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Source: Field of Cell and Gene Therapy
On May 9, 2023, the National Health Commission (NHC) issued the "Somatic Cell Clinical Research Guidelines (Draft for Comment)", which once again stirred up a cloud of waves, causing the market to discuss and predict the regulatory model of Cell and GeneTherapy (CGT) products. Why has CGT product regulation always been a subject of concern for Chinese regulators? Because compared with traditional pharmaceutical products, its development has a high degree of personalization, complex process, difficult research and development, rapid technology development, coordination with clinicians and other characteristics, so the supervision and management departments of various countries, including China, always regard the supervision of CGT products as a long-term research topic. This paper attempts to briefly explain the current regulatory system and new trends of CGT therapeutic products in China.
一. Relevant definitions
CGT therapeutic products, including cell therapy products and gene therapy products, specifically:
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terminology |
basis |
definition |
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Cell therapy |
Technical Guidelines for Research and Evaluation of Cell Therapy Products (Trial) (Food and Drug Administration Circular No. 216 of 2017) |
Cell therapy products referred to in these Guidelines refer to live cell products of human origin that are used to treat human diseases, whose source, operation and clinical trial process meet ethical requirements, and are developed and registered in accordance with relevant regulations on drug administration. These Guidelines do not apply to blood components used in blood transfusions, prescribed hematopoietic stem cell transplantation without in vitro treatment, reproductive related cells, and tissue and organ products composed of cells. |
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Guidelines for Quality Control of Cell Therapy Products (Trial) |
Cell therapy products (hereinafter referred to as cell products) referred to in this Guide refer to human live cell products prepared by appropriate in vitro operations (such as isolation, culture, amplification, gene modification, etc.) approved for marketing, including cells with or without genetic modification, such as autologous or allogeneic immune cells, stem cells, histocytes, or cell lines; It does not include blood components for blood transfusion, hematopoietic stem cells for transplantation, reproductive related cells, tissues and organ products composed of cells, etc. |
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Gene therapy |
Technical Guidelines for Pharmaceutical Research and Evaluation of in Vivo Gene Therapy Products (Trial) |
Gene therapy products generally work by introducing foreign genes (or gene editing tools) into target cells or tissues to replace, compensate, block, correct, increase, or knock out specific genes. In vivo gene therapy products introduce foreign genes (or gene editing tools) directly into the human body through an appropriate carrier to play a therapeutic role, while in vitro gene therapy products generally introduce foreign genes (or gene editing tools) into cells in vitro, prepare them into genetically modified cells or cell-derived products, and finally transfuse them back to play a therapeutic role. |
Even with the above definition, there is no clear judgment as to whether "cell products genetically modified in vitro" (such as Car-t) are cell therapy products or gene therapy products. According to the relevant guidelines and guidelines, Chinese regulatory authorities place in vitro genetically modified cell products as cell or cell-derived products, but such products exist in the definition of both cell therapy products and gene therapy products, which belong to the overlapping area of the two categories of products.
二. the evolution of the dual-track supervision model
The CGT product itself is also a therapeutic process, which is the difference between the CGT treatment model and the traditional drug treatment model. At present, the supervision of CGT therapeutic products in China adopts a dual-track model: On the one hand, the NHC records and manages the cell therapy technology carried out by medical institutions in their own medical institutions based on clinical studies; On the other hand, in the form of cellular drugs, clinical trials are completed in accordance with the drug regulatory model and registered after approval by the State Drug Administration and its subordinate departments (NMPA).
On March 2, 2009, the Ministry of Health (since revoked) promulgated the "Administrative Measures for Clinical Application of Medical Technology" (the original number is "Medical Political Development [2009] 18", now "National Health Commission of the People's Republic of China Order No. 1") and the "Catalogue of the first batch of the third type of medical technology allowed for clinical application" (" Catalogue of Clinical Application Allowed in 2009 "). Autologous immune cell (T cell, NK cell) therapy technology, cell transplantation therapy technology (except stem cells), cord blood hematopoietic stem cell therapy technology, hematopoietic stem cell therapy technology (except cord blood stem cell) therapy technology is listed as the first batch of allowed clinical application of the third category of medical technology catalog to carry out clinical application. The cell therapy technologies listed in the list are permitted for clinical use, but need to complete the application capability review in advance. According to the Letter of Reply to the proposal No. 0543 of the Fifth Meeting of the 12th National Committee of the CPPCC (Medical Sports Category No. 056) published on the official website of the Health and Family Planning Commission on January 4, 2018, due to the lack of scientific and standardized clinical research conclusions and evidence-based support for the declared medical institutions, The former National Health and Family Planning Commission did not approve any medical institution to carry out the clinical application of immune cell therapy technology [1].
