ICH E17 Guideline relevant margin. If, after extensive attempts to reach consensus among regulatory author- ities, it is the case that different regulatory requirements remain due to well-described scientific arguments, the most stringent margin should be considered for sample size cal- culation. There are some situations that do not fit into the framework for sample size allocation described above and where more flexibility will be required. In studies of rare diseases or an infectious disease outbreak, for example, disease prevalence may differ substantially between regions, and it may be necessary to allow one or more regions to dominate the trial for recruitment to be feasible.
The recruitment strategy should be discussed with the regulatory authorities during planning. In summary, comparing with sample size requirements in regional or local studies, the potential increase of the overall sample size in MRCTs should be due primarily to the increased variability anticipated for a multi-regional population and not due to overly stringent or arbitrary regional sample size requirements. The use of a well-justified and pre-specified strategy for pooling regions and/or subpopulations in conjunction with a carefully thought out sample allocation plan can facilitate meeting the objectives of the MRCT.
2.2.6 Collecting and Handling of Efficacy and Safety Information Adherence to GCP, as described in ICH E6, is critical for any clinical trial to meet its stated objectives and is particularly important in an MRCT, because of the coordination required to conduct a trial in diverse geographic regions. Methods of collecting and han- dling efficacy and safety information should be standardised across participating regions. It is also important to provide standardised training for investigators and study personnel in each region before initiating the trial in that region to ensure that the trial objectives are met through standardised implementation of the study protocol.
Safety reporting should be conducted in accordance with ICH E2. When local regulations specify different requirements, such as timelines and criteria for expedited reporting, these should also be adhered to locally. The specific timeframe for safety reporting 18