Barriers to Integrating Real-World Evidence into Health Systems for Post-Market Drug Safety: Governance, Infrastructure, and Workforce Challenges Across Three Jurisdictions

Foundational real-world evidence (RWE) frameworks are now established across the U.S. Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA), but their integration into the health systems responsible for post-market drug safety remains uneven and is being reshaped by 2025–2026 regulatory shifts. In the United States, the ASTP/ONC Health Data, Technology, and Interoperability Rule 5 (HTI-5) proposed rule signals a retreat from prescriptive federal interoperability mandates toward a leaner Fast Healthcare Interoperability Resources (FHIR)-based ecosystem; if finalised as proposed, it would accelerate data access for aligned institutions while widening the participation gap for those that are not. In the European Union, the European Health Data Space Regulation (EU 2025/327) sets a firm March 2029 deadline for secondary-use provisions. These developments converge on a single governance problem: health systems with RWE-capable infrastructure but insufficient pharmacoepidemiology workforce will be excluded from federated safety surveillance networks as those networks become the regulatory standard. This review identifies four barriers to RWE integration—data governance fragmentation, health information technology infrastructure gaps, workforce capacity deficits in pharmacoepidemiology and informatics, and layered cross-jurisdictional privacy compliance—and argues that each reflects an organisational leadership and governance failure, not a technical one. An operational framework with 12- and 24-month implementation indicators is offered for health-system, regulatory, and pharmacovigilance leaders.