Post-market study requirements and associations with timely submission and regulatory action for oncology drugs receiving accelerated approval, 2011-2023.
Authors: Martin Kurian, William J. Ferrell, Ernesto Ulloa Perez, Rebecca Hubbard, Steven Joffe, Holly Fernandez Lynch, Ronac Mamtani, Ravi Bharat Parikh
Journal: Journal of Clinical Oncology (2024)

11028 Background: For oncology drugs receiving accelerated approval (AA), the Food and Drug Administration (FDA) enforces Postmarketing Requirements (PMRs) to verify clinical benefit prior to regular approval. Although previous work has characterized the rigor and timeliness of confirmatory studies, the association between specificity and scope of PMR statements and the timeliness of PMR submission and ultimate approval status is not well understood. Methods: We identified 161 oncology indications granted AA between January 2011 and July 2023 using FDA’s Cancer AA database. We linked indications to 181 corresponding PMR statements using the Drugs@FDA database. We analyzed PMR statement scope and specificity based on the presence or requirement of eight characteristics: target population, comparator (active or placebo-controlled), randomization, multicenter trial, blinding (double-blind or open-label), enrollment target, follow-up duration, and endpoints. We used chi-square and t-tests to analyze associations between PMR characteristics and two primary outcomes: indication approval status (regular vs. withdrawn) and PMR timeliness (on time vs. late). We defined “late” submissions as PMRs submitted or withdrawals occurring after an expected PMR Final Report submission date. Ongoing PMRs were excluded from the timeliness analysis unless expected dates occurred before August 2023. Results: Among 181PMR statements, 98% percent specified target population, 81% endpoint (44% overall survival), 63% use of randomization, 54% comparator (40% active; 14% placebo-controlled), 30% follow-up duration 26% enrollment targets, 24% multicenter trial, and 13% double-blinding (and 8% open-label). Among AAs converted to regular approval, 82% of PMRs were submitted on time vs. 24% on-time for withdrawn AAs (p=0.001). Regular approval PMRs were submitted 10.2 months ahead of expected dates, whereas withdrawn AAs were submitted 14.5 months behind expected dates (p&lt;0.001). Compared late PMR submissions, on-time PMR submissions had lower enrollment (400 vs. 665, p=0.01), less blinding (19% vs. 40%, p=0.03), more frequent use of a single trial for both AA and PMR (38% vs. 8%, p=0.001), and primary endpoints other than overall or progression-free survival (36% vs. 5%, p&lt;0.001). Compared to late PMR submissions, on-time PMR submissions more often followed PMR statements that specified follow-up duration (39% vs. 13%, p=0.006) and non-survival primary endpoints (30% vs. 8%, p=0.01). Conclusions: There is marked variability in the contents of PMR statements for oncology AA drugs. Several characteristics of PMRs – including smaller enrollment size, surrogate endpoints, and single trials for AA and PMR – are associated with timely submission. These findings inform the specificity and scope of future FDA PMRs for oncology AA indications.