Regenerative Therapy (Dec 2022)
Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan
Abstract
In recent years, extracellular vesicles (EVs)11 Extracellular vesicles; the positioning paper of the International Society of Extracellular Vesicles (ISEV) (Minimal Information for Studies of Extracellular Vesicles [MISEV] 2018, Journal of Exarcellular Vesicles [JEV]; Updating MISEV, 2021, JEV) states that authors are urged to consider use of operational terms for EV subtypes that refer to a) the physical characteristics of EVs, such as size (“small EVs” (sEVs) and “medium/large EVs” (m/lEVs), with defined ranges, for instance, 200 nm [large and/or medium], respectively) or density (low, middle, high, with each range defined). Therefore, although we use the term EVs in this report, we are particularly conscious of sEVs and so-called exosomes. In addition, we recognize that EVs include extracellular vesicles of various sizes and production processes other than EVs that may be included at the time of preparation, as well as protein components included in cell culture supernatants. 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 cells22 The term “processed cells” is defined in the Act on the Safety of Regenerative Medicine (RM Safety Act), which regulates individual regenerative medicine and cell therapy (RM/CT) at the discretion and responsibility of medical practitioners, as well as non-commercial clinical research on RM/CT. In the RM Safety Act, a cell-based therapeutic product that is manufactured by substantial or more-than-minimal manipulations of somatic/stem cells is called “processed cells.” “Processed cells” other than “cell-processed products,” as defined in the Pharmaceuticals and Medical Devices Act (PMD Act), are called “specified processed cells” in the RM Safety Act. In other words, the term “cell-processed products” in the PMD Act refers to “processed cells” that are intended for marketing. 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 cellsb; 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 Japan33 The scope of the RM Safety Act is non-commercial clinical research on treatments using specified processed cells and individual medical treatments with specified processed cells at the discretion of medical practitioners.. 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.
