Weigh! The "consistency assessment" of vaccines is coming

Yigu news, today (December 24), in order to further standardize and improve the level of vaccine clinical research and development, and strengthen the supervision of vaccine quality and safety, the State Food and Drug Administration issued the technical guidelines for clinical comparability research of vaccines for prevention (hereinafter referred to as the guidelines) It is understood that the guiding principles are divided into six parts: preface, consideration before clinical trial, general consideration of clinical trial design, statistical consideration of clinical trial design, data management and quality assurance, and evaluation of clinical trial results It is based on the investigation of relevant technical requirements of domestic and foreign research and production enterprises and evaluation institutions, and combined with the current domestic vaccine clinical requirements The actual research and development is based on the characteristics of non innovative vaccines As for the scope of application, the guiding principles make it clear that the guiding principles are applicable to non innovative vaccines that use immunogenicity as an alternative end point for effectiveness evaluation The so-called non innovative vaccines refer to vaccines that have already been listed in China and are comparable with the same vaccines that have been listed in terms of quality, safety and effectiveness, and changes in prescriptions and production processes If it is necessary to further evaluate the feasibility of the change through clinical comparability study, please refer to the guidelines For preclinical research, the guiding principles usually should first carry out a pharmaceutical and non clinical comparative study between the candidate vaccine (or trial vaccine) and the same vaccine (or control vaccine) which has been listed on the market The comparative data combined with the clinical trial results are used to evaluate the comparability of the two vaccines The general consideration of clinical trial design should be in line with ethical and scientific requirements, and also consider recent epidemiological characteristics of disease (transmission route, incidence rate, etc.), the impact of the application of similar vaccines on the epidemiological characteristics of the disease, coverage of vaccine application and population immunity level When there are differences in immune procedures, immunogenicity characteristics and evaluation criteria among different populations, clinical trials should be designed separately to evaluate safety and effectiveness For the statistical consideration of clinical trial design, the key clinical trials of vaccine registration application should be randomized, controlled and blind trial design In principle, the attribution of adverse events, the determination of clinical end-point events (such as pathogenic cases, etc.), the immunogenicity test, and the formulation of statistical analysis plans should be carried out in a blind manner, and statistical analysis should be based on statistical analysis plans The study of vaccine clinical comparability usually adopts non inferiority experimental design, and the consistency evaluation of vaccine clinical batches (Times) adopts equivalence test In the equivalence / non inferiority test, confidence interval method is generally used to calculate the bilateral 95% confidence interval of rate difference (absolute risk difference, RD), rate ratio (relative risk ratio, RR) or inter group GMT (or GMC) ratio For the evaluation of clinical trial results, the guiding principles especially emphasizes that the scheme design, implementation process and statistical analysis of vaccine clinical trial should be scientific and feasible and meet the relevant laws, regulations and management requirements Immunogenicity and safety should also be considered in the evaluation of clinical comparability of vaccines with immunogenicity alternative end points In order to further standardize the clinical trials of preventive vaccines (hereinafter referred to as vaccines) and improve the level of clinical research and development, ensure the similar safety and effectiveness of similar vaccines when they are registered on the market, and guide the clinical research and development and evaluation of non innovative vaccines, this guiding principle is hereby formulated The non innovative vaccines mentioned in these guidelines refer to the vaccines that have already been listed in China and are comparable with the same vaccines that have been listed in terms of quality, safety and effectiveness This guideline is applicable to non innovative vaccines that use immunogenic alternative endpoints for effectiveness evaluation For vaccines involving changes in prescription and production process, if it is necessary to further evaluate the feasibility of changes through clinical comparability study, please refer to the guidelines The clinical trial of vaccine shall strictly abide by the drug administration law of the people's Republic of China, the vaccine administration law of the people's Republic of China, and implement the relevant provisions of the drug registration administration measures, in accordance with the GCP, the guiding principles for the quality management of clinical trial of vaccine, the technical guiding principles for clinical trial of vaccine, and the vaccine for prevention Guidelines for grading standards of adverse events in clinical trials This guiding principle only represents the current view and understanding, and will be revised and improved with the deepening of research and understanding 2、 Pre clinical trial considerations for non innovative vaccines, the effectiveness and safety of clinical use of the same vaccines should be fully evaluated in the R & D project Generally, we should first carry out the pharmaceutical and non clinical comparative study between the candidate vaccine (or trial vaccine) and the same vaccine (or control vaccine) which has been put on the market The comparative data combined with the clinical trial results are used to evaluate the comparability of the two vaccines The acceptability limits of the key quality standard items (such as antigen content / titer, virus titer, product and process related impurities, etc.) of the listed vaccine shall not only be determined according to the pharmaceutical research data such as production process capacity and stability research, but also be analyzed and demonstrated by combining the verification results of non clinical research batches and results, registered clinical trial batches and the safety and effectiveness results of clinical trials Rationality Therefore, on the basis of fully considering the expected enlargement of production scale, change of production process address, adjustment of production parameters, variation of key quality attributes of products, degradation of product shelf life and other factors, we should select the trial vaccine that can represent the trial production on the market and enter the