Presentation (CTI)

OBJECTIVES: FDA expedited review pathways allow approval of therapies for serious or life-threatening rare diseases based on limited pre-approval evidence, with postmarketing requirements to verify clinical benefit. The goal of this study was to understand the frequency and status of postmarketing requirements in orphan drugs.
METHODS: We searched FDA databases to identify orphan drug indications approved via an expedited pathway (Priority Review, Fast Track, Breakthrough Therapy, or Accelerated Approval) between January 1, 2015, and December 31, 2024. We then assessed postmarketing evidence by reviewing FDA indication approval letters and the Postmarketing Requirements and Commitments database to capture the presence, type, and status of postmarketing requirements, including confirmatory trials, along with approval characteristics (drug type, therapeutic area, and pathway used). Descriptive analyses were conducted.
RESULTS: A total of 184 orphan indications were approved via an expedited pathway during the study period (32/184 were approved via 1 pathway and 152/184 were approved via >1 pathway). Of all expedited indications, 80.4% (148/184) had postmarketing requirements, with 54.7% (81/148) requiring a confirmatory trial and 45.3% (67/148) requiring a non-confirmatory trial. Among indications requiring a confirmatory trial, 33.3% (27/81) verified clinical benefit, 51.9% (42/81) had trials ongoing or pending, 7.4% (6/81) had a negative trial (benefit not confirmed), and 7.4% (6/81) withdrew or did not conduct the trial. Among indications approved via 1 pathway that had postmarketing requirements (71.9%; 23/32), the most common pathway was Priority Review (56.5%; 13/23), followed by Accelerated Approval (21.7%; 5/23), Breakthrough Therapy (17.4%; 4/23), and Fast Track (4.3%; 1/23).
CONCLUSIONS: The vast majority of orphan indications approved through FDA expedited pathways carry postmarketing requirements, yet few confirmatory trials have been completed and verified clinical benefit to date. Future research should explore the timing of postmarketing study completion to ensure clinical value for patients with rare diseases.