Estimation of causal effect in integrating randomized clinical trial and observational data - An example application...

Safety evaluation of drug development is a comprehensive process across the product lifecycle. While a randomized clinical trial (RCT) can provide high-quality data to assess the efficacy and safety of a new intervention, the pre-marketing trials are limited in statistical power to detect causal elevation of rare but potentially serious adverse events. On the other hand, real-world data (RWD) sources play a critical role in further understanding the safety profile of the new intervention. Bringing together the breadth and strength of RWD and RCT data, we can maximize the utility of RWD and answer broader questions. In this manuscript, we propose a three-step statistical framework to corroborate findings from both RCT and RWD for evaluating important safety concerns identified in the pre-marketing setting. By the proposed approach, we first match the observational study to RCT, then the causal estimation is validated via the matched observational study with the target RCT by targeted maximum likelihood estimation (TMLE) method, and lastly the evidence from RCT and RWD can be combined in an integrative analysis. A potential application to cardiovascular outcome trials for type 2 diabetes mellitus is illustrated. Finally, simulation results suggest that the heterogeneity of patient population from RCT and RWD can lead to varying degrees of treatment effect estimation and the proposed approach may be able to mitigate such difference in the integrative analysis.