registration clinical trial It is suggested that commercial scale vaccines should be used in key registered clinical trials (including enhanced immunization) for marketing approval 3、 The main purpose of clinical trials is to evaluate the safety and effectiveness of the vaccine compared with the control vaccine The design of clinical comparability research plan is in line with ethical and scientific requirements It also considers the recent epidemiological characteristics of disease (transmission route, incidence rate, etc.), the impact of the application of similar vaccines on the epidemiological characteristics of the disease, the coverage of vaccine application and the level of immunity of the population When there are differences in immune procedures, immunogenicity characteristics and evaluation criteria among different populations, clinical trials should be designed separately to evaluate safety and effectiveness （1） Randomized controlled clinical trials 1 The selection of control vaccine refers to the vaccine that has been approved for marketing in China and is intended to be used as a reference control in clinical trials When choosing the control vaccine, we must consider that it has sufficient safety and effectiveness data and has been widely used in clinical practice Generally, the original product should be selected as the control vaccine Sufficient and reasonable basis shall be provided for the selection of non original products In principle, the same control vaccine (including pharmaceutical and non clinical studies) should be used at all stages of the trial vaccine development process to ensure the preciseness of the analysis of research results The control vaccine shall meet the requirements of relevant national laws and regulations, generally shall have the necessary supporting documents such as the batch inspection report issued by China, and the antigen content / titer value shall be determined It is also necessary to consider the consistency between the experimental vaccine and the control vaccine in terms of the target vaccinated population, immune procedures, routes / methods of vaccination, etc., and comprehensively analyze the influence of the differences between the two vaccines on the clinical data in terms of seed batches (virus species, genotype and serotype), cell matrix, dosage form, antigen / titer test results before the test Encourage the use of evidence-based medicine to analyze the clinical research data of the control vaccine scientifically and objectively, and as the basis for the formulation of clinical trial plan For the listed vaccines involving changes in the prescription and production process, if clinical trials need to be carried out, the vaccines before and after the change should be selected for comparative study 2 The samples for clinical trials (i.e research vaccine, including trial vaccine and control vaccine) provided for the management and quality control of research vaccine in accordance with the requirements of laws and regulations shall be clearly coded and easy to identify, and shall have the review and inspection report or batch issuance report issued by the legal Laboratory testing agency, and the name, batch number, specification, preparation or production date of the vaccine shall be consistent with the report Establish and study the vaccine compliance management system, including the receipt, storage, preparation, recovery, return / destruction, cold chain management of vaccines and the treatment of vaccines with cold chain interruption, and record and reflect the effective and traceable quality control measures in detail Blind management should be maintained throughout the blind test It is suggested that the antigen content / titer of the test vaccine and the control vaccine used in the registered clinical trial site should be retested simultaneously The validity period of the trial vaccine and the control vaccine should be comparable as far as possible The determination results of antigen content / titer of the experimental vaccine can provide reference and accumulate technical data for the establishment of the upper limit of safety and lower limit of validity of the test items in the quality standard 3 Immunogenicity alternative end point for most vaccines with clear correlation between immunogenicity and clinical protection effect, immunogenicity can be used as the alternative end point for effectiveness evaluation, with the help of reliable laboratory testing methods and determination of reasonable clinical effectiveness judgment criteria for comparability judgment In the absence of a reliable alternative end point for immunogenicity, clinical efficacy trials should generally be carried out, reasons should be clarified when efficacy trials cannot be provided, and other evidence to support registration should be provided When the immunogenicity evaluation index is the main end point of validity judgment, the representative subjects should be selected reasonably and be consistent with the target population of clinical application as far as possible The effective sample size should be determined according to the purpose of the experiment and the design of the study At the same time, the difference of the immunogenicity test method and the variation degree of the immune response of the test population should be considered The baseline conditions of the subjects, such as demographic characteristics, epidemiological background (susceptible and non susceptible population), should be taken into account in the establishment of the evaluation criteria of immunogenic substitution end point In order to accurately evaluate the immune response level induced by vaccine, we should fully consider the infection status of the pathogen in the local population based on the characteristics of the trial vaccine during the trial design, in principle, we should select the susceptible as the research object and the main evaluation population; we should evaluate and draw up the proportion of the susceptible in the clinical research site, in order to obtain the evaluation meeting the relevant technical requirements Price data The immunogenicity evaluation should also be based on the comprehensive analysis of the dynamic law of the immune response of the control vaccine, and select the time point that can better reflect the immunogenicity characteristics of this kind of vaccine to collect biological samples The immune procedure and sample collection time should be consistent with the control vaccine, and comprehensively reflect the immune success rate and immune persistence (or immune memory reaction) of the test vaccine If there is a clear long-term protective alternative end point and response level, it should be taken as the main end point and judgment standard in principle The immunogenicity alternative end point of humoral vaccine is usually the immune response rate (including antibody positive rate, etc.) and geometric mean titer (GMT) / geometric mean concentration (GMC) and its growth multiple In view of the development of immunology theory and detection method