Beijing Releases "Guidelines for Ethical Review of Clinical Research in CAR-T Cell Immunotherapy"

Recently, the Beijing Municipal Health And Wellness Commission officially released the "CAR-T cell immunotherapy clinical research ethics review guide."
, the guidelines apply to ethical reviews of CAR-T clinical research conducted by healthcare organizations, including drug clinical trials and exploratory clinical studies initiated by researchers, according to the document.
the same time, medical institutions should bear the main responsibility of research, and should establish a complete quality management system, data information management and related risk management mechanism for the whole process of cell preparation and clinical research.
The institution conducting the CAR-T clinical study shall not charge the subject any research-related fees and shall purchase third-party insurance to cover the cost of treatment and the corresponding financial compensation or compensation for the subject who has suffered research-related injury or death.
addition, the document provides a detailed description of the requirements of the relevant researchers and their teams, the key points of the study programme review, the points of informed consent, the points of continuous follow-up review, etc.
The Ethical Review Guidelines for Clinical Research on CAR-T Cell Immunotherapy Show good application prospects in the exploration and development of cell therapy.
CAR-T technology is still an emerging area, and its technical standards, clinical efficacy and potential risks require more assessment data, and there are many challenges in clinical research supervision.
These guidelines are formulated to guide medical and health institutions in Beijing to conduct a scientific and normative ethical review of CAR-T clinical research under the current policy, fully assess the risk-benefit ratio of the study, and implement the rights and interests of the subjects.
, scope of application This guide applies to ethical reviews of CAR-T clinical research conducted by healthcare organizations, including drug clinical trials and exploratory clinical studies initiated by researchers.
II, CAR-T cell immunotherapy definition car-T cell immunotherapy, refers to the separation of T lymphocytes from the subject's blood, through genetic engineering technology to import containing specific antigen recognition fragments, T cells to activate molecules, co-stimulation signal molecules of CAR gene modification T cells, so that it not only obtains the ability to identify tumor cell surface-specific antigens, but also obtains cell activation ability.
will be built of this CAR-T cells through in vitro amplification, purification and back into the subject's body, so as to achieve the goal of targeting and killing tumor cells, treatment of disease.
III. Research institutions and ethics committees require medical and health institutions to have the appropriate qualifications and conditions for conducting clinical research, and recommend that research projects have been completed and researched within the scope of the project, in accordance with the Code of Quality Management of Drug Clinical Trials (GCP), the Technical Guidelines for Research and Evaluation of Cell Therapy Products (Trial) (Trial) (2017), and the Measures for the Management of Stem Cell Clinical Research (Trial).
trials of drugs and devices should be conducted in institutions qualified for clinical trials.
medical institutions to bear the main responsibility of research, we should establish a complete system of quality management, data information management and related risk management mechanisms for the whole process of cell preparation and clinical research.
The institution conducting the CAR-T clinical study shall not charge the subject any research-related fees and shall purchase third-party insurance to cover the cost of treatment and the corresponding financial compensation or compensation for the subject who has suffered research-related injury or death.
should have an independent ethics committee composed of high-level experts appropriate to the conduct of CAR-T clinical studies.
The organizational structure, system and standard operating procedures of the Ethics Committee shall, in addition to meeting the general requirements of the regulations for ethical review, refer to the relevant requirements of the Stem Cell Clinical Research Management Measures (Trial) and meet the following necessary conditions: (1) the composition of the members shall include experts with relevant medical background in cell immunotherapy or employ experts with CAR-T clinical research and basic medical background as independent consultants.
examination, members shall sign non-disclosure agreements and declarations of non-conflict of interest, with the consent of more than two thirds of the statutory members present.
(iii) In addition to receiving training in routine medical ethics review, members should take the initiative and continue to participate in training on relevant new technologies, topics of new projects, and training in adaptation regulations and guidelines.
4. The researchers and their team require that, in addition to meeting the requirements of the relevant national management systems and guidelines, the researchers and their teams should have the following conditions: (1) the main researchers should have senior title, have rich experience in cell therapy, have the corresponding capacity to bear the risks that may occur in the study and the ability to allocation of relevant emergency treatment resources.
