The Technical Guidelines for Clinical Trials of Immunocell Therapy Products (Draft for Comments) was published.

On July 6, CDE released the Technical Guidelines for Clinical Trials of Immunocellular Therapeutic Products (Draft for Comments):
this Guideline sedative introduces the general considerations of immunocellular therapy products in the conduct of clinical trials and the special considerations of individualized therapeutic products, expounds the research objectives, research methods and evaluation methods of exploratory and confirmed clinical trials of immunocellular therapy products, and puts forward the relevant requirements for long-term follow-up of immunocellular therapy products.
the following is the full text of the Technical Guidelines for Clinical Trials of Immune Cell Therapeutic Products (Draft for Comments):
, Overview
(A) Preamble
2017, the former State Administration of Food and Drug Administration issued the Technical Guidelines for Research and Evaluation of Cell Therapy Products (Trial), which provides a general elaboration of the technical requirements for research and development of cell therapy products in accordance with relevant drug regulations. Since the issuance of the guiding principles, the number of research and development and registration declarations of cell therapy products in China has increased significantly, especially immunocellular therapy products.
immunocellular therapy is the use of the human body itself or donor source of immune cells, through in vitro culture amplification or activation, and then back to the patient, stimulate or enhance the body's immune function, thereby eliminating tumor cells, pathogens or viral infections and other abnormal cells of the treatment, including pass-through cell therapy (ACTrapy), therapeutic vaccines. Depending on the mechanism of action, the current types of cell immunotherapy research hot topics include: tumor-infiltrating lymphocytes ,tumor-infiltrating lymphocytes, TILs), chimeric antigen receptor T cells (chimeric antigen receptor, CAR-T) and T-cell receptor inlay T cells (T-cell-receptor-engineered T cells, TCR-T), in addition, there are other immune cell-based treatments such as natural killer cells (cells, cells) or denthrochid cells (dendritic cells, DC) CIK) and so on.
When immunocellular therapeutic products enter clinical trials, they should follow the general principles of the Code of Quality Management (GCP) for Drug Clinical Trials and the International Coordinating Technical Coordination Committee on Human Drug Registration (ICH)E6. At the same time, the cell source, type, in vitro operation and so on of immune cell therapy products are more heterogeneous, the treatment principle and the body action are more complex than traditional drugs. In order to achieve the desired therapeutic effect, immunocellular therapy products may need to be administered through specific surgical measures, methods of administration, or combination of treatment strategies. Rigorous and scientific clinical trials are critical to ensuring the safety of subjects and producing reliable clinical trial data, and given the special biological characteristics of immunocellular therapeutic products, a holistic clinical trial strategy that differs from other drugs is required in clinical trial studies. Therefore, within the framework of the above guidelines, it is necessary to further refine the technical recommendations for conducting clinical trials of immunocellular therapy products in order to provide more targeted advice and guidance to applicants for drug development registration (hereinafter referred to as applicants) and researchers who conduct clinical trials of drugs (hereinafter referred to as researchers).
(ii) Purpose and scope of application
This Guiding Principles apply to immunocellular therapy products developed and registered in accordance with relevant regulations on drug administration, and are intended to provide the necessary technical guidance for the overall planning, test program design, test implementation and data analysis of clinical trials for such products, in order to maximize the safety and legitimate rights and interests of subjects participating in clinical trials, and to standardize the evaluation methods for the safety and effectiveness of immunocellular therapeutic products.
also has the characteristics of gene therapy products for genetically modified immunocellular therapy products such as CAR-T and TCR-T. The purpose of this Guiding Principle is not to identify its regulatory attributes or classifications, but to make recommendations and recommendations on a number of technical issues in clinical trials of immunocellular therapeutic products based on existing understanding, which are not mandatory and will continue to be revised and improved as research and understanding deepen. Applicants are encouraged to communicate in due course with the Drug Review Centre on the design, implementation and results of specific pilot programmes.
