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Professor, postgraduate supervisor, Dean of Department of pharmaceutical management, School of international pharmaceutical business, China Pharmaceutical University. The main teaching and research fields are: registration, production management, quality management and quality safety supervision of medical products (including medical devices, cosmetics, food, etc.), including GMP, GLP, GSP, GCP, gap, HACCP, ISO series, etc. More than 220 papers have been published in professional academic journals at home and abroad. He has edited 5 planning textbooks and 8 monographs for medical colleges and universities in China. He has presided over more than 60 scientific research projects, won 2 national scientific research awards and 2 provincial awards, served as the editorial board of more than 10 domestic well-known pharmaceutical professional journals, and served as the chief audit officer of pharmaceutical quality in China of many pharmaceutical enterprises in Germany, Denmark, Italy and other countries.
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Management of cell therapy products in Japan and Its Enlightenment to China
Abstract: as a breakthrough new treatment, cell therapy has revolutionary significance in the treatment of cancer and other major refractory diseases, and has become one of the most potential treatment approaches. For many years, Japan has been a global leader in technology research and development and regulatory policies for cell therapy products, thanks to its complete legal system and special approval policies. In order to provide reference for the establishment of safe, standardized, stable and traceable cell therapy product management, this paper systematically compares the relevant laws and regulations, department responsibilities and approval paths in the clinical management of cell therapy products between China and Japan.
On January 5, 2017, kite Pharma announced that it would sign a strategic cooperation agreement with Daiichi Sankyo company limited to jointly develop car-t products in Japan, jointly explore cancer treatment methods and commercialize it in the Japanese market. The total amount of the agreement is up to 450 million US dollars. At present, the global cell therapy industry is developing rapidly as a strategic emerging industry, which has brought unprecedented challenges to pharmaceutical companies and regulatory agencies. Its growth hot spots cover all aspects from cell bank to cell preparation, cell therapy technology research and development, cell clinical research, etc. In recent years, due to the growing aging of the population, the medical cost is increasing, and the field of cell therapy is developing rapidly in Japan. Cell therapy products are also regarded as the key driver of the growth of its research-based pharmaceutical industry in the industry, and the field of research and development has also made breakthroughs. From 2012 to 2018, there are three Japanese scientists, Shinichi yamanakayama, Yoshiyuki Okura and Yoshiyuki Benshu, who are in stem cells , autophagy mechanism, immunotherapy and other outstanding achievements have won the Nobel Prize in physiology and medicine. All of this has made Japan a global leader in research and development of cell therapy products and policies. This paper introduces the clinical trial management of cell therapy products in Japan, in order to provide suggestions for the standardization and safety construction of cell therapy industry in China.
1. Concept, approval and marketing of cell therapy products in Japan
1.1 Japanese concept of cell therapy products
In Japan, cell therapy products are called regenerative medical products, which refer to drugs or medical devices containing or composed of human cells or tissues of the same origin or from the same origin, which are used for chemical therapy, changing biological characteristics and artificial gene operation to proliferate or activate cells for treatment of diseases or tissue repair and regeneration. PMDA, an independent administrative legal person in Japan, regulates it as the third kind of product independent of drugs and medical devices.
1.2 approval and marketing of cell therapy products in Japan
As a powerful country in research and development of cell therapy products in Japan, by the end of 2017, two finished adult cells had been listed, namely, the self cultured epidermis of Jace company and the self cultured cartilage of JACC company, both of which were regenerated by cultivating patients' own cells and then transplanting them back into patients' bodies. The stem cell products already on the market in Japan are the allogeneic mesenchymal stem cells named temcell sold by JCR pharmaceutical company and the autogeneic mesenchymal stem cells of stemirac of NIPRO company. The former is used for the treatment of acute graft versus host reaction (GVHD), one of the serious complications after hematopoietic stem cell transplantation. In September 2015, it obtained the complete treatment of MHLW in Japan Approved and put on the market for 4 years, good economic and social benefits have been achieved; the latter was approved in December 2018 for patients with traumatic spinal cord injury to improve neurological symptoms and dysfunction related to spinal cord injury.
In terms of tumor immunotherapy, Novartis purchased contract development manufacturing organization (cdmo) services in Japan in 2018. In February 2019, MHLW officially approved the car-t drug kymriah developed by Novartis for the treatment of CD19 positive relapse or refractory (R / R) B-cell acute lymphoblastic leukemia (all) and CD19 positive R / R diffuse large B-cell lymphoma (DLBCL). Kymriah has also become the first car-t therapy approved in Asia for the above two B-cell malignancies.
