The Data Monitoring Experience in Empagliflozin Randomized Clinical Trials Between 2011 and 2024.

Abstract

In November 2007, a black box warning was mandated for rosiglitazone in type 2 diabetes mellitus (T2DM) based on an increased risk of ischemic cardiovascular (CV) events. The Food and Drug Administration (FDA) issued a directive that a CV outcomes trial must be done for any new diabetes drug to demonstrate no CV harm. Therefore, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial was started in 2011 alongside 13 additional randomized clinical trials (RCTs) of empagliflozin in T2DM. The results of EMPA-REG OUTCOME set the stage for later RCTs in heart failure. Results from these clinical trials have changed the outlook for patients both with and without T2DM and with and without heart failure. A Program Data Monitoring Committee (DMC) with the same core members was utilized for these trials between 2011 and 2024. This committee is likely to be one of the longest serving DMCs since it served 28 trials with empagliflozin between 2011 and 2024. The committee encountered several important challenges which are discussed in this article. Moreover, the committee provides several important take-home messages which we hope will be of value in discussing issues in creating, developing and running DMCs in the future. These include: 1. Whether and when to be blinded and unblinded; 2. How to proceed when the primary endpoint shows no evidence of benefit, but there is evidence for a mortality benefit; 3. Development of presentation of data using figures and boxplots for rapid review of adverse events and laboratory data to assess clinical challenges; 4. How to manage a catastrophic serious adverse event; 5. Suggestions for an ideal structure of the report for the DMC closed session; and 6. The relation between the DMC, sponsor and Contract Research Organization. Our experience emphasizes the value of continuity with the same members serving over a 13-year period.