(169) Application of the Target Trial Emulation Framework to External Comparator Studies

Background: External comparator studies are increasingly being used to generate evidence that supports the evaluation of emerging pharmacological treatments for regulatory and HTA purposes. However, the reliability of evidence generated from external comparator studies can vary and there are no underlying methodological frameworks that supports the design and analysis of external comparator studies.

Objectives: In this paper, we aim to outline how an existing framework for causal inference, the target trial emulation (TTE) framework, can be appropriately applied to improve the design and analysis of external comparator (EC) studies.

Methods: Applying the TTE framework involves specifying the protocol of an ideal, hypothetical target trial which would answer the causal question of interest, then emulating its key elements under RW settings. We describe each component of the original TTE framework and explain how it can be applied to EC studies, supplemented with practical recommendations. We also highlight special considerations and limitations in applying the TTE framework to EC studies.

Results: It may appear that the TTE framework can be directly applied to the EC setting by conceptualising EC studies as typical observational causal analyses. However, there are methodological nuances in the application of the TTE framework to EC studies due to the combination of data from two distinct settings (i.e., experimental and observational) that do not share a common data-generating mechanism. For example, in the EC setting, time zero should be aligned across all treatment arms. For an EC with an active comparator treatment, the assignment of time zero is straightforward: time zero begins at treatment initiation for all patients in the referent trial and the comparator arm. However, when patients in the comparator arm can meet eligibility criteria at multiple time points (e.g., because the comparator treatment strategy is ‘no treatment’ or is an active treatment that can be delivered in multiple treatment lines), there are a variety of approaches to defining time zero. We illustrate such nuances in applying all components of the TTE framework in EC settings using an example case study.

Conclusions: This paper outlines the nuances of applying the TTE framework to EC settings. The application of the well-established TTE framework to the EC setting can improve clarity, transparency, and robustness in the design and analysis of EC studies. Further methodological work is needed to provide stronger evidence-based methodological recommendations in applying the TTE framework to EC studies.