ICH E17 Guideline the success or failure of the MRCT is consistent across regions and among regulatory authorities. Agreement on the primary endpoint ensures that the overall sample size and power can be determined for a single (primary) endpoint based on the overall population and also agreed upon by the regulatory authorities. If agreement cannot be reached due to well-justified scientific or regulatory reasons, a single protocol should be developed with endpoint-related sub-sections tailored to meet the respective requirements of the reg- ulatory authorities.
In this case, because regulatory approvals are based on different pri- mary endpoints by different authorities, no multiplicity adjustment is needed for regula- tory decision-making. Using MRCTs may introduce the need for further consideration regarding the definition of the primary endpoint. While endpoints like mortality or other directly measurable out- comes are self-explanatory, others may require precise and uniform definitions (e.g., pro- gression-free survival). Of specific concern in MRCTs are those endpoints that could be understood and/or measured differently across regions. Examples are hospitalisation, psychometric scales, assessment of quality of life and pain scales.
To guarantee that such scales can be properly interpreted, the scales should be validated and their applicability to all relevant regions justified before starting the MRCT. The primary endpoint of MRCTs should be one for which experience is already available in the participating regions. In cases where prior experience with an endpoint only exists in one or a subset of regions involved in the MRCT, its adoption as primary endpoint will require discussion and agreement with regulatory authorities regarding the basis for the evidence, keeping in mind that the forthcoming trial can add information about clinical relevance of the agreed upon endpoint.
In addition to endpoint selection and definition, regulatory agreement should also be ob- tained on the timing and methods of the primary endpoint assessment. Secondary Endpoints Where possible, harmonisation of secondary endpoints is encouraged to maintain the fea- sibility and improve the quality of trial conduct. However, in some cases, individual regulatory authorities may propose different secondary endpoints relevant to their inter- ests and experience. Even in such cases, all secondary endpoints, including those selected 12