Risk-of-Bias Assessment of Target Trial Emulation Studies at Regulatory and Policy Decision Points Along the Medical Product Life Cycle: Protocol for a Scoping Review and Stakeholder Survey

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Abstract
Background: Target trial emulation (TTE) studies are increasingly important for regulatory decision‑making and health technology assessments (HTAs), but current risk-of-bias (RoB) tools are not specifically tailored to assess biases central to TTE studies—such as immortal time bias, misaligned eligibility criteria, and prevalent user bias. RoB assessment for TTE studies thus remains difficult, and it is unclear which tools and adaptations researchers currently use or how well they work. Objective: This study aims to analyze the RoB assessment of TTE studies at regulatory and policy decision points along the medical product life cycle by providing a systematic overview of tools developed, used, adapted, or evaluated for TTE studies and the perceived importance and feasibility of assessing TTE studies by HTA assessors, regulators, systematic reviewers, and methods experts. Methods: This is a protocol for a scoping review and online survey among systematic reviewers, methods experts, European HTA organizations, and regulators. We will collect data on the name, description, and feasibility of RoB tools used, adapted, and developed for TTE studies, as well as RoB assessment results and the RoB sources relevant for TTE studies. Two authors will use qualitative content analysis to analyze the data independently. The systematic search for published and gray literature in 4 electronic databases (PubMed, Scopus, Web of Science, and the Cochrane Library), on relevant websites (eg, Cochrane, HTA and regulatory agencies), and through reference list checking was conducted in May to June 2026. Results: As of August 25, 2026, screening is ongoing, and 78 references have been preliminarily included in the scoping review. We will analyze the scoping review and survey data and provide an overview of the types, feasibility, and assessment results of RoB tools currently used, adapted, or developed for TTE studies, as well as the RoB sources considered relevant for TTE studies by HTA assessors, regulators, systematic reviewers, and methods experts. Analysis results of the literature review and survey are expected in September 2026 and November 2026, respectively. Conclusions: The analysis of the scoping review and survey data will inform users of TTE evidence about the feasibility of RoB tools; future development and training needs; and the perceived value of assessing the RoB in HTAs, regulatory decisions, and systematic reviews. International Registered Report Identifier (IRRID): DERR1-10.2196/107499

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