US FDA Approvals of Drugs and Devices from Non-Randomized Trials

A new study from City of Hope National Medical Center and Stanford University is exploring how often the US Food and Drug Administration approves drugs and devices based on data from nonrandomized clinical trials(non-RCTs) and if those approvals are associated with the magnitude of treatment effects.

The systematic review and meta-analysis found 10% of the 606 drugs and 71 medical devices that had been approved during the study period were based on non-RCTs.

Investigators downloaded 606 drug applications for the Breakthrough Therapy Designation from the FDA website for a timespan ranging from the inception of the program in January 2012 until January 2017. A subsequent update was performed in August 2018.

For medical device applications, investigators pulled data from the Humanitarian Device Exemption program from the inception of the program in June 1996 until August 2017. Investigators noted they excluded studies where the applications were denied and studies with nonextracteable data.

Magnitude of effect was measured based on overall response rate, overall survival, objective response rate, and remission rate. Investigators also considered other primary outcomes for devices including clinical improvement and reoperation rate.

Upon analyses, results revealed that 68 (10.0%) of the 677 drug and device approvals were approved based on non-RCTs. Estimates of effects were larger when no further RCTs were required (mean natural logarithm of the odds ratios, 2.18 vs 1.12; odds ratios, 8.85 vs 3.06; P=0.03).

Estimated effects were approximately 2.5-fold greater for treatments or devices that were approved based on non-RCTs than for treatments or devices which further testing in RCTs was required (6.30 (95% CI, 4.38-9.06) vs 2.46 (95% CI, 1.70-3.56); P<0.001).

Additionally, 9 of the applications approved based on non-RCTs had relative risks of 10 or greater and 12 had relative risk of 5 or greater. Investigators could not detect a threshold above which the FDA approval led interventions based on the magnitude of estimated effect alone.

This study, “US Food and Drug Administration Approvals of Drugs and Devices Based on Nonrandomized Clinical Trials,” was published online in JAMA Network Open.