Review of Statistical Methods for Biomarker-Driven Clinical Trials

Abstract

The discovery of somatic driver mutations in kinases and receptors has stimulated the development of molecularly targeted treatments that require companion diagnostics and new approaches to clinical development. This article reviews some of the clinical trial designs that have been developed to address these opportunities, including phase II basket and platform trials as well as phase III enrichment and biomarker adaptive designs. It also re-examines some of the conventional wisdom that previously dominated clinical trial design and discusses development and internal validation of a predictive biomarker as a new paradigm for optimizing the intended-use subset for a treatment. Statistical methods now being used in adaptive biomarker-driven clinical trials are reviewed. Some previous paradigms for clinical trial design can limit the development of more effective methods on the basis of prospectively planned adaptive methods, but useful new methods have been developed for analysis of genome-wide data and for the design of adaptively enriched studies. In many cases, the heterogeneity of populations eligible for clinical trials as traditionally defined makes it unlikely that molecularly targeted treatments will be effective for a majority of the eligible patients. New methods for dealing with patient heterogeneity in therapeutic response should be used in the design of phase III clinical trials.