Implementing Optimal Designs for Dose–Response Studies Through Adaptive Randomization for a Small Population Group

Abstract

In dose-response studies with censored time-to-event outcomes, D-optimal designs depend on the true model and the amount of censored data. In practice, such designs can be implemented adaptively, by performing dose assignments according to updated knowledge of the dose-response curve at interim analysis. It is also essential that treatment allocation involves randomization-to mitigate various experimental biases and enable valid statistical inference at the end of the trial. In this work, we perform a comparison of several adaptive randomization procedures that can be used for implementing D-optimal designs for dose-response studies with time-to-event outcomes with small to moderate sample sizes. We consider single-stage, two-stage, and multi-stage adaptive designs. We also explore robustness of the designs to experimental (chronological and selection) biases. Simulation studies provide evidence that both the choice of an allocation design and a randomization procedure to implement the target allocation impact the quality of dose-response estimation, especially for small samples. For best performance, a multi-stage adaptive design with small cohort sizes should be implemented using a randomization procedure that closely attains the targeted D-optimal design at each stage. The results of the current work should help clinical investigators select an appropriate randomization procedure for their dose-response study.

On Optimal Designs for Clinical Trials: An Updated Review

“…Adaptive optimal designs can be cast in two or more stages and they have been developed and implemented in practice [16,17]. Since most phase II studies are randomized, controlled, parallel-group designs, careful choice of a randomization procedure that adjusts optimal allocation ratio at interim analyses is essential [95].…”

“…Since the majority of phase II studies are randomized, careful calibrations of a randomization procedure to implement the chosen optimal design is warranted. Ryeznik et al [94,95] investigated multi-stage adaptive D-optimal designs for dose-response studies with time-to-event outcomes. They found that both the choice of the allocation design and the randomization procedure can affect the quality of model estimates.…”