Robert Califf—a professor at Duke University School of Medicine and a former FDA commissioner under former President Barack Obama's administration—said, "People should ask their doctors about the evidence for drugs and devices being prescribed or use, and they should support research and participate."
Further, people should "should encourage their doctors to participate; too many doctors just 'go with the flow' rather than demanding high-quality evidence about what they are prescribing and implanting, and actively joining into appropriate clinical trials," Califf wrote (Boggs, Reuters, 8/15; Diamond, "Pulse," Politico, 8/16).
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