OBJECTIVES: Healthcare decision makers and manufacturers make judgments on the effectiveness of new technologies, but relating efficacy data to real-world practice is a major challenge. The IMI GetReal project reviewed recently published regulatory documents and health technology assessments (HTAs) for new Chronic Obstructive Pulmonary Disease (COPD) medicines. Agencies’ questioning of uncertainty around the validity and applicability of efficacy data was categorized. This will help inform a decision-making framework for including RWE earlier in drug development to reduce such uncertainties.  METHODS: COPD drugs approved since January 2010 by the EMA, Health Canada, and the TGA in Australia (N=10) were identified within the Context Matters application. The regulatory approvals (n=29), as well as associated HTAs (n=55) from NICE, SMC, HAS, G-BA/IQWiG, CADTH, and PBAC, were analyzed for mentions of uncertainty in the effectiveness evidence. These uncertainties were categorized and compared across agencies. RESULTS: Challenges to the effectiveness estimates (uncertainties in validity/applicability) were commonly discussed in regulatory and HTA documentation. For example, regulatory agencies were concerned with clinical significance of the results and adverse events, while HTA agencies were concerned with appropriateness of comparators. Regulatory and HTA agencies focused on different aspects, based on their roles and priorities within the healthcare system: not surprisingly, the primary concerns of regulatory agencies were safety and efficacy, while HTA agencies concentrated on estimating effectiveness in country-specific populations and at specific points in treatment pathways. The presentation will include a detailed comparison of the themes identified by each agency. CONCLUSIONS: Both regulatory and HTA bodies raised challenges to the efficacy evidence. Based on this analysis, the GetReal Initiative has identified areas where RWE can potentially mitigate these challenges. For example, RWE can incorporate trials of longer duration that seek to demonstrate effectiveness in the multiple treatment pathways and populations relevant to country-specific standards of care.