FDA approved opioids based on limited data, sometimes ‘flawed’ trial designs

The FDA has often approved new drug applications for opioids based on trials of inadequate length that included only patients who could tolerate the drugs, according to researchers.

“Despite the scope of America’s ongoing opioid epidemic, little is known regarding the FDA’s approval of new opioid products over the past 2 decades,” G. Caleb Alexander, MD, MS, professor at the Center for Drug Safety and Effectiveness at the Johns Hopkins Bloomberg School of Public Health, told Healio Primary Care. “We examined one important facet of opioid regulation: how high a bar the FDA has set for new products reaching the market.”

Alexander and colleagues examined 48 new drug applications (NDAs) that were approved by the FDA between 1997 and 2018.

Chronic pain drugs

According to the researchers, most of the 48 NDAs were evaluated for new dosage forms (52.1%) or new formulations (18.8%), and only one was for a new molecular entity. Of the 39 NDAs that were approved for the treatment of chronic pain, 21 were supported by at least one pivotal trial. These trials had median of 299 patients (IQR = 174–525), and lasted a median of 84 days (interquartile range [IQR] = 25–84 days).

“Many individuals take these medicines for much longer periods of time,” Alexander said.

The researchers also found that 17 of these products were approved on the basis of trial designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits — known as the enriched enrollment randomized withdrawal (EERW) design, which Alexander called “fundamentally flawed.” Only eight NDAs for chronic pain (20.5%) included pooled safety reviews that reported systematic assessment of diversion, seven (17.9%) reported systematic measurement of nonmedical use of opioids, and 15 (38.5%) assessed the development of tolerance.

Acute pain drugs

Alexander and colleagues reported that eight of the nine NDAs for acute pain were supported at least 1 pivotal trial. These trials enrolled a median of 329 patients (IQR = 199–456) and lasted a median of 1 day (IQR = 1–2 days). The researchers noted that none of the pivotal trials for the acute pain drugs followed the EERW design.

Alexander said that “while spontaneous or ‘open-ended’ adverse event reports were common, the systematic collection of other important information, such as diversion or nonmedical use of opioids, was uncommon.

“The FDA could have required drug companies to have generated much more useful and clinically relevant information about the safety — and effectiveness — of prescription opioids,” he said.

An FDA spokesperson declined to comment on the study’s findings, noting that the FDA uses studies “to further our understanding about a particular issue and assist in our mission to protect public health.”