Meta-analysis Approach to Establish Cardiovascular Safety
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*Stefan Hantel, Boehringer Ingelheim Pharma GmbH & Co. KG 

Keywords: meta-analysis,

According to the FDA guideline "Guidance for Industry Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes", the sponsor has to establish cardiovascular safety for a new antidiabetic drug by showing that the upper confidence limit of the hazard ratio (HR) for cardiovascular events of the new compound versus comparator(s) is below 1.8 at time of submission and to show that the upper confidence limit is below 1.3 after the approval. One approach to rule out the cardiovascular risk is to run a meta-analysis including trials, which are completed at time of submission and using interim data from still ongoing trials. This talk will illustrate how this can be achieved by a pre-defined meta-analysis of phase 2 and phase 3 clinical trials including in addition data from an ongoing cardiovascular outcome trial. The meta-analysis offers also the option to show cardiovascular safety based on the 1.3 non-inferiority margin or even superiority. The meta-analysis addresses also the multiplicity issue of repeated tests similar to a group-sequential design.