FDA fails to enforce requirements
- by Larry Husten, CardioBrief September 20, 2017
Pharmaceutical and device companies are often taking advantage of a lenient (or, some would say, negligent) FDA to shirk their obligation to perform timely post-approval studies, a new Perspective published in the New England Journal of Medicine shows.
The topic has gained increasing visibility and importance as the FDA has granted approval to many new drugs and devices without all the evidence that might ideally be required.For safety as well as efficacy, the FDA has allowed much of the burden of proof to shift from pre-approval to the post-approval period.
But in an analysis of 614 post-approval requirements and commitments imposed by the FDA in 2009 and 2010 (the first full years after the FDA gained the power to require these studies), Steven Woloshin at Dartmouth Institute for Health Policy and Clinical Practice and colleagues showed that only 54% of these studies were completed after 5-6 years. They found that 20% of "required" studies had not been started and 25% were delayed or ongoing as of September 2015.
"It's not a secret that we need a better post-market system," said former FDA Commissioner Robert Califf, now at Duke University. "The good news is that technology is no longer the limiting factor -- it's all about culture, organization and priority setting by policy makers, clinicians and patients and their 'carers' (families and loved ones)."
The authors observed that in many cases there didn't appear to be any good reason for the delays. For instance, more than 5 years after approval of buprenorphine/naloxone film (Suboxone), no protocol had been submitted for assessing the risk of QT-interval prolongation, "even though the design of such studies is highly standardized and participants are observed for a limited period."
"The slow, irregular pace of post-approval studies contrasts starkly with the short, rigid deadlines and other shortcuts used to speed marketing approval," the authors wrote.
The FDA should "do more to ensure that sponsors meet post-approval deadlines," the authors urged. Although the FDA has the power to impose fines or other penalties on companies that fail to live up to their obligations, "to our knowledge, it has never imposed such fines." They also recommend that the FDA set shorter deadlines for post-approval studies.
"Woloshin and colleagues offer some useful insights into the FDA's use of post-approval studies to confirm and further evaluate drugs' safety and efficacy at the time of approval," said Joe Ross of Yale University. "While more than half were completed, many were not. This study is only made possible by the efforts at FDA to provide public transparency of the post-approval requirements, but more information could help the public and the profession understand why certain requirements were not fulfilled, whether these studies were intended to provide key clinical information to inform practice (as opposed to safety info that instead came from another clinical study), and even for those studies that were completed, whether the results were published and made available."
Sanjay Kaul of Cedars-Sinai Medical Center said that it is not unreasonable to shift "the regulatory burden from the pre-approval phase to a life cycle-based approach. However, the success of such an approach is predicated on a rigorous and timely post-approval phase. That 1 in 5 post approval studies had not even been started after 5 to 6 years calls into question the degree to which the changes in the FDA's regulatory authority in 2007 have resolved the challenge of reducing the number of unfulfilled post-approval requirements. This can hardly be reassuring given the 21st Century Cures Act which calls for faster marketing of drugs and devices at the cost of stringent evidentiary standards! Even though the FDA has congress-legislated authority to revoke approval of drugs and devices that failed to confirm clinical benefit on post approval studies, it rarely does so! It is difficult to put the genie back into the bottle."
The "bottom line," said Kaul, is that "marketing drugs and devices faster can only be justified if there are much better post-market data to reliably support efficacy and safety."