Adaptive Signature Design- review of the biomarker guided adaptive phase -III controlled design.

Genomics having a profound impact on oncology drug development necessitates the use of genomic signatures for therapeutic strategy and emerging medicine proposals. Since its advent in the arena of clinical trials biomarker-related predictive methods for the identification and selection of patient subgroups, with optimal treatment response, are widely used. Genetic signatures which are accountable for the differential response to treatments are experimentally recognizable and analytically validated in phase II stage of clinical trials. The availability of robust and validated biomarkers in phase III is limited. Hence, the development of a clinical trial design without the availability of biomarker identity for treatment-sensitive patients becomes indispensable. Adaptive Signature Design (ASD) is a design procedure of developing and validating a predictive classifier (diagnostic testing strategy) when the signature of subjects responding differentially to treatment is remote in the context of the study. This review provides a detailed methodology and statistical background of this pioneering design developed by Freidlin and Simon (2005). In addition, it concentrates on the advances in ASD regarding statistical issues such as predictive assay identification, classification techniques, statistical methods, subgroup search, choice of differentially expressed genes, and multiplicity correction. The statistical methodology behind the design is explained with the intent of building the ground steps for future research approachable, especially for beginning researchers. Most of the existing research articles give a microcosmic view of the design and lack in describing the details behind the methodology. This study covers those details and marks the novelty of our research.