Target Trial Emulation in Practice: From Conceptual Frameworks to Regulatory-Grade Evidence

Target trial emulation (TTE) has emerged as a transformative methodological framework for generating causal evidence from real-world data (RWD) by explicitly anchoring observational analyses to the design principles of randomised controlled trials (RCTs). Despite widespread adoption in academic research, translating TTE into analyses that meet the evidentiary standards required by regulators, health technology assessment bodies, and payers remains a significant challenge. This Research Topic brings together methodologists, pharmacoepidemiologists, clinicians, and regulatory scientists to examine the full lifecycle of a target trial emulation study — from the initial specification of the target trial protocol through to the communication and interpretation of findings for regulatory decision-making. Contributions are welcomed that address the conceptual underpinnings of TTE, including the formal specification of eligibility criteria, treatment strategies, assignment procedures, follow-up rules, outcomes, and causal contrasts, dynamic borrowing methods, together with the handling of intercurrent events such as treatment discontinuation, initiation of subsequent therapy, and death as a competing risk. The collection will highlight advances in analytic implementation, including approaches to handling time-varying confounding, immortal time bias, competing risks, and missing data. Emulations to reproduce the estimate or the regulatory conclusion of the index randomized clinical trials by using RWD and digital twins are also welcomed. A particular focus is placed on the gap between methodological best practice and regulatory acceptance: what constitutes regulatory-grade real-world evidence, how TTE studies are currently received by agencies such as the EMA, FDA, and PMDA, and what transparency and reporting standards are needed to build confidence in TTE-derived estimates. Case studies demonstrating TTE applied across therapeutic areas — including oncology, cardiovascular disease, rare diseases, and vaccine effectiveness — are especially encouraged. Topic editors: Hoa Le, Shivani Aggarwal Source: https://www.frontiersin.org/research-topics/83262/target-trial-emulation-in-practice-from-conceptual-frameworks-to-regulatory-grade-evidence