J Comp Eff Res. 2026 Feb 27:e250183. doi: 10.57264/cer-2025-0183. Online ahead of print.
ABSTRACT
Aim: Real-world evidence (RWE) – defined here as clinical evidence derived from the analysis of real-world data (RWD) on patient health status and healthcare delivery – has become a cornerstone of regulatory and health technology assessment (HTA) decision making. However, despite broad consensus on its value, policy frameworks governing RWE generation and evaluation remain heterogeneous across jurisdictions. Importantly, this heterogeneity partly reflects the distinct purposes for which RWE is used, including regulatory safety assessment, effectiveness evaluation, health-economic modeling and natural-history research. These functional differences are not inherently problematic; however, fragmented operational requirements can create duplication, inefficiency and delays in patient access. Materials & methods: This study employed a narrative comparative policy review of RWE guidance issued by twelve major regulatory and HTA agencies, including the Medicines and Healthcare products Regulatory Agency (MHRA), the EMA, the US FDA and the Canadian Agency for Drugs and Technologies in Health (CADTH). Frameworks were compared across four domains: data quality, statistical methods, registry governance and transparency. Harmonization is defined as alignment across these domains sufficient to enable consistent planning, analysis and interpretation of RWE across jurisdictions, rather than uniformity of decision making. Results: The analysis identified convergence in high-level principles but persistent divergence in operational expectations. The MHRA emphasizes flexibility and scientific dialogue; the EMA prioritizes consistency and structured governance; and the FDA provides comprehensive but resource-intensive guidance, reflecting detailed documentation requirements, prespecified analytic expectations and extensive methodological review. HTA bodies apply additional evidentiary criteria related to comparative effectiveness and value, sustaining functional fragmentation even within the same healthcare systems. Conclusion: RWE fragmentation reflects both legitimate functional differences and avoidable operational misalignment. Progress toward harmonization therefore requires shared minimum standards and transparency mechanisms rather than additional guidance documents. The UK’s post-Brexit autonomy positions it as a test environment for collaborative pilots with the European Medicines Agency, the International Council for Harmonization (ICH) and the International Coalition of Medicines Regulatory Authorities (ICMRA). Six strategic actions are proposed to support pragmatic alignment while preserving contextual flexibility.
PMID:41757419 | DOI:10.57264/cer-2025-0183
