Table 1.

The purpose, timing, and content/method of BD studies in guideline documents of ICH founder countries/region and ISSCR.

Guideline Developer	Purpose	Timing	Content/Method
MHLW (Japan)	Prediction of efficacy and safety and demonstration of rationality of the administration method/route	Although the actual timing is not specified, investigation of the presence of cell engraftment site and its identification are considered necessary before or during conducting the non-clinical safety study at the latest.	Appropriate methods that are technically feasible should be selected case by case. Technologies are selected through discussion with the agency as necessary.
FDA (US)	One of the considerations for determination of the cell fate, which becomes the basis for mechanism of action (MOA) and the content of safety study of cell therapy.	Although the actual timing is not specified, BD studies are considered to be conducted for the purpose of examining conditions for non-clinical studies.	Assessment for each cellular product and mode of administration. Methods with the highest sensitivity currently available. Desirable to use multiple animal models.
EMA (EU)	Assessment of adverse events and efficacy from BD and cell state of cells where they are localized.	Required as a part of non-clinical data to submit to the agency.	Survival, engraftment, proliferation, differentiation, migration, integration, tumorigenicity, and ability/duration of active humoral factor secretion. Evaluation methods are not specified. Emphasis on advantage of using small animals.
ISSCR	Used for interpretation of efficacy and adverse events through understanding of the nature and extent of distribution, tissue engraftment, and differentiation of cells	Although the actual timing is not specified, BD studies are considered to be conducted for the purpose of examining conditions in non-clinical studies.	Long-term survival and integration of cells. Use of highly sensitive methods. Studies in rodents are required. Studies in large animals are recommended.