2 overview of clinical management of cell therapy products in Japan
2.1 regulatory regulations
In order to establish a more efficient channel for the transformation of scientific and technological achievements, Japan's regulatory agencies borrowed from the regulation of cell therapy products in South Korea, and established a relatively complete legal system of regenerative medicine in Japan based on the revision of the original regulation in Japan. In general, the Japanese government manages the technology and products of cell therapy products separately. For the safety and effectiveness requirements of all clinical research using processing cell medical technology, please refer to the act on the safety of regenerative medicine (rmact) issued in 2014; for the production and marketing of regenerative medicine and cell therapy products, please refer to the pharmaceutical and medical devices act Act，PMDAct）。
Among them, the regenerative medicine safety law provides an important legal support for the regulatory approval and product safety of regenerative medicine, which states that the three-level hierarchical system of risk assessment should be adopted for the impact on human health, and the regenerative medicine technology should be divided into three categories to determine the level required for research quality supervision. The specific classification standard is shown in Figure 1. For low-risk products, such as processed somatic cells, the "identified regenerative medicine and other committees" shall review them, and the applicant shall submit the clinical trial plan to the Minister of MHLW. For high-risk regenerative medical products [including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs)] and medium-risk regenerative medical products [including adult stem cells (SSCs)], medical institutions need to apply for research permission from a special committee designated by MHLW. For class I (high risk) products, in addition to the assessment of the special committee, MHLW will consult the Health Science Council within 90 days to make a judgment based on the opinions of the Health Science Council.
In addition, Japan's health regulatory authorities have issued a series of research guidelines, including the guidelines for clinical research of stem cells and the guidelines for quality control and safety of human autogenous cells / tissue products. Among them, the clinical trial part of stem cell clinical research guide includes general principles, conditions and responsibilities of research institutions, informed consent, clinical research process and other projects. This guideline also serves as a clinical standard for stem cell clinical research treatment.
2.2 supervision departments and their responsibilities
Japan's cell therapy products are supervised by PMDA in accordance with the drug and medical device act, and its drug evaluation center has a special committee for cell tissue processing products, which is responsible for the approval. As for some cell therapy carried out in qualified medical institutions, MHLW will supervise it in accordance with the regenerative medicine safety act.
2.3 approval path
In Japan, clinical trials of regenerative medical products can be divided into two types (dual track system), registration trials and clinical studies according to their application purposes. Among them, the registration test is for the purpose of product marketing license, the applicant is generally a pharmaceutical enterprise, which needs to submit clinical test application to PMDA, while the clinical research is for the purpose of doctors applying medical products to patients in medical institutions, and the scientific and ethical research and application form of new technology or new therapy only need to be submitted to the review committee of clinical trial institutions, Supervised by MHLW.
Generally speaking, after an enterprise submits an application for listing license, PMDA will review the quality, effectiveness and safety of the regenerative medical products according to the existing level of science and technology, and adopt a 30 day filing system. If PMDA does not send a letter within 30 days, it will be deemed to approve the application. Japan also stipulates that if the safety of products with different homogeneity, such as regenerative medicine, can be determined and its effectiveness can be estimated, it can be recognized by additional conditions and time limit, especially in the early stage. Then, the safety and effectiveness of the product are verified again to determine whether it will be listed as a product or withdrawn from the market for a long time. However, the maximum time limit for granting approval for listing shall not exceed 7 years. The innovation of this policy has greatly accelerated the process of regenerative medical products, and made Japan's personalized medical management take a big step forward again.
3 current situation of clinical management of cell therapy products in China
3.1 regulatory regulations
In December 2017, the former State Food and Drug Administration (CFDA) issued the technical guidelines for research and evaluation of cell therapy products (Trial) and began to implement it. The document points out the path for the development, production and registration of cell therapy drugs, aiming to further standardize the research and development of cell therapy products and improve their safety, effectiveness and quality controllability. As for clinical trials, it is pointed out that in view of the special biological characteristics of cell therapy products, the overall strategy of clinical trials different from other drugs should be adopted in clinical trials. In the aspect of stem cell clinical research management, in 2016, the former CFDA issued "stem cell clinical research management measures (Trial)", which made detailed requirements and specifications for stem cell clinical research process and stem cell preparations, and pointed out that stem cell treatment related technologies will no longer be managed according to the third type of medical technology. Then the former national health and Family Planning Commission and the former CFDA jointly established the national stem cell clinical research expert committee, whose members are composed of 33 experts in the fields of stem cell foundation and clinical related disciplines, stem cell preparation and quality control, providing technical support for the standardized management of stem cell clinical research. In 2019, the national health and Health Commission issued the measures for the administration of clinical research and transformation application of somatic cell therapy (Trial) (Draft for comments) and the regulations for the administration of clinical application of new biomedical technologies (Draft for comments). These two regulatory documents mainly focus on cell therapy, which specifies that medical institutions as the main body of responsibility can carry out somatic cell therapy and other new technologies After obtaining safety and effectiveness data, we can apply for clinical application and charge for it. In order to make up for the gaps in regulations and technologies in the production and quality inspection of cell therapy products in China, and further improve the long-term regulatory mechanism of cell therapy products, the national vaccine inspection center and the National Drug Administration (nmpa) food and drug audit and Inspection Center issued the GMP appendix cell therapy products (Draft for comments) on November 28, 2019, which is applicable to Transportation, receiving and production of donor materials