Post-Approval Studies Aren’t Being Conducted

October 5, 2017

A study finds that a significant number of FDA-mandated studies are unfinished.

The FDA is increasingly intent on approving drugs quickly and is relying on post-approval studies for many drugs to guarantee safety. While preapproval studies are rigorously scrutinized and set to a tight time frame, post-approval studies are often never finished.

This is according to a study in the New England Journal of Medicine examining the outcomes of 614 post-approval requirements. The authors looked at the latest Federal Register status report on requirements from 2009 and 2010, the earliest years covered by the report. In 2009, 296 post-approval studies were established, and another 318 in 2010.

The studies reported on all studies that came after the FDA Amendments Act of 2007 (FDAAA), which gave the FDA additional powers to require companies to conducts studies. The FDAAA was created in response to criticisms over little oversight for post-approval studies and low completion rates.

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After five to six years, 20% of those 614 studies had not even been started and 25% were delayed or ongoing. A total of 54% had not been completed. Of those that were incomplete, only 16% were ongoing and on schedule, while 5% were on schedule but marked as pending since they had not enrolled any patients.

Nine percent of studies had missed FDA-specified deadlines. One delayed study highlighted was to confirm the clinical benefit and define the proper use of Folotyn (pralatrexate). Folotyn was approved under the accelerated approval designation, meaning that it is required to conduct such studies. Two studies were required at the drug’s approval in 2009-one missed multiple deadlines and was delayed while the other was still ongoing as of July 31, 2017. Another two studies required to meet the accelerated approval requirements, but both were delayed. In its initial approval studies of 111 patients, 26% had a complete or partial response, while 44% experienced a serious adverse event. The Folotyn label still carries a warning that its clinical benefits have not been proven.

In another example, Gilenya (fingolimod), was supposed to be studied to determine the efficacy and safety of a lower dose (0.25 mg). More than 6 years after approval, the study was still not completed because of recruitment difficulties. During that time, the drug’s sales totaled $2.8 billion.

Of the studies marked incomplete, 15% are classified as “release” by the FDA, meaning that the FDA has released the sponsor from its obligation to conduct a study because “is either no longer feasible or would no longer provide useful information.” But the authors said that some of these studies could have still provided useful information. They gave the example of Stelara (ustekinumab), for which the FDA required a lactation study to determine the safety of the drug in nursing women. For reasons unspecified, the FDA released the study, even though, as the authors note, “a substantial proportion of women with psoriasis are of childbearing age.”

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The authors gave several recommendations, the most basic of which was for the FDA to more fully utilize the powers granted to it by the FDAAA. The FDA could impose fines or other penalties on sponsors who fail to meet their deadlines, but the authors could find no evidence that the FDA has ever imposed such fines. They also want the FDA to make public the reasoning for its decisions releasing studies, which it does not currently do. Finally, they suggest that FDA shorten the completion deadlines for studies. Many pharmacokinetic and pharmacodynamics studies, they say, could be done in months rather than years.

The problem is made potentially worse by the fact that more and more medications are approved by the FDA through some accelerated process. In 2016, 16 of the 22 FDA-approved novel drugs were in at least one expedited program. FDA commissioner Scott Gottlieb has still been pushing for faster drug approvals.