ICH E17 Guideline should be described in the protocol, and the investigators should receive sufficient train- ing in accordance with ICH E6 and other relevant guidelines. In the case of MRCTs, important safety information should be handled both with adherence to any local regula- tions and in adherence to ICH E2A. Important safety information should always be pro- vided to the relevant stakeholders (e.g., investigators, ethics committees) in a timely man- ner.
In MRCTs of long duration, where special concerns (e.g., serious adverse events) have been identified, and/or where operational regions are quite large (usually Phase III con- firmatory studies), the use of a central independent data monitoring committee (with rep- resentation from participating regions to adequately assess the context of the trial) should be considered, in order to monitor the accumulating efficacy and/or safety information from the MRCT while maintaining integrity of the ongoing trial. If adjudication of end- points and/or events is planned, a centralised assessment by a single adjudication com- mittee should be considered.
For endpoints based on laboratory or imaging assessments, it is generally recommended to use a centralised laboratory or centralised adjudication of imaging. If multiple labora- tories are used, appropriate cross-validation of methods between laboratories should be conducted before testing clinical samples. Coordinated site initiation is particularly important in MRCTs to ensure proper conduct, completion and reporting of results without any delays among regions. To comply with the quality management described in ICH E6, the sponsor should implement a system to manage quality in design, conduct, oversight, recording, evaluation, reporting and archiv- ing of MRCTs.
In this aspect, centralised and risk-based monitoring may be particularly useful for MRCTs to identify variability across regions and sites in protocol compliance (e.g., differences in follow-up, compliance with study medications, adverse event report- ing and/or extent of missing data). Mitigation approaches should take regional variations into consideration. It could also be considered to use electronic data capturing and re- porting, to gather information and data (including relevant intrinsic and extrinsic factors) from all regions in a standardised way without delays.
If trial related documents (e.g., a case report form) are translated to local languages, consistency of documents between languages should be ensured (e.g., by reverse translation). As described above, careful 19