Drivers and methodological considerations associated with the acceptability of real-world evidence for effectiveness/efficacy by regulators and HTAs: evidence from North America, Europe, and Australia

Background: The use and acceptance of real-world evidence (RWE) by sponsors and competent authorities has grown and RWE is increasingly included in submissions to regulators and Health Technology Agencies (HTAs). However, details are scarce on what characteristics drive their acceptability. Objectives: Identify considerations and optimal approaches that enhance confidence in the use of RWE for effectiveness/efficacy in regulatory and HTA decisions across North America, Europe, and Australia. Methods: A list of medicinal products-indications for which RWE was used to support efficacy of randomized clinical trials and/or assess effectiveness in observational settings, was compiled from a targeted review. Five regulators (FDA, Health Canada, EMA, MHRA, TGA) and six HTAs (HAS, IQWIG, NICE, CADTH, PBAC, ICER) were included. An exploratory subset, including both examples in which RWE was considered pivotal/supportive and not adequate, was prioritised for review. For each product-indication submission, publicly available information was reviewed by two analysts. The review aimed to characterise the type of RWE approach used, identify which elements discussed by the authorities’ reviewers had an impact on their decisions, and identify whether there was any impact of existing regional or national policy or guidance. A broad range of authorities were included to identify convergence and divergence in RWE perception and use. Results: From the 87 medicinal products-indications identified, 16 were selected for detailed review, covering 86 submissions across the 11 authorities. Key dimensions of discussion while considering the evidentiary value and acceptability of RWE included: A. Clinical context, e.g., unmet need, rarity, disease severity, were mentioned to different degrees in all applications analysed, and were considered as supportive to the acceptability of RWE B. Strength of evidence, e.g., adequacy of data sources and pharmacoepidemiological methods, adjustment of biases/confounding, and effect size, correlated with the acceptability of RWE C. Process, e.g., emphasising early engagement with authorities was mentioned in most submissions When a comparison across authorities was possible, the level of details presented and discussed on RWE differed, and some examples with different decisions on RWE acceptability were found. Conclusions: Knowledge of the circumstances in which authorities are more accepting of RWE approaches that support efficacy/assess effectiveness can help researchers to plan how to better meet the needs of authorities. More granularity on key characteristics driving their decisions, and areas of convergence and divergence, can also assist authorities’ development of guidance and their collaborative efforts on an RWE framework.