Release of technical guidelines for clinical research of TCM new drugs with syndrome

Today (November 6), the official website of the State Food and Drug Administration (SFDA) updated the notice on the release of technical guidelines for clinical research of new TCM drugs with syndromes (No 109, 2018) In order to inherit and carry forward the characteristics and advantages of diagnosis and treatment of traditional Chinese medicine, improve the technical evaluation system in line with the characteristics of traditional Chinese medicine, and implement the relevant provisions of the measures for the administration of drug registration and the supplementary provisions for the administration of registration of traditional Chinese medicine, the State Drug Administration has organized and formulated the guiding principles for clinical research technology of new TCM syndromes, which are now published Annex: 1 The guiding principle of clinical research technology of TCM new drugs of syndrome type syndrome (syndrome for short) is a high-level summary of the etiology, disease nature, disease location and disease situation of the disease (generally referring to non-health) at a certain stage The specific performance is a group of internally related symptoms and signs, which is the basis of clinical diagnosis and treatment of TCM In order to better inherit and carry forward the characteristics and advantages of traditional Chinese medicine, the State Drug Administration, in accordance with the relevant laws and regulations on drug registration, has specially formulated the guiding principles for clinical research technology of TCM new drugs with syndromes (hereinafter referred to as the guiding principles) Syndrome new Chinese medicine refers to the new Chinese medicine compound preparation which mainly treats syndrome The guiding principles are intended to provide basic guidance for the clinical trials, effectiveness and safety evaluation of TCM syndromes Each principle requirement in the text can be further enriched and developed into more detailed and specific technical standards with the continuous deepening of follow-up research 1、 The prescription sources and basic requirements of new TCM syndromes should come from clinical practice, conform to the theory of TCM, and embody the principle of consistency of theory, method, prescription and medicine There should be sufficient documentary materials of human use history for clinical trials of TCM new drugs of syndrome type, including the source of prescription, the rationality of prescription, clinical application (including the evolution process of providing clinical practice to improve the prescription), the main treatment of function, usage and dosage, etc For example, the new TCM drugs of syndrome type to be developed are from the accumulation of clinical experience of TCM For the common clinical basic syndromes, relevant certificates shall be provided; for the relatively mature and effective prescriptions found in the comparative analysis and research of medical cases, typical medical cases and series of medical cases shall be provided; for the mature and effective prescriptions with certain clinical research basis and corresponding data proof, relevant certificates shall be provided For the relevant clinical research summary report, the specific TCM syndromes, efficacy characteristics and safety information should be specified in the summary report; if the clinical research results originated from the national science and technology project, the summary data and related results identification materials of the clinical research part should be provided When establishing and developing new TCM drugs of syndrome type, we should pay attention to the evaluation of the difference between the clinical value of the drugs and the same drugs on the market, so as to determine whether they have the clinical development value 2、 The clinical location of new TCM syndromes new TCM syndromes should be located in eliminating, improving or controlling the main clinical symptoms and signs of a group of diseases with internal relevance, and also in achieving the purpose of disease treatment through syndrome improvement 3、 Syndrome diagnosis of TCM new drugs of syndrome type the determination of TCM syndrome of new drugs to be developed should be based on clinical practice and follow the theory of TCM TCM syndrome diagnosis standards can be formulated by referring to relevant national standards, industry standards or group standards If there is no applicable diagnosis standard, it can be formulated by itself and reach consensus through expert argumentation The components of syndrome diagnosis can be qualitative or semi quantitative, or primary and secondary disease, encourage the development of syndrome diagnosis scale with Chinese characteristics, and can be supplemented with objective diagnosis indicators according to specific research content 4、 Basic research ideas and experimental design of new TCM syndromes (I) basic research ideas There are many models for clinical research of new TCM syndromes, such as pure TCM syndrome research model, TCM disease syndrome combination research model or TCM syndrome integration western medicine disease research model No matter what research model, the research of new TCM syndromes should have a clear definition of the dynamic change rule of the studied syndromes and the specific stage of related western medicine diseases 1 Select a suitable group of people who meet the diagnostic criteria of TCM syndrome for the study of TCM syndrome alone, and observe the improvement of symptoms, signs and related indicators of TCM Syndrome by drugs 2 On the basis of meeting the diagnosis standard of a disease in traditional Chinese medicine, select a syndrome of the disease to study, and observe the improvement of the symptoms, signs and related indicators of the syndrome by drugs 3 Combination of syndrome and disease Under the guidance of TCM diagnosis and treatment thinking mode of "treating different diseases with the same treatment" and "treating diseases with syndrome", based on the occurrence and development of different diseases in a certain stage with the same pathogenesis characteristics and similar syndrome elements, at least three different Western medicine diseases can be selected under the same syndrome for research, highlighting the design concept of syndrome as the center, observing the curative effect of drugs on TCM syndrome and Western medicine The efficacy of the disease （2） Design considerations 1 The formulation of inclusion criteria should take into account the purpose of clinical trials and the implementation process, including the provisions of relevant diagnostic standards, and the subjects' baseline consistency in terms of condition, course of disease, etc It is suggested that the patients with stable symptoms and basic treatment should not be included in the dynamic adjustment stage of basic treatment We should pay attention to the relationship between syndromes and Western medicine treatment when we include western medicine diseases The test designer can make reasonable inclusion criteria according to the needs of the test Subjects should voluntarily participate in the clinical trial with full informed consent 2 The exclusion criteria