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FDA moves slowly on required postapproval drug studies; other agency procedures scrutinized

More than 3 years passed before the efficacy of most drugs given accelerated approval by the FDA from 2009 to 2013 was validated, according to findings published in JAMA.

A second study, also in JAMA, suggests that more than half of the changes made to high-risk medical devices that were approved by the FDA occurred after trials that were not masked, controlled or randomized.

Quality of evidence regarding drugs

Medications designed to treat life-threatening or serious conditions sometimes receive accelerated approval from the FDA based on how they perform in surrogate measures that may not always be indicative of the actual clinical benefit, according to researchers, who added that confirmatory trials are then required to determine whether these effects indeed lead to clinical improvements.

“Although [this] ... can be highly effective in facilitating the approval of certain new drugs, these pathways have also been a source of controversy,” Huseyin Naci, PhD, of the London School of Economics in England, and colleagues wrote. “Drugs approved via expedited pathways may have greater safety risks to patients. Implementation of the accelerated approval pathway in recent years has not been characterized.”

Naci and colleagues looked at primary endpoint, comparator, masking and randomization features of preapproval and confirmatory studies, the approximate time between accelerated approval and fulfillment of regulatory requirements and the regulatory decisions that followed. Twenty-two drugs, covering 24 indications, were given accelerated approval during the period studied; follow-up ceased on April 7 of this year.

Researchers found that there were 30 preapproval studies that supported the 24 indications. Only half of the 38 required confirmatory studies were finished within 3 years.

Of these, 25 were intended to evaluate clinical efficacy, seven assessed longer follow-up and six centered on safety.

In addition, Naci and colleagues found that the proportion of studies with randomized designs did not differ before and after accelerated approval. Postapproval requirements were finished and showed efficacy in 10 of 24 indications on the basis of trials that evaluated surrogate measures. Researchers also stated that research regarding 14 of the 24 indications had not yet finished all the requirements: at least one of the confirmatory studies failed to demonstrate clinical benefit, two confirmatory studies were terminated and three were delayed by more than 1 year. For the remaining seven indications, researchers found that studies were following target timelines. However, clinical benefit had not yet been validated for eight indications that had been first approved 5 or more years earlier.

“Even though the majority of completed studies showed positive results in the postmarketing period, all completed confirmatory studies demonstrating drug benefit evaluated surrogate measures of disease activity rather than clinical outcomes,” Naci and colleagues wrote.

Quality of evidence regarding medical devices

In the second article, Sarah Y. Zheng, MD, of the department of psychiatry at the University of California, San Francisco, and colleagues defined the quality of the data and clinical studies utilized to reinforce FDA approval of panel-track medical device supplements from April 19, 2006, to Oct. 9, 2015.

“[S]upplementary changes mean many high-risk devices differ substantially from the originally approved device,” researchers wrote. “Furthermore, the total number of supplements has been increasing.”

Zheng and colleagues reviewed 83 studies covering 78 panel-track supplements for the reporting of sex and age, use of analyses after the fact, clinical vs. surrogate primary endpoints, type of controls, masking and the use of randomization.

Researchers found that 71 of the panel-track supplements were supported by a single study. Only 37 of these studies were randomized clinical trials, 33 did not report age, 25 were masked and the same number did not report sex for all enrolled patients. There was a mean of 1.8 primary endpoints per study. Of primary endpoints with controls, six were retrospective controls and 51 were active. Zheng and colleagues also reported that 121 of the primary endpoints were surrogate endpoints, and the FDA mandated postapproval studies for only 29 of the 78 panel-track supplements.

“The findings that few supplementary changes require clinical data and that when they do the data are often low-quality raise uncertainty about performance of many commonly used devices,” Zheng and colleagues wrote. “[P]atients lack legal recourse if a [pre-market approval] device is faulty and adversely affects health outcomes. Thus, it is vital to ensure safety and effectiveness by requiring high-quality clinical data before high-risk devices reach the market.”

Former FDA commissioner weighs in

The findings of these two studies “raise concerns,” Robert M. Califf, MD, former FDA commissioner and currently an adviser with Verily Life Sciences, wrote in an accompanying editorial.

“A sweeping overhaul of the overall system is needed. Fortunately, such a transformation is underway,” he wrote. “It is now time to seriously consider how to use these increasingly robust data and analytic capabilities and more efficient prospective research systems to deal with the issues raised by these articles.”

Califf also noted that full-time FDA employees with no financial conflicts guide the decisions about postmarket requirements and monitoring of the studies mentioned by Naci, Zheng and others.

“These civil servants are charged with considering the complex issues involved when a presumably effective therapy is on the market but additional evidence is needed. While general principles apply, in the case of accelerated approval and device modifications, judgment is needed,” he wrote. “This underscores the importance of a talented workforce at the FDA with the variety of skills needed to assimilate information about manufacturing, quality systems, clinical outcomes and the well-being and preferences of patients.” – by Janel Miller

References:

Califf R. JAMA. 2017;318:614-616.

Naci H, et al. JAMA. 2017;doi:10.1001/jama.2017.9415.

Zheng SY, et al. JAMA. 2017;doi:10.1001/jama.2017.9414.

Disclosure: Neither Naci nor Zheng report any relevant financial disclosures. Califf currently receives consulting fees from Merck. Please see the study for a full list of the other researchers’ relevant disclosures.