FDA Approvals of Opioids Based on Insufficient Efficacy and Safety Data


A new cross-sectional study uncovers shortcomings in pivotal trials supporting new drug applications for opioid analgesics, which range from study design to duration.

James Heyward, MPH

James Heyward, MPH

For the past 2 decades, the US Food and Drug Administration (FDA) has approved new drug applications (NDAs) for based on pivotal trials that lacked robust safety and efficacy data.

For example, most of the approved new drug applications (NDAs) for chronic pain were supported by phase 3 trials that had a general duration of only ≤12 weeks.

Furthermore, many of these trials used enriched enrollment randomized withdrawal (EERW) designs, which exclude patients who do not tolerate or respond well to the drug in the pre-randomization period. As a result, this limits generalization to a real-world population as well as increases the likelihood of the results overstating opioid benefits.

A team led by James Heyward, MPH, and colleagues at the Johns Hopkins Bloomberg School of Public Health assessed publicly available data published by the FDA in order to characterize the quality of efficacy and safety data in opioid product NDAs between 1997-2018.

Characteristics of interest for each NDA included the number, size, duration of pivotal trails; trial control groups; the use of EERW designs; and systematically measured safety outcomes.

Thus, within the study period, they identified 48 opioid NDAs that were approved by the FDA. Of the total, only 1 was considered a new molecular entity (NME); the remaining NDAs were either new dosage forms, new combination products, new formulations, or were products previously marketed with no NDA.

Among the non-NME NDAs, 30 indicated utilization of the 505(b) pathway and referenced a previous approval.

Additionally, only 29 of the 48 NDAs were approved with pivotal efficacy data.

Heyward and team noted that a total of 39 NDAs was indicated for chronic pain, and 9 were for treatment of acute pain.

Only 21 of the NDAs approved for chronic pain were supported by at least 1 pivotal trial. Furthermore, the total number of these trials (n = 28) had a median duration of 84 days (interquartile range [IQR], 25-84 days), and enrolled a median of 299 patients (IQR, 174-525).

As many as 17 (81%) of these 21 NDAs had designs that excluded patients who could not tolerate the drug, had early adverse events, or reported few immediate benefits.

Of the 39 chronic pain NDAs, only 8 included pooled safety reviews that reported systematic assessment of diversion, 7 reported systematic measurement of nonmedical use, and 15 assessed development of tolerance.

As for the approved products for the treatment of acute pain, 8 were supported by at least 1 pivotal trial. The total number of trials (n = 19) had a median duration of 1 day (IQR, 1-2), and enrolled a median of 329 patients (IQR, 199-456).

“These findings are important because of the central role that prescription opioids have played in driving the opioid epidemic, as well as the FDA’s vital role as the regulator of the pharmaceutical marketplace in the United States,” the investigators wrote.

The investigators proposed several steps the FDA can implement to increase the amount and quality of safety and efficacy data generated by trials of new opioids. 

These steps include, but are not limited to, enacting more explicit regulatory guidance and requirements, decreasing reliance on EERW designs, requiring new pivotal trials to systematically define and assess information regarding frequently occurring adverse events, and mandating such trials to have a duration of ≥24 weeks.

“Optimizing the efficacy and safety data drug manufacturers provide to the FDA would help ensure more informed prescribing and reduce the public health risk of these products,” they concluded.

The study, “Key Evidence Supporting Prescription Opioids Approved by the U.S. Food and Drug Administration, 1997 to 2018,” was published online in Annals of Internal Medicine.

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