In a recent, a large cardiovascular outcomes MRCT known as ‘PLATO’, unexpected evidence of regional heterogeneity emerged during the analysis where by results in US patients appeared qualitatively different to results in non US patients. Much dialogue with FDA followed including an important Advisory Committee discussion at which the observed regional interaction ad associated statistical issues were a major focus. In evaluation of the data evidence emerged that concomitant long term aspirin dose was the likely explanatory factor. This led to US labelling that limited concomitant aspirin dosage and included wording warning of a potential loss of effect with higher aspirin doses. This example highlights the challenges of MRCTs in drug development and the critical role of reasoned statistical analysis when an unexpected regional interaction is encountered. This talk will discuss this example and the statistical thinking and methodology that went into the evaluation of the data and will offer recommendations for the future design and analysis of MCRTs.