Vaccine "Consistency Evaluation Guidelines" issued six directions to improve the quality of clinical research and development of vaccines.

On December 24, the State Drug Administration issued the Technical Guidelines for Clinical Comparability Research on Preventive Vaccines, which will further standardize and improve the level of clinical research and development of vaccines and strengthen the safety and safety of vaccine quality and safety.

guidelines include a total of six sections: "Preamble," "Pre-Clinical Trial Considerations," "General Considerations for Clinical Trial Design," "Statistical Considerations of Clinical Trial Design," "Data Management and Quality Assurance," and evaluation of Clinical Trial Results.
guidelines briefly describe the considerations in clinical research and development of vaccines, pharmaceutical and non-clinical research and development prior to the conduct of clinical comparability studies, and elaborate the specific requirements of the selection of controlled vaccines in clinical comparability studies, the study of vaccine management and immunogenic substitution indicators, and reaffirm the consideration of safety evaluation and the general principles to be followed in statistical treatment in clinical comparability studies.
on August 26, 2019, the newly amended Drug Administration Law of the People's Republic of China was voted in and came into effect on December 1.
was implemented on the same day as the Vaccine Management Act, which was voted on by the Standing Committee of the National People's Congress on June 29.
the introduction of this guiding principle, is in accordance with the two new laws to make the provisions and adjustments.
there is also the Drug Registration Management Measures, which are in the process of soliciting opinions, which is also one of the reference bases of this guidance.
2005, the CFDA issued six technical guidelines on vaccines, including the Guidelines for Preclinical Research for Preventive Vaccines, the Technical Guidelines for Preclinical and Clinical Research of Combined Vaccines, and the Technical Guidelines for Combined Vaccine Quality Control and Clinical Research.
non-innovative vaccine is a vaccine that is already available in China and comparable to the same vaccine on the market in terms of quality, safety and efficacy.
apply to non-innovative vaccines that use immunogenic alternative endpoints for effectiveness evaluation.
there is still a gap between China's vaccine industry and developed countries, overcapacity of ordinary vaccines, homogenization in vaccine production, and a lack of innovative vaccines.
combined with the uneven quality and level of clinical research and development, the effectiveness and safety evaluation of vaccines have brought many challenges.
with the development of economy and industry, the number of declarations of vaccine products for preventive use has increased year by year, and the research and development of non-innovative vaccines has been increasing.
the requirements of strengthening the quality and safety supervision of vaccines, clarifying and harmonizing clinical technical standards, and ensuring that similar safety and efficacy of similar vaccines are registered and effective when they are registered on the market.
at present, China can produce 64 vaccines to prevent 35 diseases.
this Guiding Principles, for preclinical studies, it is generally important to first conduct a pharmaceutical and non-clinical comparison of a candidate vaccine (or experimental vaccine) to a listed vaccine (or a controlled vaccine), and that the comparative data combine clinical trial results to evaluate the comparability of the two vaccines.
clinical studies, clinical comparability studies of vaccines are usually designed with non-inefficiacivy, while clinical batch (secondary) consistency evaluation of vaccines is evaluated with equivalent tests.
guidelines will drive the development of innovative vaccine companies.
in terms of supervision, China will also speed up the construction of drug information traceability system, by the end of December 2019 to prepare a unified information-based traceability standards.
vaccine simply purchased by the end of next year and the state will be "one yard" in the field.
specific content sas follows: Guidelines on Clinical Comparability Research For Preventive Vaccines I. Foreword, for the purpose of further standardizing clinical trials of preventive vaccines (hereinafter referred to as vaccines) and improving clinical research and development levels, ensuring similar safety and effectiveness when similar vaccines are registered and marketed, and guiding clinical research and evaluation of non-innovative vaccines, these guidelines are formulated.
non-innovative vaccines referred to in these Guidelines are vaccines that are already available in China and are comparable to those of comparable vaccines on the market in terms of quality, safety and efficacy.
this guideline applies to non-innovative vaccines that use immunogenological alternative endpoints for effectiveness evaluation.
use these guidelines for vaccines that involve changes in prescriptions and production processes that require further evaluation of their feasibility through clinical comparability studies.
vaccine clinical trials shall strictly abide by the Drug Administration Law of the People's Republic of China, the Law of the People's Republic of China on Vaccine Management, implement the relevant provisions of the Measures for the Administration of Drug Registration, and carry out in accordance with the relevant requirements of the Code of Quality Management of Drug Clinical Trials (GCP), the Guiding Principles for Quality Management of Vaccine Clinical Trials, the Technical Guidelines for Vaccine Clinical Trials, and the Guidelines for the Classification of Adverse Events in Preventive Vaccine Clinical Trials.
this guiding principle represents only current views and understandings, and will continue to be revised and refined as research and understanding deepen.