(iii) the characteristics of immunocellular therapy products
the characteristics of immunocellular therapy products are significantly different from traditional drugs, e.g.,
starting raw materials from diverse sources (e.g. autologous sources, allogeneic sources, etc.); Antigen incubation, in vitro activation, genetic modification, etc., failure or delay in production may result in the subject being unable to receive treatment as planned, transport and storage conditions are demanding, autologous products are highly individualized, production scale is limited, quality studies and quality control are difficult, and often accompanied by medications (e.g., pretreatment chemotherapy).
preclinical animal experimental data extrapolation is limited and influenced by a variety of factors, such as selected animal models, pathways of administration, starting dose, biological distribution, immune response, off-target effects and tumor
-causing;
replication virus (RCR/RCL), genotoxicity, tumor-causing uncertainty,
based on long-term survival and persistence in the body, long-term efficacy and safety follow-up,
the complexity of the preparation process of different types of immunocellular therapy products, the biological characteristics of the body have significant differences, and there are significant differences in safety risk in clinical applications. Non-homogenous heterogeneous use, import of exogenous gene fragments, in vitro induced differentiation, systemic action and other factors may affect the biological characteristics of cell retransmission. Complex in vitro operations, the use of a variety of exogenous factors or reagents, etc. can increase the difficulty of cell quality control, which in turn can improve the safety risk of clinical applications. For example, CIK's preparation process and exogenous intervention are relatively simple and generally well tolerated. In contrast, CAR-T cells express exogenous gene fragments, the complexity of in vitro operations is much higher than DC-CIK, in the significant enhancement of Anti-killing specificity and activity in T cells, cytokine storm (cytokine release syndrome, CRS), CAR-T cell-related encephalopathy syndrome (CAR-type-encephalopathy syndrome, CRES) or phage cell lymphocytic serotonin
immunocellular therapy products have obvious differences in the way of action with other types of drugs, therefore, the design of clinical trials need to take into account the characteristics of such products, combined with past clinical experience and domestic and foreign clinical research progress, timely improvement of the trial design and risk control programs.
2. Clinical trial design
(i) generally consider
1, the study population
select clinical trial participants should fully consider the expected benefits and potential risks, at different stages of clinical research, should use available research evidence to analyze the subject's benefit-risk expectations. In early clinical trials of immunocellular therapy products, potential benefits or risks can be estimated based on mechanisms of action, preclinical research data, and past human research and application experience, and animal models selected for preclinical studies should be meaningfully and predictable to extrapolate the human body. In addition to the assessment of potential benefits and risks, the evaluatability of the trial data is also an important consideration in selecting the study population.
(1) Healthy volunteers
immune cell therapy products in the body survival and duration of long, long-term safety risk is not clear, and cell collection and product administration often need to require invasive operations, may increase the risk of safety of subjects, therefore, immunocellular therapy products are usually not considered in the health volunteers in clinical trials.
(2) the stage or severity of the disease
when selecting immunocellular therapy products in the clinical trial of the subject population, the disease stage or severity is one of the most important considerations. Considering that subjects with a more severe or late stage of the disease may be more vulnerable to the risk of cellular immunotherapy, or that their condition is more likely to support the rationality of taking the risk. As a result, applicants often limited the participants from the early trial strain to those with more severe or later stages. However, in some cases, it may be more appropriate to select subjects who stage the disease earlier or less severely. For example, when the time between the ontherand the cell infusion time is longer, the selection of late or severely ill subjects may not be conducive to effectiveness observations, and the applicant will consider clinical trials in earlier or less severe subjects without significantly increasing the risk of safety.
advanced or severely progressive subjects may not be able to collect qualified raw materials for preparation, or be unable to produce standard-compliant cell products, or to wait for the production time of immunocellular therapy products (which usually takes weeks), or to tolerate invasive operations (e.g. single-extraction of blood cells) or combined medications (e.g., pretreatment of clean-up). Therefore, before deciding on the severity of the disease studied in a clinical trial, it is important to consider the expected nature and severity of the risks posed to the subjects and the effects of these risks on different stages or severity of the disease.
