Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics.
To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018.
Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications.
Patients with pain who participated in phase 3 pivotal trials.
FDA-approved opioid analgesics.
Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes.
Most of the 48 NDAs evaluated were for new dosage forms ( = 25 [52.1%]) or new formulations ( = 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials ( = 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials ( = 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings.
The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only.
Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare.