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.

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

Figure 1.

Flow diagram of selected manuscripts.

Figure 2.

Overview of single-stage clinical trial designs. Τ is the experimental treatment, С is the control treatment. Solid lines indicate deterministic decisions whereat dashed lines indicate that a randomization procedure is involved.

Figure 3.

Adaptive multi-stage design.