Previously FDA-Approved Opioid Products Did Not Have Adequate Safety Assessment

Researchers from the Johns Hopkins Bloomberg School and George Washington University found that the evidence for new opioid analgesic drug approvals by the Food and Drug Administration (FDA) between 1997 and 2018 relied on short- or intermediate-term studies that largely did not adequately analyze safety outcomes. These findings, from a cross-sectional analysis, were published in the Annals of Internal Medicine.

New drug applications for opioid products (n=48) approved by the United States Food and Drug Administration (FDA) for the treatment of acute or chronic pain were aggregated by investigators. Study details and safety assessments for each drug were interrogated.

Of all approved opioids, 30 sought approval through the 505(b)(2) pathway, an abbreviated process that allows for applications to use previously submitted data or published literature. A total of 47 pivotal trials were conducted to approve these 48 opioid products. Ten of the new drug applications were made publicly available.

The median number of pivotal trials for each approved drug was 1 (interquartile range [IQR], 0-1). The number of trials varied for type of drug; new molecular entities were supported by a median of 2 pivotal trials, while new pivotal trials were uncommon for new formulations (1 out of 9) or previously marketed products (0 out of 6). Only 29 of the drug applications had underlying data from placebo-controlled trials.

The drugs were approved for use among patients with acute pain (n=9) or chronic pain (n=39). Of the drugs approved for chronic pain, 6 were approved for cancer-related use.

The studies ─ which allowed for approval of the 9 acute pain drugs ─ had median trial durations of a single day (interquartile range [IQR], 1-2 days) and did not have enriched enrollment randomized withdrawal (EERW) designs.

Among the opioid products approved for chronic pain, the median duration of these was 84 days (IQR, 25 to 84 days) with a median of 299 patients enrolled (IQR, 174-525). Of these approved drugs, 81% had underlying studies with an EERW, and no drug was approved with support from both EERW and non-EERW trials.

Among new drug applications for chronic pain (n=39), 38.5% assessed drug tolerance, 20.5% assessed diversion of the study drug, 17.9% assessed aberrant drug use, and 12.8% assessed overdose symptoms. No study included all these measurements to assess systematic safety.

One limitation of this study was that preclinical studies were not included in the dataset. As most of these studies followed the 505(b)(2) pathway, some submitted evidence may have included important safety or efficacy data that supported the subsequent approval.

These data underscored that the 48 new opioid products that were approved by the FDA over a 20-year period were done so based on data from studies that lasted fewer than 12 weeks, typically including a narrowly defined population, and with inadequate assessment of safety.

“These findings suggest several opportunities for the FDA to use its regulatory discretion to increase the safety and efficacy data generated in support of new opioid approvals,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Heyward J, Moore TJ, Chen J, Meek K, Lurie P, Alexander GC. Key evidence supporting prescription opioids approved by the U.S. Food and Drug Administration, 1997 to 2018. Published online September 29, 2020. Ann Intern Med. doi:10.7326/M20-0274