Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan.

In recent years, extracellular vesicles (EVs) have attracted attention as a new therapeutic tool. In Europe, the United States, and Asia, there is an accelerating trend of moving beyond basic research on clinical trials. However, treatment using EVs is still in the research and development stage, and the general public has insufficient awareness and understanding of the risks involved in ensuring safety and efficacy, the status of laws and regulations, and global research and development trends regarding their use. The Japanese Society for Regenerative Medicine, which has promoted the research and development of regenerative medicine, an innovative medical technology based on the principle of delivering it safely, effectively, and promptly, including the establishment of laws and regulations, would like to express two positions in light of the rapid development of therapies using EVs: 1) concern about treatments that are based solely on the discretion of medical practitioners, and 2) active promotion of treatments based on sound scientific evidence. Because EVs are released from cells, there are many similarities between EVs and processed cells in terms of manufacturing processes and safety hazards. As for efficacy, the mechanism of action of EVs is still unclear, as is the case with specified processed cells; in such cases, it is difficult to measure potency, identify efficacy-related quality attributes, and evaluate the comparability of quality before and after a change in the manufacturing process. In other words, the number of quality attributes that can be obtained for EVs is limited because of their complex characteristics, and it is difficult to grasp their quality through specifications and characterization. Therefore, while designing a quality control strategy for EVs, it is important to ensure the quality of the final product (EVs) by controlling the raw materials and manufacturing process. On the contrary, since EVs do not contain living cell components and are not classified into specified processed cells, non-commercial clinical research on treatments using EVs and individual medical treatments with EVs at the discretion of medical practitioners are out of the scope of the Act on the Safety of Regenerative Medicine of Japan. At present, there are no relevant laws or regulations for the use of EVs other than the Medical Practitioners' Act and the Medical Care Act in Japan. Therefore, there is a concern that treatment will be performed without sufficient objective evaluation of the scientific basis for safety and efficacy. Despite these concerns, the development of therapies using EVs is underway worldwide. This could potentially lead to a wide variety of new therapeutic areas if the methods needed to stably secure and mass cultivate cells as raw materials and the technologies needed for the mass production of EVs can be developed, in addition to understanding the risks involved and developing relevant laws and regulations. As part of the Japanese Society for Regenerative Medicine, we will continue to work on the development of these methods and technologies and hope that such a promising field will be promoted with a high level of safety before reaching the public.