Methods for identification and confirmation of targeted subgroups in clinical trials: A systematic review

J Biopharm Stat. 2016;26(1):99-119. doi: 10.1080/10543406.2015.1092034.


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.

Keywords: Enrichment design; personalized medicine; precision medicine; predictive biomarkers; subgroup identification.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Biomarkers
  • Clinical Trials as Topic / statistics & numerical data*
  • Humans
  • Precision Medicine
  • Research Design / statistics & numerical data*


  • Biomarkers

Grants and funding

This work was conducted as part of the InSPiRe (Innovative methodology for small populations research) project funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number FP7 HEALTH 2013-602144.