. Considerations Before Clinical Trials For non-innovative vaccines, the effectiveness and safety of clinical use of similar vaccines that have been marketed should be fully evaluated in the development of research and development projects.
should usually be the first to compare the pharmaceutical and non-clinical aspects of a candidate vaccine (or experimental vaccine) with a listed vaccine (or a controlled vaccine), and the comparative data combined with clinical trial results to evaluate the comparability of the two vaccines.
acceptable limits for key quality standards items for the listed vaccine (e.g. antigen content/efficacy, virus titer, product and process-related impurities, etc.), it is necessary not only to determine based on pharmaceutical research data such as production process capability and stability research, but also to analyze and demonstrate the rationality of non-clinical research batches and results, approved results of registered clinical trial batches and safe and effective results of clinical trials.
therefore, the experimental vaccine that can be selected on behalf of the listed production shall be selected on behalf of the listed experimental vaccine to enter the registered clinical trial on the basis of the expected amplification of production scale, change of production process address, adjustment of production parameters and variation of key quality attributes of the product, and degradation of product shelf life.
recommendthe sized vaccines for use in key registered clinical trials (including enhanced immunity) for listing permits.
. General consideration for clinical trial design For non-innovative vaccines, the main purpose of clinical trials is to evaluate the vaccine's comparability in terms of safety and efficacy of the control vaccine.
the design of clinical comparability research programs in line with ethical and scientific requirements, but also to consider the recent epidemiological characteristics of disease (transmission pathways, morbidity, etc.), the application of similar vaccines on the prevention of disease epidemiological characteristics, vaccine application coverage and population immunization level.
when there are differences in immune procedures, immunogenicity characteristics, evaluation criteria, etc. in different populations, clinical trials should be designed separately to evaluate safety and effectiveness.
(i) Select edited vaccine for randomized controlled clinical trials 1. A controlled vaccine is a vaccine that has been approved for domestic market and is intended to be used as a reference control vaccine in clinical trials.
the selection of a controlled vaccine should take into account its adequate safety and effectiveness data and has been widely used in clinical practice.
should generally select the original research product as a control vaccine.
should provide a full and reasonable basis for selecting non-original research products.
principle, the same control vaccine (both pharmaceutical and non-clinical) should be used at all stages of the pilot vaccine development process to ensure the rigour of the analysis of the results.
control vaccine should comply with the relevant national laws and regulations, usually with China's approval and issuance of inspection reports and other necessary supporting documents, and antigen content / efficacy value determination.
also need to consider the consistency of the experimental vaccine and the control vaccine in the target population, immune procedures, vaccination pathways/methods, etc., and comprehensively analyze the effects of differences between the two on clinical data in seed batch (bacterial species, genotype and serotype), cell matrix, dosage form, pre-test antigen/efficacy test results, etc.
encouragethe use of evidence-based medicine to scientifically and objectively analyze the clinical research data of the proposed controlled vaccine and serve as a basis for the development of clinical trial plans.
for listed vaccines that involve changes in prescriptions and production processes, if clinical trials are required, the control vaccine should consider selecting a pre-change vaccine for a comparative study of the vaccine before and after the change.
2. Research vaccine management and quality control Clinical trial samples (i.e., research vaccines, including experimental and controlled vaccines) as required by regulations shall be clearly coded, easily identifiable and have a review inspection report or batch issuance report from a statutory laboratory testing agency, and the name, batch number, specification, date of preparation or production of the vaccine shall be consistent with the report.
establish a research vaccine compliance management system covering the reception, storage, preparation, recovery, return/destruction of vaccines, cold chain management of vaccines, and the disposal of vaccines with cold chain interruption, with detailed documentation and reflecting effective and traceable quality control measures.
blind test should maintain the blind state management throughout.
recommends simultaneous retesting of antigen content/efficacy on experimental and controlled vaccines used at the site of registered clinical trials.
trial and control vaccines should be as valid as possible.
the antigen content/efficacy determination results of the experimental vaccine can provide reference and accumulate technical data for the setting of the safety ceiling and lower limit of the project in its quality standard.
