Adaptive seamless designs with interim treatment selection: a case study in oncology.

Abstract

The planning of an oncology clinical trial with a seamless phase II/III adaptive design is discussed. Two regimens of an experimental treatment are compared to a control at an interim analysis, and the most-promising regimen is selected to continue, together with control, until the end of the study. Because the primary endpoint is expected to be immature at the interim regimen selection analysis, designs that incorporate primary as well as surrogate endpoints in the regimen selection process are considered. The final testing of efficacy at the end of the study comparing the selected regimen to the control with respect to the primary endpoint uses all relevant data collected both before and after the regimen selection analysis. Several approaches for testing the primary hypothesis are assessed with regard to power and type I error rate. Because the operating characteristics of these designs depend on the specific regimen selection rules considered, benchmark scenarios are proposed in which a perfect surrogate and no surrogate is used at the regimen selection analysis. The operating characteristics of these benchmark scenarios provide a range where those of the actual study design are expected to lie. A discussion on family-wise error rate control for testing primary and key secondary endpoints as well as an assessment of bias in the final treatment effect estimate for the selected regimen are also presented.