Methodologies for the Emulation of Biomarker-Guided Trials Using Observational Data: A Systematic Review.

Abstract

Background: Target trial emulation involves the application of design principles from randomised controlled trials (RCTs) to observational data, and is particularly useful in situations where an RCT would be unfeasible. Biomarker-guided trials, which incorporate biomarkers within their design to either guide treatment and/or determine eligibility, are often unfeasible in practice due to sample size requirements or ethical concerns. Here, we undertake a systematic review of methodologies used in target trial emulations, comparing treatment effectiveness, critically appraising them, and considering their applicability to the emulation of biomarker-guided trials. Methods: A comprehensive search strategy was developed to identify studies reporting on methods for target trial emulation comparing the effectiveness of treatments using observational data, and applied to the following bibliographic databases: PubMed, Scopus, Web of Science, and Ovid MEDLINE. A narrative description of methods identified in the review was undertaken alongside a critique of their relative strengths and limitations. Results: We identified a total of 59 papers: 47 emulating a target trial ('application' studies), and 12 detailing methods to emulate a target trial ('methods' studies). A total of 25 papers were identified as emulating a biomarker-guided trial (42%). While all papers reported methods to adjust for baseline confounding, 40% of application papers did not specify methods to adjust for time-varying confounding. Conclusions: This systematic review has identified a range of methods used to control for baseline, time-varying, and residual/unmeasured confounding within target trial emulation and provides a guide for researchers interested in emulation of biomarker-guided trials.