Development Approaches and Statistical Considerations to Assess the CV Risk of New Therapies for Type 2 Diabetes
*Mary-Jane Geiger, Regeneron Pharmaceuticals Inc 


Members of the Cardiac Safety Research Consortium (CSRC) have authored a paper discussing clinical development approaches and statistical methodological issues to satisfy the 2008 FDA Guidance for Industry that requires sponsors to demonstrate a new antidiabetic therapy does not increase cardiovascular (CV) risk to an unacceptable extent. Prior to submission, sponsors are required to compare the incidence of major CV events occurring with the investigational agent versus the control group to show that the upper bound of the two-sided 95% confidence interval (CI) for the estimated risk ratio is less than 1.8. If the CI includes 1.3, a postmarketing trial will be necessary to definitively show that the upper bound of the 95% CI for the estimated risk ratio is then less than 1.3. Meta-analysis of adjudicated MACE or MACE-plus events reported in Phase 2 and 3 trials, with or without interim data from an ongoing CV outcome trial (CVOT), has been a common approach used by sponsors to exclude the 1.8 risk margin. To ensure accrual of the number of CV events needed to exclude the 1.3 risk margin (about 611), a CVOT in patients at high risk for CV events is needed. An overview of these approaches, including case examples and a discussion of the pros and cons, will be presented along with possible alternative approaches.