While clinical trials have undergone rapid globalization, this has come with regional variation in comorbidities, clinical parameters, and even clinical outcomes and treatment effects across international sites. These issues have now highlighted knowledge gaps about the conduct of trials, selection of study sites, and an unmet need to develop and identify "ideal" sites. There is a need for all stakeholders, including academia, investigators, healthcare organizations, patient advocacy groups, industry sponsors, research organizations, and regulatory authorities, to work as a multidisciplinary group to address these problems and develop practical solutions to improve trial conduct, efficiency, and execution. We review these trial-level issues using examples from contemporary studies to inform and optimize the design of future global clinical trials in heart failure.