Expected vs observed effect sizes for survival endpoints in phase 3 oncology trials.

Abstract

More than half of randomized phase 3 oncology trials fail to meet their primary endpoints, often despite favorable results from phase 1 and phase 2 trials. One potential reason for this high failure rate is effect size selection practices for powering these trials. In a systematic review of phase 3 oncology trials published in 10 top medical journals in 2023, we identified a pattern of effect size overestimation for survival endpoints, where the expected hazard ratios (average HR = 0.66) were stronger than those observed in the primary analyses (average HR = 0.72; 2-sided signed-rank test P = .0035). Across 111 trials, 82 of 143 (57.3%) observed hazard ratios for primary survival endpoints were weaker than expected; among 5 journals with 2023 impact factors between 9.9 and 56.7 (vs 58.7-98.4 for the top 5 journals), this ratio was 70.2% (59/84). These results suggest that phase 3 oncology trials are likely underpowered, contributing to the high failure rates in oncology research.