Mapping the Use of Real-World Evidence Across the EU Health Technology Assessment Regulation: Methodological Considerations, Challenges, and Opportunities for Harmonization.

Methodological guidelines for real-world evidence (RWE) in European Union (EU) joint clinical assessments (JCA) are lacking. This manuscript explores RWE potential in EU health technology assessment (HTA) and offers recommendations for generating high-quality RWE. An environmental scan of peer-reviewed and gray literature was conducted to review RWE frameworks and documents in EU regulatory and HTA decision-making. Extraction elements were standardized across key RWE themes: data quality, methodological rigor, stakeholder engagement, and applications. In JCA, RWE has multiple uses, including informing PICO simulation exercises, understanding disease landscape, identifying prognostic factors and effect modifiers, and directly or indirectly informing comparative clinical assessments. Methodological guidance from the HTA Coordination Group is limited to cases in which evidence from non-randomized studies is used as direct inputs in comparative assessments. Individual HTA bodies provide more detailed guidance, missing an opportunity to leverage RWE within JCAs that can offer insight for local Member State submissions. Generating high-quality RWE that is credible, actionable, and acceptable for JCA submissions and local HTA bodies requires careful attention to methodological considerations and early planning. Broader RWE integration that reflects patient journeys is needed. Expanding the HTA Coordination Group guidance can unlock RWE's full potential in supporting EU JCA submissions.