The Measures for the Management of Clinical Research Projects in Medical and Health Institutions issued on October 16, 2014 (No. 80 of the National Health and Health Institute) (the Measures for the Management of Clinical Research) stipulates that clinical research must implement the project approval system in medical and health institutions, and only clinical research approved by medical and health institutions can be implemented in the institution [2].
On June 29, 2015, the Health and Family Planning Commission issued the Notice of the National Health and Family Planning Commission on the cancellation of the approval of the clinical application of the third type of medical technology (National Health and Medical Hair (2015) No. 71) and the Medical Technology Limited in Clinical Application (2015 version) (the catalogue of restricted medical technology for 15 years), and abolished the Catalogue of Allowed Clinical Application in 2009. The "15-year Restricted Medical Technology Catalogue" stipulates that other listed technologies not included in this catalogue, but in the "2009 Allowed Clinical Application Catalogue" shall be implemented in accordance with the relevant provisions of clinical research. Because immune cell therapy technology is not included in the restricted list, it can only be used as clinical research and should not be used in clinical applications.
On December 18, 2017, the former State Food and Drug Administration promulgated the "Technical Guidelines for Research and Evaluation of cell therapy Products (Trial)" (Food and Drug Administration Circular No. 216 of 2017), which determined that cell therapy products can be used as drugs to carry out clinical research, registration applications and industrial production.
On August 13, 2018, NHC reissued the "Measures for the Management of Clinical Application of Medical Technology", changing the clinical application of medical technology from a classified and graded management mode to a "negative list management" system [3], making it clear that the supervision and management of cell therapy technology does not apply to this regulation [4]. Somatic cell therapy technologies that are not intended for marketing have been explicitly prohibited from direct clinical use. At the same time, investigator-initiated clinical research (IIT) using somatic cell therapy technology shall be registered and managed according to clinical research. If the technology involved in the IIT wishes to be commercialized as a product (drug) in the future, drug registration and related clinical trials under the supervision of the NMPA are still required.
On March 29, 2019, the NHC issued the "Management Measures for Clinical Research and Transformation Application of Somatic Cell Therapy (Trial)" (draft for comment), which stipulates that medical institutions and clinical research projects of somatic cell therapy that meet the corresponding conditions can be filed in the NHC and carry out clinical transformation applications within the scope of the filed projects. It means that cell therapy can be clinically applied through the form of filing. If this method is implemented, under the premise of complying with the relevant provisions of NHC, cell therapy as a medical technology will be allowed to enter the transformation application in medical institutions, and the medical structure can apply for fees instead of staying in the non-chargeable IIT stage, without the need for drug regulatory approval.
On August 26, 2020, the NHC issued the "Reply of the National Health Commission to the Recommendation No. 4371 of the Third Session of the 13th National People's Congress", "Cell preparations such as stem cells and immune cells have obvious pharmaceutical properties. The national drug regulatory department has formulated supporting policies for relevant preparations to pass drug approval, and after approval, they can be widely used rapidly, which is not only conducive to ensuring medical quality and safety, but also conducive to industrialization and high-quality development "[5].
On May 9, 2023, the Science and Education Department of the National Health Commission issued the "Guidelines for Somatic Cell Clinical Research (Draft for Comment)" (Draft for Comment). Compared with the "Management Measures for Clinical Research and Transformation Application of Somatic Cell Therapy (Draft for Comment)", the draft for comment has no relevant provisions on transformation and application. Instead, it is expressly prohibited to charge or disguise research fees from subjects. It can be seen that the NHC is more inclined to prohibit somatic cell therapy technologies from being charged to patients/subjects before they are marketed as drugs.
三. Regulatory requirements for CGT treatment of IIT
As mentioned earlier, the NHC has become increasingly clear on the regulation of CGT therapeutic techniques, preferring to regulate them as non-marketable IIT research. In this context, Iits for CGT treatment are subject to the following (but not limited to) regulatory requirements:
1. Management Measures for Clinical Research Projects Carried Out by Medical and Health Institutions
According to the Administrative Measures for Clinical Research issued on October 16, 2014, clinical research refers to the clinical application observation of new technologies in all medical research involving human drugs (including experimental drugs) and medical devices (including in vitro diagnostic reagents) carried out in medical and health institutions [6]. The IIT of immune cell therapy belongs to the category of "clinical research" and needs to comply with the provisions of the "Clinical Research Management Measures". However, due to the relatively long history of the Clinical Research Management Measures, it does not provide clear guidelines for cell therapy.
2. Administrative Measures for Conducting investigator-Initiated Clinical Studies in Medical and Health Institutions (Trial)
The "Administrative Measures for Conducting Investigator-initiated Clinical Studies in Medical and Health Institutions (Trial)" issued on September 9, 2021 and implemented on a pilot basis in Beijing, Shanghai, Guangdong and Hainan states: "Non-product development of somatic cell clinical research with reference to the Management of Stem Cell Clinical Research Measures (Trial) management [7]", that is, if the pilot area of medical institutions to carry out clinical research of non-registered cell therapy must refer to the application of Stem Cell clinical research management Measures (trial).
