Justin Stebbing

Background Phase III trials with prospective biomarker validation are essential to drug development in the era of personalized oncology. However, concerns have emerged regarding the design and reporting of phase III trials with prospective biomarker validation. Methods We searched MEDLINE for phase III oncology trials with prospective biomarker validation published in high-impact medical journals from 2011 to 2020. Information regarding trial design and reporting were extracted. Descriptive methods were used to summarize the results. Results We identified 45 phase III trials with prospective biomarker validation. There was a trend for increasing use of biomarker validation phase III trials (from 1 trial in 2011 to 12 trials in 2020). For 39 (86.7%) trials, results in biomarker-negative population were either listed as an exploratory subgroup analysis (62.2%) or not mentioned in the methods (24.4%). Twenty-one (46.7%) trials were originally designed without biomarker validation but were then apparently modified to incorporate prospective biomarker validation after trial commencement, albeit only 15 (33.3%) trials reported this change. Treatment effect and primary outcome values in biomarker-negative patients were not reported in 24.4% and 40.0% trials, respectively. For 18 trials with statistically significant results in the overall population, only 7 trials reported a hazard ratio less than 0.8 in the biomarker-negative population. Conclusions Although biomarker validation in phase III trials have been increasingly used in the past decade, issues regarding changes in trial design after commencement without disclosure, underreporting of results in biomarker-negative groups, and recommending treatment in biomarker negative groups despite modest effects require substantial improvement.