Design differences explain variation in results between randomized trials and their non-randomized emulations

Abstract

ABSTRACTObjectivesWhile 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.MethodsWe 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.ResultsMost 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).ConclusionsThis analysis suggests that a substantial proportion of the observed variation between results from RCTs and RWE studies can be attributed to design emulation differences.What is already known on this topicReal-world evidence (RWE) studies can complement randomized controlled trials (RCT) by providing insights on the effectiveness of a medical treatment in clinical practice. Concerns about confounding have limited the use of RWE studies in clinical practice and policy decisions.What this study addsA large share of the observed variation in results between RCT-RWE study pairs could be explained by design emulation differences.