(ii) the research team should include appropriate clinical staff, laboratory personnel, quality control personnel and other relevant personnel.
the main research team should be trained in the quality management specifications of drug clinical trials and qualified accordingly.
, the main points of the review of the research programme are to examine the scientific and ethical rationality of the programme, including the scientific design and implementation of the study, the safety of the subjects and the protection of rights and interests.
(i) Scientific and social value of the study 1. Research background: should include the epidemiological characteristics of this adaptation certificate, such as morbidity, pathological sub-type, prone population;
2. Possible benefits: Subjects may or may not benefit from treatment, diagnosis, and examination by participating in clinical studies to cure, alleviate, or alleviate symptoms.
3. Possible risks: Research drugs may not achieve the desired efficacy and may produce toxic and adverse reactions such as cytokine release syndrome (CRS), immuno-effect cell-related neurotoxic syndrome (ICANS), uncontrolled T-cell amplification, fever, long-term hemoglobular reduction and infection, infection macrophage activation syndrome/lymphocytosis syndrome (TLS), etc.
(ii) The research basis (non-clinical research data and preclinical data) CAR-T as a gene cell drug, with the diversity and complexity of biological products, traditional drug clinical trial project design is not necessarily applicable to CAR-T drugs.
, the content of non-clinical research evaluation of cell therapy products depends on cell type and clinical use.
for non-clinical research data and information, it is recommended to refer to the Technical Guidelines for Cell Therapy Product Research and Evaluation to reflect the safety and effectiveness of cell therapy products in a more comprehensive approach.
1. Pharmacodynamics: (1) Target antigen distribution, affinity detection between CAR molecules and target antigens, off-target effect detection.
(2) in-body drug effect: cell killing and factor release experiments.
(3) In vivo llermic effects: pharmacological studies in mouse models of lotus tumors.
2. Pharmacodynamics: Detection of tissue distribution of CAR-T cells in mouse models of tumors, and duration in the blood.
3. Toxicology: (1) A single dose toxicity test in a non-holoma mouse model.
a single dose toxicity test in a mouse model with a lotus tumor (2).
(3) tumor test.
(4) Genotoxicity: Insertion Point Analysis.
(5) allergic test, hemolysis test, local stimulation test.
. For exploratory clinical trials, it is necessary to consider the mechanism of action of different products, in vivo biological behavior, possible differences and uncertainties in future clinical applications, and the urgency of future clinical applications.
, the effectiveness of the drug should be demonstrated in vivo and external models, and the tissue distribution of CAR-T cells in the mouse model of the tumor should be tested for the duration of survival in the blood.
toxicology should complete at least one toxicity test, which initially proves the safety of drugs and preparations.
(iii) Entry criteria (subject selection)1. Due to the risk uncertainty of cell therapy products and the complexity of the mode of drugation, early clinical trials should take full account of the severity of the subject's disease and the different stages of the disease, as well as the available treatment methods, and choose not to treat from the existing treatment For subjects who benefit from the means, blood tumors should consider at least subjects who fail second-line treatment, primary drug resistance, and subjects who relapse after transplantation;
2. Children and adolescent subjects and adult subjects should not be recruited in a clinical study at the same time, underage subjects such as children may be recruited after gaining experience in adult subjects' studies, or scientific and reasonable trial programmes should be designed to conduct separate studies among children and adolescent subjects and adult subjects based on the characteristics of clinical morbidity and treatment prognosiosm of subjects of different ages.
(iv) The rationality of the research method (sample size calculation, measurement monitoring index) varies from research type to research type and stage to research stage, and its research purpose, research design, sample size and observation index are different.
1. Dosage setting: Due to differences in immune systems between different species and the specificity of CAR-T cells, it is not possible to calculate or calculate the human body's starting dose or maximum toned dose with an effective dose or toerable dose of animals in preclinical studies.
the rationality of the initial dose should be scientifically considered in the design of the study, not only to take full account of the subject's safety and tolerance, but also to avoid the subject's excessive exposure to ineffective low dose.
setting of each incremental dose should be scientific and reasonable, and provide the corresponding basis.
in the process of dose increment, it is recommended to set a reasonable group time interval, each dose level of the subjects back to the drug interval of not less than 2 weeks.
limiting toxicity (DLT) should take into account the characteristics of CAR-T products and the characteristics of clinical trials of tumors, and at least 28 days after cell infusion.
