The maze of real-world evidence frameworks: from a desert to a jungle! An environmental scan and comparison across regulatory and health technology assessment agencies.

Abstract

Aim: Regulatory and health technology assessment (HTA) agencies have increasingly published frameworks,guidelines, and recommendations for the use of real-world evidence (RWE) in healthcare decision-making. Variations in the scope and content of these documents, with updates running in parallel, may create challenges for their implementation especially during the market authorization and reimbursementphases of a medicine'slifecycle. This environmental scan aimed to comprehensively identify andsummarize the guidancedocumentsfor RWEdeveloped by most well-establishedregulatory and reimbursement agencies, as well asother organizations focused on healthcare decision-making, and present their similarities and differences.Methods: RWE guidance documents, including white papers from regulatory and HTA agencies, werereviewed in March 2024. Data on scope and recommendations from each body were extracted by two reviewers and similarities and differences were summarized across four topics: study planning, choosing fit-for-purpose data, study conduct, and reporting. Post-authorization or non-pharmacological guidance was excluded. Results: Forty-six documents were identified across multiple agencies; US FDA produced the most RWE-related guidance. All agencies addressed specific andoften similar methodological issues related to study design, data fitness-for-purpose,reliability, and reproducibility,although inconsistency in terminologies on these topics was noted. Two HTA bodies (National Institute for Health and Care Excellence [NICE] and Canada's Drug Agency) each centralized all related RWE guidance under a unified framework. RWE quality tools and checklists were not consistently named and some differences in preferences were noted. European Medicines Agency, NICE, Haute Autorité de Santé, and the Institute for Quality and Efficiency in HealthCare included specific recommendations on the use of analytical approaches to address RWE complexities and increase trust in its findings. Conclusion: Similarities in agencies' expectations on RWE studiesdesign, quality elements, and reporting will facilitate evidence generation strategy andactivitiesfor manufacturers facing multiple, includingglobal,regulatory and reimbursementsubmissions and re-submissions. Astrong preference by decision-making bodiesfor local real-world datageneration may hinder opportunities for data sharing and outputs from international federated data networks. Closer collaboration between decision-makingagencies towards a harmonized RWE roadmap, which can be centrally preserved in a living mode,will provide manufacturers and researchersclarity on minimum acceptance requirements and expectations, especially as novel methodologies for RWE generationare rapidly emerging.