3. The immunogenicity replacement endpoint For most vaccines that have a clear correlation between immunogenicity and clinical protection effectiveness, immunogenicity may be used as the effectiveness evaluation alternative endpoint, and comparable judgments can be made using reliable laboratory testing methods and reasonable clinical effectiveness criteria.
in the absence of a reliable immunogenic alternative endpoint, clinical protective efficacy trials should normally be conducted, justifications should be given in the absence of protective efficacy trials, and other evidence of support registration should be given.
when the immunogenicity evaluation index is the main effectiveness determination endpoint, the representative subject population should be reasonably selected, and as far as possible with the target population of clinical application.
effective sample size should be determined according to the purpose of the experiment and the design of the study, and should also take into account the differences in immunogenicity detection methods and the degree of mutation of immune response in the subject population.
the development of immunogenicity-substitution endpoint evaluation criteria should take into account the baseline situation of the subject population, such as demographic characteristics, epidemiological background (vulnerable and non-vulnerable populations).
in order to accurately evaluate the level of immune response induced by vaccine, in the trial design should be based on the characteristics of the experimental vaccine, taking full account of the infection status of the population targeted by the vaccine in the region, in principle, should select the susceptible as the research object, and as the main evaluation population;
immunogenicity evaluation should also be based on a comprehensive analysis of the dynamic laws of the immune response of the control vaccine, select the time to better reflect the immune-immunity characteristics of this vaccine to collect biological samples, immune procedures and sample collection time should be consistent with the control vaccine, a comprehensive reflection of the experimental vaccine immunization success rate and immune persistence (or immune memory response).
if there is a clear long-term protective alternative endpoint and response level, in principle should be the main endpoint and the criteria for determination.
a body fluid-based vaccine, whose immunogenological replacement endpoint usually uses post-vaccination immune response rate (including antibody impotence rate, etc.) and antibody geometric mean titness (GMT)/geometric mean concentration (GMC) and its growth multiple.
in view of the rapid progress in immunology theory and detection methods, the simultaneous exploration of cellular immunology indicators is encouraged to reflect the vaccine-induced immune response more fully.
4. Safety Clinical trial scenarios should develop uniform safety evaluation standards and methodologies in the light of the corresponding guidelines issued by the National Bureau, and actively monitor and follow-up vaccine safety.
in principle, safety monitoring should last until at least 6 months after the last vaccination and, if necessary, long-term follow-up throughout the study population or in the study subgroup.
pilot programmes should pre-determine the time, follow-up and duration of post-vaccination safety monitoring.
determine the monitoring time based on the characteristics and type of vaccine, the active monitoring period of inactivated and recombinant vaccine is usually not less than 7 days, and the live vaccine for detoxification is not less than 14 days;
safety observations should contain at least adverse reactions, common adverse reactions, expected and unintended adverse reactions reported in clinical applications or literature of similar vaccines that have been listed.
safety analysis content generally includes overall adverse events, general adverse reactions, local/whole body (inoculation site/non-inoculation site) adverse reactions, other adverse events (adverse events unrelated to vaccines), individual symptoms (signs, diseases, clinical indicators, etc.), serious adverse events, etc.;
analysis indicators generally include the frequency and severity of occurrence.
should also be analyzed separately according to the time of occurrence, vaccination, subgroup (e.g. specific age group).
may closely monitor and report on sUSARs and potential safety risks associated with similar vaccine safety at home and abroad, and, if significant safety risk warnings or reports are in place, develop risk control plans and take necessary measures to protect the safety of subjects.
shall regularly summarize and analyze safety monitoring data in clinical trials in accordance with the relevant requirements.
(ii) batch (ii) batch (second) consistency clinical study of inter-batch (second) consistency clinical study, that is, the use of commercial scale products, through human vaccination of immunogenicity indicators to evaluate the quality of continuous batch of experimental vaccine stability and process repeatability, to ensure that the quality of registered on the market can be controlled.
generally, a sufficient batch of commercially produced experimental vaccines should be used first, with a sufficient pharmaceutical comparison of batch vaccines for consistency and quality stability of inter-batch production processes.
clinical comparative study of multi-batch consistency of experimental vaccines for experimental vaccines with high variability in production processes or some qualitative differences between products to be marketed and clinical samples.
batch consistency clinical study should include at least three consecutive batches of commercialized scale vaccines to demonstrate the clinical comparability of commercially produced vaccines with batch vaccines for clinical trials or marketed control vaccines, and to demonstrate each.