A general framework of marker design with optimal allocation to assess clinical utility.

This paper proposes a general framework of marker validation designs, which includes most of existing validation designs. The sample size calculation formulas for the proposed general design are derived on the basis of the optimal allocation that minimizes the expected number of treatment failures. The optimal allocation is especially important in the targeted design which is often motivated by preliminary evidence that marker-positive patients respond to one treatment better than the other. Our sample size calculation also takes into account the classification error of a marker. The numerical studies are conducted to investigate the expected reduction on the treatment failures and the relative efficiency between the targeted design and the traditional design based on the optimal ratios. We illustrate the calculation of the optimal allocation and sample sizes through a hypothetical stage II colon cancer trial.