should exclude the population of other syndromes that affect the diagnosis of target syndrome or the judgment of syndrome efficacy The exclusion criteria should be considered based on the safety of the subjects The situations that may lead to the concealment of the progress of the disease by improving the symptoms should be excluded The specific population that will have serious consequences or accelerate the progress of the disease after taking the medicine should be excluded 3 A variety of experimental designs can be used for exploratory research of experimental design according to the purpose of the experiment Confirmatory research should follow the principles of random, double-blind, control and repetition, and estimate the sample size based on the preliminary results of exploratory research If the loading design is adopted, the basic treatment must be specified in advance, such as the indication, type, dosage, method and time of the basic treatment 4 Placebo should be the first choice for the control drug If a Chinese patent medicine for the syndrome has been listed, the Chinese patent medicine recognized in the industry can be selected for positive control, but the effectiveness of the medicine must be confirmed by placebo control Placebo should be as close as possible to the test drug in terms of dosage form, appearance, smell, taste, texture and other characteristics, so as to ensure that clinical researchers and subjects conduct research in a blind state If positive drug control is used and dosage forms are inconsistent, double blind and double simulation technology shall be used to ensure blind implementation If the clinical research involves multiple western medicine diseases, it should be combined with the disease situation included, and adopt stratified random, so as to ensure that the baseline between groups is comparable, so as not to affect the efficacy evaluation of drugs 5、 The observation time and course of treatment should be set reasonably according to the characteristics of drugs and the information of previous studies, and the way, time and content of follow-up should be designed scientifically according to the different research purposes 6、 To evaluate the efficacy of TCM new drugs, we should adopt the scientific and accepted evaluation standard of TCM syndrome efficacy, determine the main efficacy index and secondary efficacy index according to the research purpose, and pay attention to the clinical value evaluation of syndrome efficacy To improve the target symptoms or signs, the disappearance rate / recurrence rate of the target symptoms or signs, or clinical control rate should be used as the efficacy evaluation index, but at the same time, we should pay attention to the evaluation of the recovery time and / or onset time of the target symptoms or signs 2 2 It is suggested to introduce the outcome indicators of patients' report, and combine patients' self-evaluation with doctors' other evaluation 3 Encourage the use of objective response indicators that can reflect the efficacy of syndromes for evaluation Objective indexes of syndrome efficacy include physical and chemical indexes and biomarkers in modern medicine During the clinical trial, it is necessary to observe and evaluate the onset time, remission time or disappearance time of TCM syndrome efficacy 4 Based on the consideration of quality of life or living ability and improvement of adaptability, it is recommended to adopt the universal or specific scale of quality of life or living ability and adaptability to evaluate the curative effect The therapeutic effect evaluation tool of TCM syndrome based on scientific principles can also be used 5 Encourage the use of outcome indicators or alternative indicators reflecting the disease for efficacy evaluation 7、 Safety evaluation safety evaluation can be evaluated in combination with the subject's disease-related examination, such as some physical and chemical examination indicators that can reflect the progress of the disease; safety evaluation must reflect the safety of the test drug by parallel control with placebo or positive drug During the clinical trial, researchers need to pay attention to the changes of TCM syndromes and the progress of disease, and timely assess the possible medication risks 8、 Experimental quality control and data management (1) information collection of TCM four diagnosis information collection is the necessary means of modern TCM syndrome research, and the information collection of TCM data is conducive to the quality control of clinical trials It is suggested that the information collection of the four diagnosis of traditional Chinese medicine should refer to the latest "four diagnosis operation specifications of traditional Chinese medicine (TCM diagnosis branch of the Chinese society of traditional Chinese Medicine)", according to which researchers should formulate and strictly implement the "four diagnosis information collection standard operation procedures (SOP)" Before the clinical trial, we should carry out standardized training of four diagnosis information collection in each clinical research center, and evaluate the consistency of the four diagnosis information collection of researchers in each clinical research center Four diagnosis information collection should follow the objective principle Its information collection tools can be paper-based collection tables, or image and text collection system based on computer software, and even the application of traditional Chinese medicine artificial intelligence and cloud computing in the future The four diagnosis information collection table / system can be universal or specific, and presented in the form of quantitative evaluation It is encouraged to introduce a more mature four diagnosis information acquisition instrument approved by the state for listing, such as tongue diagnosis instrument, pulse diagnosis instrument, etc., which should have the function of real-time display, storage and re reading, which is conducive to the traceability of clinical trial data （2） The sponsor and researcher of data management should strengthen the data management, and suggest that an independent data supervision committee should be set up for clinical research projects of TCM syndromes, and encourage researchers to collect data through electronic data collection system to ensure the authenticity and reliability of research data In addition, clinical research projects should develop clinical trial risk control plans and measures, clinical trial data management plans and reports, data verification plans and reports, statistical analysis plans and reports, etc., to promote the overall quality control level of clinical trials of TCM syndromes （3） The main researcher of the researcher must be a person with a senior technical title or above in the major of traditional Chinese medicine or integrated traditional and Western medicine The researcher must have the associate senior technical title of TCM or integrated traditional Chinese and Western medicine 9、 The principle of writing the instruction manual: the content of the instruction manual [function indications] of TCM new drugs with syndromes should conform to the terminology of TCM, and the content of the item [clinical trial] will support the listing of the medicine