title: Methods for identification and confirmation of targeted subgroups in clinical trials: A systematic review.
abstract: Important objectives in the development of stratified medicines include the identification and confirmation of subgroups of patients with a beneficial treatment effect and a positive benefit-risk balance. We report the results of a literature review on methodological approaches to the design and analysis of clinical trials investigating a potential heterogeneity of treatment effects across subgroups. The identified approaches are classified based on certain characteristics of the proposed trial designs and analysis methods. We distinguish between exploratory and confirmatory subgroup analysis, frequentist, Bayesian and decision-theoretic approaches and, last, fixed-sample, group-sequential, and adaptive designs and illustrate the available trial designs and analysis strategies with published case studies.
authors.affiliation: a Center for Medical Statistics and Informatics, Medizinische Universität Wien , Vienna , Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ondra
authors.affiliation: b Center for Statistics in Drug Development, Quintiles , Overland Park , Kansas , USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Dmitrienko
authors.affiliation: c Department of Medical Statistics , Universitaetsmedizin , Göttingen , Göttingen , Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Friede
authors.affiliation: a Center for Medical Statistics and Informatics, Medizinische Universität Wien , Vienna , Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Graf
authors.affiliation: d Statistiska institutionen, Stockholms Universitet , Stockholm , Sweden.
authors.forename: Frank
authors.initials: F
authors.lastname: Miller
authors.affiliation: e Department of Statistics and Epidemiology , University of Warwick , Coventry , UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Stallard
authors.affiliation: a Center for Medical Statistics and Informatics, Medizinische Universität Wien , Vienna , Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Posch
mesh_terms: D015415:Biomarkers; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D006801:Humans; D057285:Precision Medicine; D012107:Research Design / Q000706:statistics & numerical data*
chemical_list: D015415:Biomarkers
keywords: Enrichment design; personalized medicine; precision medicine; predictive biomarkers; subgroup identification