DESIGN DIFFERENCES EXPLAIN VARIATION IN RESULTS BETWEEN RANDOMIZED TRIALS AND THEIR NON-RANDOMIZED EMULATIONS.

Objectives: While randomized controlled trials (RCTs) are considered a standard for evidence on the efficacy of medical treatments, non-randomized real-world evidence (RWE) studies using data from health insurance claims or electronic health records can provide important complementary evidence. The use of RWE to inform decision-making has been questioned because of concerns regarding confounding in non-randomized studies and the use of secondary data. RCT-DUPLICATE was a demonstration project that emulated the design of 32 RCTs with non-randomized RWE studies. We sought to explore how emulation differences relate to variation in results between the RCT-RWE study pairs. Methods: We include all RCT-RWE study pairs from RCT-DUPLICATE where the measure of effect was a hazard ratio and use exploratory meta-regression methods to explain differences and variation in the effect sizes between the results from the RCT and the RWE study. The considered explanatory variables are related to design and population differences. Results: Most of the observed variation in effect estimates between RCT-RWE study pairs in this sample could be explained by three emulation differences in the meta-regression model: (i) in-hospital start of treatment (not observed in claims data), (ii) discontinuation of certain baseline therapies at randomization (not part of clinical practice), (iii) delayed onset of drug effects (missed by short medication persistence in clinical practice). Conclusions: This analysis suggests that a substantial proportion of the observed variation between results from RCTs and RWE studies can be attributed to design emulation differences. (238 words).