FDA Review Deadlines Caused Safety Issues: Study

FDA Review Deadlines Caused Safety Issues: Study

February 2nd, 2012 // 1:59 pm @

The latest buzz about the FDA is that the agency is approving more drugs in the past and, the trend has been especially noticeable in recent days with the approval of several medications, including a new type of treatment for some people who suffer from cystic fibrosis (see here and here). But what if the race to meet approval deadlines caused some unintended consequences?

A new study suggests that might have been the case. After examining data from FDA advisory committees, a group of researchers from Harvard University, Stanford University and Brown University found that a relationship exists between approvals made closest to deadlines and post-market safety problems, such as drug withdrawals, major labeling revisions or safety alerts issued by the agency.

Although the researchers do not maintain that a strict cause-and-effect relationship has been established, they suggest the implications ran wide and deep. To wit, in the quest to meet deadlines, approvals may have inadvertently led to adverse health outcomes – which raised costs for patients and payers – and caused setbacks for drugmakers that expect predictable financial returns.

The findings, which were published in the American Journal of Political Science, appear as the House Energy & Commerce Committee holds a hearing today on the virtues of the Prescription Drug User Fee Act (you can watch here and see the agenda here). Known as PDUFA, the initiative was first passed in 1992 and ushered in a new era in approvals as drugmakers now pay fees to fund reviews – these cover about 60 percent of the cost- and the agency has specific requirements to meet.

The purpose of the paper was to examine how Congress uses deadlines to control regulatory agencies, and PDUFA offered a useful lesson. “By imposing specific deadlines and linking agency compliance to the agency revenue source – the penalty for not meeting the deadline was not simply embarrassment and congressional pressure, but also the possibility that tens of millions of dollars in user fees would no longer be available for personnel costs – PDUFA represented a significant effort to influence FDA actions,” the researchers write.

To test their hypothesis, they examined the approval process for 1,034 new molecular entities that were approved between 1950 and 2008, when – the Food and Drug Administration Amendment Act – was passed and began to require advisory committee meetings for NMEs. What did they find? Well, the so-called review clock can be problematic. “Our analyses suggest that deadlines have altered the timing of FDA decisions,” they conclude.

For instance, they compared reviews before and after PDUFA began 20 years ago, and found that reviews suddenly piled up in as the six-month deadline neared for those drugs after the legislation went into effect. But there was no such piling in the years before PDUFA. This suggests that deadline pressure altered the timing of reviews and raising the possibility of post-market problems, since this may have compromised the ability of the FDA to gather and distribute info through advisory panels.

Moreover, they assert that, if a drug is approved in the two months before the deadline, then that same drug will, on average, experience higher rates of safety issues in the years after approval, compared both to drugs approved quickly, which was three or more months before the deadline, and to drugs approved more slowly, which would have been after the deadline.

Specifically, they found the probability of a drug approved in the two months before the deadline receiving a new black-box warning is 3.27 times greater than a drug approved at some other time, according to a model used to examine NMEs approved between 1993 and 2007. For NMEs approved between 1993 and 2007, safety-based withdrawal is 6.92 times greater for a drug approved in the two months leading up to its approval deadline than for comparable drugs approved at other times.

“The bottom line is that there remains a relationship between approvals at-the-deadline and the raised incidence of post-market safety problems several years later,” Daniel Carpenter, the Allie S. Freed professor of government at Harvard University and one of the researchers and the author of ‘Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA,’ writes us.

“Although we are still not claiming baldly that the deadlines necessarily cause – in a physics-like notion of causality – these post-market problems, the observational evidence seems to be mounting, and the manuscript uses a variety of statistical controls and tests, including a form of statistical analysis called ‘non-parametric matching,’ to tease out the relationships,” he continues. “And it suggests that one mechanism for this relationship may be compromised consideration of the drug later in the review stage, including occluded or shortened advisory committee consideration.”


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