2. Sample size design: different types, different clinical research stages, different research purposes, the sample size requirements are different, sample size calculation should have a scientific basis, reasonable and feasible.
3. Measurement and monitoring indicators: The scientific, necessary and feasible indicators such as safety, effectiveness, cell proliferation metabolism and immune function detection need to be evaluated.
testing methods and long-term safety evaluation, such as replication lysovirus (RCL), drug-resistant antibody (ADA) related testing.
(v) The car-T clinical research on risk prevention and control management should formulate a complete safety risk prevention and control plan, clarify the responsibilities of applicants and researchers and safeguards for significant risks to subjects, including: 1. CAR-T clinical research quality management and risk control system should be established, and have the risk management and capacity to adapt to the research carried out.
2. Before conducting clinical studies, ensure that there are reserves of first aid drugs, emergency treatment conditions and co-operation and support with relevant departments such as the ICU.
3. Subjects are hospitalized for CAR-T cell infusions and are usually hospitalized for observation until the 14th-21st day after infusion.
if the researchers determine that there is a need to remain in hospital to observe the condition of the disease can continue to be hospitalized.
Upon discharge from the hospital, the subject shall issue a researcher's contact card and provide health education to the subject and his/her family, informing the subject and his/her family that they should live near the hospital for at least 4 weeks after discharge or within 2 hours of receiving prompt medical attention.
. For adverse reactions of clinical significance and special concern, including but not limited to adverse reactions such as CRS and ICANS, plans for monitoring, early identification and clinical disposal should be provided.
5. The criteria for subject withdrawal from research and termination of clinical studies should be clearly defined in the programme.
The subject may withdraw from the study at any time as he wishes, or at any time, for reasons of safety, non-follow-up to the study or management, the researcher or the candidate may withdraw the subject from the study at any time.
In addition, when CAR-T cell preparation is not successful and is not suitable for re-extraction, can not obtain a sufficient amount of clinical cell dose in line with quality standards, the subject should be clearly informed, and legal, appropriate and ethical treatment, allowing the subject to withdraw, but the subject needs to provide medical advice and guidance, and safe follow-up.
6. It should be made clear in the programme that subjects receiving cell therapy should be followed up to a long period of time, up to 15 years after treatment, or until death, to understand the long-term safety information of cell therapy.
important issues and treatment found in follow-up visits should be reported to the higher health administrative departments and drug supervision and administration departments in a timely manner in accordance with GCP requirements.
. The bidder shall provide researchers and research institutions with adequate clinical trial insurance and other safeguards to compensate or compensate for damage to subjects associated with clinical trials and the resulting loss to researchers or research institutions.
8. Recording and reporting requirements for adverse events (AEs), serious adverse events (SAEs), or special concern adverse events (AESI, if applicable): including, but not limited to, diagnosis or symptoms of AE, start and end of AE, duration, severity, need for treatment, impact on research treatment, relevance to research products, relevance to pretreatment of clearing, whether SAE and transfer.
For SAE/AESI, researchers and bidders should report to the drug regulatory authorities, health administration departments, and ethics committees in accordance with GCP and related regulatory requirements, and for suspicious and unexpected serious adverse reactions ("SUSAR") that occur during clinical studies, both inside and outside China("SUSAR"), Bidders shall report quickly to the National Drug Review Authority within the prescribed time frame in accordance with the Standards and Procedures for Rapid Reporting of Safety Data during Drug Clinical Trials, and in view of CAR-T clinical research risk management, researchers should promptly report SAE/SUSAR to the Ethics Committee within 24 hours of being informed of the Incident at the Center.
(vi) Preparation Preparation Management 1. For registered drug clinical trials, cell preparation should be carried out in a production workshop that meets the requirements of the Production Quality Management Practice (GMP);
2. Cell preparation should be carried out in clean rooms and sterile protective facilities that meet the cleanliness requirements of sterile production, production sites and equipment should be regularly cleaned and disinfected, and a complete standard operating process should be in place to ensure the control of the entire sterile process.
3. Measures to prevent pollution and cross-contamination should be developed in the process of cell preparation to prevent errors