Randomized phase II trial designs with biomarkers.

Efficient development of targeted therapies that may only benefit a fraction of patients requires clinical trial designs that use biomarkers to identify sensitive subpopulations. Various randomized phase III trial designs have been proposed for definitive evaluation of new targeted treatments and their associated biomarkers (eg, enrichment designs and biomarker-stratified designs). Before proceeding to phase III, randomized phase II trials are often used to decide whether the new therapy warrants phase III testing. In the presence of a putative biomarker, the phase II trial should also provide information as to what type of biomarker phase III trial is appropriate. A randomized phase II biomarker trial design is proposed, which, after completion, recommends the type of phase III trial to be used for the definitive testing of the therapy and the biomarker. The recommendations include the possibility of proceeding to a randomized phase III of the new therapy with or without using the biomarker and also the possibility of not testing the new therapy further. Evaluations of the proposed trial design using simulations and published data demonstrate that it works well in providing recommendations for phase III trial design.