In addition, the evaluatability of the results of the test should be considered when selecting the study population. Subjects with complex conditions may have adverse events that interfere with the analysis of results, or are receiving accompanying treatment related to underlying diseases, which can make safety or effectiveness data difficult to interpret. If the end target group is a patient with a milder condition, it may not be possible to obtain the safety and effectiveness information needed for the benefit-risk assessment when tested in subjects with severe or advanced diseases.
therefore, in clinical trials of immunocellular therapy products, when selecting appropriate subjects to be included in the study of specific diseases, the factors such as product function characteristics, disease severity and disease progression should be taken into account.
(3) Children and Adolescent subjects
For clinical trials included in children and adolescent subjects, as far as possible to obtain safety and tolerance data from adult subjects before conducting the trial. If the applicant intends to conduct a child trial without an adult safety or efficacy study, the basis for not conducting an adult study first should be provided.
(4) Other considerations
for certain product types, there are other considerations in selecting the subject population. For example, for cancer vaccines, it may be necessary to identify subjects whose tumors express a specific target antigen. For genetically modified immunocellular therapy products, existing antibodies to vector or exogenous gene expression products may affect the safety or effectiveness of the product, so the safety and effectiveness of subjects with such antibodies should be analyzed in early clinical trials to provide a reference for the selection of subjects in late-stage clinical trials.
for immunocellular therapy products with higher safety risks, the inclusion of pregnant women or childbearing age subjects preparing for pregnancy is generally not considered. Subjects should take the necessary contraception during clinical trials. In addition, the surface markers of certain immunocellular therapy products may have some similarity to abnormal tissues or cells in the subject (e.g., normal T-cells and malignant tumor cells originating from thymus or with T-cell surface markers), if the collection of peripheral blood cells mixed with abnormal cells, and the production process can not be separated, may affect the safety and effectiveness of the product, therefore, in this type of clinical trial, should consider excluding abnormal cells and peripheral blood or bone marrow subjects.
2, subject protection and clinical safety
(1) subject screening
clinical trials of some immunocellular therapeutic products are significantly at risk and the potential benefits are uncertain. As a result, clinical trials of such products tend to be only included in the group of subjects who lack response to existing treatments or have no other treatmentoptions to choose from. For the design of such clinical trials, procedures should be in place to ensure that each subject is fully evaluated at the time of screening and meets the entry criteria for clinical trials, and specific information on these assessment measures should be included in the trial design.
in clinical trials of certain immunocellular therapeutic products, subjects may be receiving treatment for indications or other diseases when they enter the group. If the subject needs to suspend existing treatment during a clinical trial, or to change the dosage or frequency of administration of an existing therapeutic drug, the applicant should carefully assess the risk that the suspension or alteration of existing treatment may lead to the progression of the subject's condition, as well as the expected clinical benefits of the trial product. Consideration is only given to the trial method when the expected clinical benefits are significantly higher than the risk of disease progression of the suspension or change of existing treatment, and it is necessary to develop a detailed remedial treatment plan to avoid delaying or aggravating the patient's condition.
(2) Adverse reaction treatment
the clinical safety of immunocellular therapy products is affected by cell type, action activity, target antigen selection, whether or not geneticmodification, and the occurrence time and severity of adverse reactions are also closely related to the survival, proliferation and distribution of cells in the body. In clinical trial programs, according to product characteristics, according to the safety risks that may arise in clinical trials, a comprehensive and operational risk control plan should be developed to describe in detail the prevention, identification, diagnosis, treatment and follow-up of specific risks.
cell immunotherapy is in a period of rapid development, for its safety risk awareness and disposal ability is also constantly improving, it is recommended that applicants timely reference to the latest clinical consensus at home and abroad or important research, and timely update and improve its risk control measures, improve the scientific and reasonable test program. For example, domestic and foreign researchers have accumulated a wealth of clinical experience in common adverse reactions related to CAR-T cell therapy, such as CRS, CRES or HLH, and their grading and disposal methods have reached a lot of consensus among domestic and foreign researchers, which is of important reference value for effectively controlling the safety risk in clinical trials.
(3) Researcher training and procedures document
some cell immunotherapy have a higher safety risk, the researcher's clinical experience and skill level are critical to the timely detection and handling of adverse events, and may require the support of intensive care and other related departments. For delivery methods involving complex administration procedures or subject to special training, such as intra- or local administration, operators.