Longitudinal changes in the relative toxicity of FDA-approved oncology therapeutics: evidence from paired initial and updated RCT reports
Abstract
Background: A growing share of oncology drugs receive FDA approval via expedited pathways based on interim RCT analyses, leaving safety data relatively immature at approval. Whether the relative toxicity of approved therapeutics shifts as trials mature remains unquantified.
Methods: Phase II-III RCTs underpinning FDA oncology approvals from 2006 to 2025 were eligible if both the approval-stage dataset and at least one subsequent publication reported grade ≥3 AEs or serious AEs (SAEs). For each trial, experimental-versus-control odds ratios (ORs) were computed at both timepoints, with within-trial change indexed by the ratio of odds ratios (ROR), defined as the updated OR divided by the initial OR (ROR > 1 indicating greater experimental-arm toxicity after maturation). Random-effects meta-analyses pooled log-scale estimates; meta-regression explored effect modifiers and sources of heterogeneity.
Results: Ninety-nine RCTs met eligibility and, after splitting seven three-arm trials, yielded 106 pairwise comparisons (103 for grade ≥3 AEs; 70 for SAEs). Pooled OR for grade ≥3 AEs rose from 1.09 (95% CI, 0.93-1.22) to 1.29 (1.03-1.43); meta-analytic ROR showed a statistically significant increase at 1.095 (1.038-1.156; p = 0.001; I 2 = 12.8%), with 78/103 comparisons shifting toward greater experimental toxicity. For SAEs, pooled OR rose from 1.32 (1.21-1.42) to 1.45 (1.27-1.59); ROR was 1.06 (0.97-1.17; p = 0.22; I 2 = 46.8%), directionally concordant but not statistically…
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