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Peek into the Process

A series of articles in the Journal of the American Medical Association this week examines the US Food and Drug Administration's approval process.

One paper from a Yale University School of Medicine-based group looks at the evidence supporting FDA's decisions to approve nearly 190 drugs between 2005 and 2012. Joseph Ross, an assistant professor of medicine at Yale, and his colleagues report that the clinical trial evidence justifying each approval varies in quality.

"Although the vast majority of indications were supported by at least 1 randomized, double-blinded trial, there was wide variation in trials' choice of comparators and end points, duration, size, and completion rate," the investigators write. "In addition, just more than one-third of indications were approved on the basis of a single pivotal efficacy trial."

FDA says that while clinical trial requirements differ from drug to drug, each therapeutic is held to the same safety and efficacy standards, the Wall Street Journal notes.

The researchers suggest that FDA adopt a sort of grading system to indicate the quality of the evidence used to determine drug safety and efficacy. "It's OK if we as society want these drugs to come to market more quickly, and be less rigorously studied at the time of approval, but I want that information conveyed to patients in a way they can understand it," Ross tells the Wall Street Journal. FDA says that new drugs come with prescribing labels and medication guides that include information regarding safety and efficacy, the WSJ adds.

Another paper, this one from FDA researchers, investigated the reasons why the approval of some drugs are delayed or denied. Rachel Sherman from FDA's Office of Medical Policy and her colleagues examined 302 new molecular entity — those not marketed before in the US — applications from between 2000 and 2012. They note that about half were approved when first submitted and that nearly three-quarters were eventually approved. Some 71 applications went through multiple submissions, with a median delay of 435 days.

"Applications that were eventually approved were often able to address initial safety, manufacturing, and labeling concerns, but efficacy concerns were less likely to be successfully managed," Sherman and her colleagues say.

And a third paper from Boston-based researchers finds that most cardiac implantable electronic devices like pacemakers are evaluated through the premarket approval process. Drawing on the agency's PMA database, the researchers examined cardiac devices approved between 1979 and 2012 as PMAs or supplements. In that time span, the investigators found that FDA approved 77 original and 5,829 supplement PMA applications for such devices. Most devices, then, they found, were approved without additional, new clinical data.

The Boston investigators note, though, that the "PMA supplement process allows manufacturers to update devices via incremental innovations" and get those improvements to patients faster. Still, they say their findings "reinforc[e] the importance of rigorous postapproval surveillance of these devices."

These reports, a related JAMA editorial notes, help to explicate what goes on in the "black box" of the FDA. "Although these reports represent important steps in improving understanding of FDA decision making," the editorial says, "further commitment to and progress toward ensuring transparency, including reducing report redactions, is needed to help the scientific community and other interested parties answer the questions these studies raise, thereby helping the FDA in its mission to find the right balance between allowing innovation and protecting the public's health."