3.Guidelines for Somatic Cell Clinical Research (Draft for Comment)
"Although the results of somatic cell clinical research may provide scientific support for the development of further somatic cell therapeutic products and technologies, the management of somatic cell clinical research is not and cannot replace the management of drug clinical trials," the draft states. Compared with the previous relevant provisions, the draft for Comment only regards IIT as "scientific support", without clarifying whether IIT results can be used for drug registration, and it remains to be seen how the FDA will apply it in supervision:
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Specified name |
Related content |
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Measures for the Administration of Clinical research on Stem Cells (Trial) |
After conducting stem cell clinical research in accordance with these measures, if applying for drug registration clinical trials, the clinical research results obtained can be submitted as technical application materials and used for drug evaluation. |
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Administrative Measures for Clinical Research and Translational Application of Somatic Cell Therapy (Draft for Comment) |
For those who meet the relevant technical requirements for drug registration, the quality management standards for non-clinical studies of drugs and the quality standards for clinical trials, the application for clinical trials can be made according to the relevant procedures for drug administration, and the obtained research data can be submitted for drug evaluation. |
The draft for Comments stipulates: "The application of human autologous, allogeneic or xenogeneic (non-human) somatic cells, after in vitro operation back into the human body (or implantation) treatment method." What is the relationship between "stem cell therapy" and "somatic cell therapy"? Hematopoietic stem cells are listed as one of the somatic cells in cell therapy in the Guiding Principles of Human Cell Therapy Research and Preparation Quality Control; In the Administrative Measures for investigator-initiated clinical Research conducted by medical and health Institutions (Trial), "stem cell therapy" and "somatic cell therapy" are separately stipulated. Therefore, the provisions are inconsistent, and it is expected to be clarified in the new regulations.
The draft for Comments stipulates that somatic cell clinical research should submit and upload information in the national Medical research registration and filing information system as required, with specific reference to the provisions of the "Management Measures for Stem Cell Clinical Research (Trial implementation)", and further stipulates the specific requirements for submitting and uploading data in the information system. The provisions of the Draft for Comment on the management procedures of somatic cell clinical research are relatively simple, and the requirements of regulatory procedures are not clear.
(4) Technical requirements
Regarding the technical conditions that medical institutions should have, the "draft for Comments" mainly puts forward technical requirements from the following aspects: the qualifications of third-grade hospitals, corresponding diagnosis and treatment subjects and clinical trial institutions; National key laboratories, national major science and technology infrastructure construction units or have the corresponding experience in cell drug clinical trials; Quality control, quality authorizer system and audit system; Personnel qualification and training requirements; Academic and ethics committees, risk management and adverse reaction handling mechanisms.
Regarding the technical requirements to be met in clinical research, the Draft for Comments mainly makes requirements from five aspects: basic requirements, somatic cell preparations, preclinical studies, research programs and ethical compliance.
The draft for Comments stipulates that medical institutions that carry out somatic cell clinical research are the responsible subjects of somatic cell preparations and clinical research quality management, and bear overall responsibility for somatic cell clinical research. In addition, the draft for Comments also clearly stipulates that in the case of preparing reagents by themselves and preparing reagents by cooperating institutions, medical institutions should bear the responsibility for quality management as the overall responsible person. At the same time, the national and provincial NHC will conduct spot checks, special inspections or causative inspections on somatic cell clinical research institutions and studies, and if necessary, extend inspections on the preparation institutions that provide somatic cell preparations.
According to the draft for Comments, subjects involved in conflicts of interest include research institutions, researchers and providers of cellular preparations, and the economic conflicts of interest of researchers are explained, and researchers holding patents for cell technology, holding stocks in pharmaceutical institutions or taking positions, receiving remuneration or having obtained large research grants may constitute economic conflicts of interest. It does not include the use of research results to write papers. In addition, the draft stipulates that researchers' immediate family members, such as spouses, children, parents and siblings, should also be included in conflict of interest management. The draft for comments stipulates that in principle, persons with conflicts of interest may not act as the person in charge or the main researcher, and it is unavoidable to assign researchers without conflicts of interest to jointly conduct the study, and to hire independent clinical research monitors. Researchers should also disclose conflicts of interest when reporting, concluding papers and publishing papers, and disclosure information will be judged by reviewers, management departments and peers on the science and reliability of the research.
四、Peroration
The field of CGT therapy is still a hot biomedical research direction, and the innovative research in this field is also developing continuously in China. At the same time, China's drug regulatory authorities and health commission departments are also adapting to changes in technology and research, formulating CGT industry and regulatory policies accordingly, and accelerating the identification of regulatory models in the field of CGT treatment. However, due to the rapid development and changes in the CGT field, it is believed that under the large regulatory framework, the specific regulatory system will continue to optimize and upgrade.