title: Comparison of different clinical development plans for confirmatory subpopulation selection.
abstract: Given ever increasing costs to develop a new drug and intense competition, adaptive enrichment designs are an attractive option for a development program that allows selecting a potential subgroup defined by a binary biomarker. Such designs explicitly factor in the possibility that the new drug might differentially benefit distinct biomarker subgroups. We have compared three clinical development plans for a time-to-event endpoint, such as overall survival, that all lead to a decision in a pivotal trial either in all comers only, in allcomers and biomarker positive, in the biomarker positive only, or to declare the drug futile. The decision about which hypothesis to test at the final analysis is made based on a fast time-to-event endpoint, such as progression-free survival, at an interim analysis. We quantify the time gain when using an adaptive enrichment Phase II/III design versus alternative development approaches and we outline what type of biomarker needs to be available prior to Phase II in each scenario. We conclude with a discussion of further features of each of the considered development plans.
authors.affiliation: Department of Biostatistics, Hoffmann-La Roche Ltd., Basel, Switzerland. Electronic address: kaspar.rufibach@roche.com.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Rufibach
authors.affiliation: Department of Biostatistics, F. Hoffmann-La Roche Ltd., Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Genentech, South San Francisco, USA.
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
mesh_terms: D015415:Biomarkers; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D018572:Disease-Free Survival; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D012107:Research Design
chemical_list: D015415:Biomarkers
keywords: Adaptive design; Biomarker; Companion diagnostic; Parallel trial strategy; Sequential trial strategy; p-Value combination