Presentation (CTI)

OBJECTIVES: To examine the European Medicines Agency's (EMA) evolving approach to real-world evidence (RWE) and assess the emerging role of target trial framework (TTF) and estimand frameworks as foundational standards for regulatory-grade observational studies.
METHODS: We analyzed EMA's third annual RWE experience report covering February 2024 to February 2025, extracting data on operational metrics including study volumes, timelines, feasibility rates, and applications across regulatory contexts. Where feasible, we reviewed the methodology section to identify advanced causal inference techniques employed and examined the TARGET-EU initiative's integration of TTF principles into regulatory RWE generation. We evaluated how EMA operationalizes the question "If a randomized controlled trial were feasible, what would it look like?" by requiring design pre-specification and assessed alignment with estimand frameworks for transparent causal contrasts.
RESULTS: EMA's regulator-led RWE studies more than doubled compared to the previous year, with median timelines reduced to four months and feasibility success rates reaching 78%, largely enabled by the DARWIN EU® network. RWE applications expanded beyond pharmacovigilance to support marketing authorisation applications, health technology assessment joint clinical assessments, and public health policy. The report documented increased use of modern causal inference methods and explicit prioritization of TTF through the TARGET-EU project, signaling a shift from passive RWE acceptance to active trial-emulation-based study design. The framework requires sponsors to define hypothetical target trials, justify RCT infeasibility, specify estimands, ensure consistent alignment of time zero and exposure definitions, and pre-register protocols.
CONCLUSIONS: TTF and estimand frameworks are transitioning from methodological options to regulatory expectations for decision-grade RWE at EMA. Sponsors must now frame observational studies within target trial paradigms rather than relying on retrospective comparisons or ad hoc matching. Early investment in trial emulation capabilities, data partnerships, and governance structures will position sponsors to proactively shape evidentiary discussions rather than reactively respond to regulatory scrutiny.