Optimal Decision Criteria for the Study Design and Sample Size of a Biomarker-Driven Phase III Trial

BACKGROUND The design and sample size of a phase III study for new medical technologies were historically determined within the framework of frequentist hypothesis testing. Recently, drug development using predictive biomarkers, which can predict efficacy based on the status of biomarkers, has attracted attention, and various study designs using predictive biomarkers have been suggested. Additionally, when choosing a study design, considering economic factors, such as the risk of development, expected revenue, and cost, is important. METHODS Here, we propose a method to determine the optimal phase III design and sample size and judge whether the phase III study will be conducted using the expected net present value (eNPV). The eNPV is defined using the probability of success of the study calculated based on historical data, the revenue that will be obtained after the success of the phase III study, and the cost of the study. Decision procedures of the optimal phase III design and sample size considering historical data obtained up to the start of the phase III study were considered using numerical examples. RESULTS Based on the numerical examples, the optimal study design and sample size depend on the mean treatment effect in the biomarker-positive and biomarker-negative populations obtained from historical data, the between-trial variance of response, the prevalence of the biomarker-positive population, and the threshold value of probability of success required to go to phase III study. CONCLUSIONS Thus, the design and sample size of a biomarker-driven phase III study can be appropriately determined based on the eNPV.