Specificity of Food and Drug Administration postmarketing requirements and associations with timely submissions and regulatory decisions for oncology accelerated approvals, 2011-2023: a cross-sectional analysis.

Abstract

Abstract:

Objectives: To assess the specificity of postmarketing requirement (PMR) statements and associations between PMR statement specificity and PMR study characteristics, timeliness and regulatory decisions.

Methods and analysis: This was a cross-sectional analysis of publicly available Food and Drug Administration (FDA) databases to characterise PMR statements for oncology accelerated approvals (AAs) between January 2011 and July 2023. Characteristics of trials supporting AA and PMR studies were identified from product labels on the Drugs@FDA database and ClinicalTrials.gov. Main outcomes and measures included PMR statement characteristics, PMR study submission timeliness (on-time vs late) and regulatory decision (regular approval vs withdrawal).

Results: We analysed 181 PMR statements for 161 oncology indications. Most PMR statements specified target population (98%), endpoints (81% (44% included clinical endpoints; 37% surrogate endpoints only)), use of randomisation (63%) and comparator (54%). Fewer PMR statements specified a particular trial or protocol (45%), follow-up duration (30%), enrolment targets (26%), multicentre trial (24%), double-blinding (13%) or enrolment diversity (8%). PMR statements for indications granted regular approval were more likely than those for withdrawn indications to specify follow-up duration <1 year (27% vs 0%, p<0.001), allow endpoints other than overall or progression-free survival (27% vs 4%, p=0.01) and mention a specific trial or protocol (71% vs 36%, p=0.003). Compared to those submitted late, on-time PMR studies had fewer sites (110 vs 156, p=0.03), less use of blinding (20% vs 42%, p=0.02), more use of a continuous trial for AA and PMR (37% vs 8%, p=0.003) and more use of primary endpoints other than overall or progression-free survival (37% vs 6%, p<0.001).

Conclusion: PMR statement specificity for oncology AAs varies substantially. Less rigorous PMR statement and study characteristics were associated with timely PMR study submission and transition to regular approval but with important trade-offs. Given that AAs are granted without demonstrated clinical benefit, improving the balance between PMR study timeliness and rigour should be a priority when negotiating PMR statements.