Regulatory agencies in different parts of the world may have different requirements for endpoints, which significantly affects the design of registrational multiregional clinical trials (MRCT). Differences between regions may involve which endpoints or timepoints are considered primary, patient populations analyzed, study design, or non-inferiority margins. Guidance on how to handle such differences is lacking and harmonized guidance would be useful. Initially, attempts should be made to reach consistency in hypotheses for a global MRCT. When a consistent approach is not accepted by all authorities, region-specific hypotheses can be pre-defined in the protocol, and because only one primary hypothesis pertains to an individual region, multiplicity adjustment may not be needed. We review approaches to handling different health authority requirements for endpoints within a global program.