Using real-world data for supporting regulatory decision making: Comparison of cardiovascular and safety outcomes of an empagliflozin randomized clinical trial versus real-world data.

In countries where a randomized clinical trial (RCT) is difficult to perform, a real-world evidence (RWE) study with a design similar to an RCT may be an option for drug regulatory decision-making. In this study, the objective was to find out to what extent the safety of empagliflozin from the RWE study in Korea is different from the one in RCT by emulating the design of foreign RCT. The outcome covers various safety outcomes including cardiovascular safety. The EMPA-REG OUTCOME trial (NCT01131676) was selected for comparison. The inclusion/exclusion criteria and follow-up method for the RWE were matched to the comparison RCT. Major adverse cardiovascular events (MACEs) were used as a primary outcome and 15 other outcomes were also included for analysis. We followed 23,126 matched patients with type 2 diabetes mellitus (11,563 empagliflozin users and 11,563 sitagliptin users) for 2.7 years (median). Empagliflozin use was associated with a significantly decreased risk of MACEs [EMPA-REG DUPLICATE RWE: adjusted HR 0.87, 95% confidence interval (CI) 0.79-0.96]. The predefined estimate agreement, regulatory agreement, and standardized difference for RCT duplication were achieved [EMPA-REG OUTCOME RCT: adjusted HR 0.86, 95% (CI) 0.74-0.99]. According to the predefined criteria for 15 outcomes, 10 outcomes were evaluated as good, and three as moderate. Our study results suggest that RWE in one country in comparison with an RCT has the potential for providing evidence for future regulatory decision-making in an environment where RCT could not be performed.