National Administration of Traditional Chinese Medicine Announcement on the Release of Technical Guidelines for Clinical Research on New Chinese Medicines for the Treatment of Influenza (No. 136, 2016)

　　To guide and standardize the clinical research of new Chinese medicines, the State Food and Drug Administration has organized and formulated the "Technical Guidelines for Clinical Research of New Chinese Medicines for the Treatment of Influenza", which are hereby released.

　　This is hereby announced.

　　Attachment: Technical Guidelines for Clinical Research of New Chinese Medicines for the Treatment of Influenza

　　Attachment

Clinical Research of New Chinese Medicines for the Treatment of Influenza

Technical Guidelines

　　I. Overview

　　Influenza, abbreviated as flu, is an acute respiratory infectious disease caused by influenza viruses. It has a high incidence rate and strong infectivity, and is easily prone to outbreaks or pandemics. Clinically, it is characterized by an abrupt onset, manifested by fever, fatigue, and general muscle aches, and may include symptoms such as nasal congestion, runny nose, and sneezing.

　　Influenza viruses can be divided into three types: A, B, and C. Type A influenza viruses are prone to mutation and are the main pathogens of human influenza, often causing pandemics and smaller epidemics. Type B influenza viruses mutate less frequently and can cause outbreaks or small epidemics. Type C influenza viruses are relatively stable and usually cause sporadic cases. Influenza has a certain seasonality. In northern China, the peak season generally occurs in winter and spring; while in southern China, it can occur throughout the year, with winter and spring and summer being the peak seasons. These guidelines mainly target drug research and development and experimental design for seasonal influenza A and B, and can also be used for influenza C.

　　According to the onset characteristics and clinical manifestations of influenza, it is similar to "Shixing Ganmao", "Fengwen", and "Shiyi" recorded in traditional Chinese medical classics. The etiology is mainly due to seasonal evils and epidemic toxins, often combined with seasonal six evils to cause disease; the pathogenesis is that evils invade the exterior, and the lung loses its function of regulating Qi. Common clinical syndromes include wind-heat invading the exterior syndrome, wind-cold binding the exterior syndrome, exterior cold and interior heat syndrome, and damp-heat stagnation syndrome.

　　These guidelines are general principles for guiding the design, implementation, and summary of clinical trials of new Chinese medicines for the treatment of influenza, and cannot replace the clinical practice of researchers. Because the types of influenza viruses prevalent in different years or regions may differ, and influenza viruses may also mutate, clinical manifestations, syndrome types, therapeutic principles and methods, etc., may vary. Therefore, clinical trials should be conducted in accordance with regulations and technical requirements, combined with the clinical background, prescription source, rationale, prescription characteristics, clinical positioning, and non-clinical research results of the research drug, to determine the objectives of the clinical trial, and based on the results of non-clinical research, combined with the progress of the discipline and clinical practice, in accordance with the requirements of Good Clinical Practice (GCP), with a scientific spirit and rigorous attitude, reasonably formulate clinical trial protocols to ensure that the safety and efficacy of the test drug can be evaluated.

　　It is important to note that the influenza referred to in these guidelines only includes naturally occurring cases; cases with unclear etiology are not included in these guidelines. At the same time, researchers must provide evidence of influenza outbreaks in the area during the study period, such as proof from the district (city) level or above disease prevention and control center (CDC) confirming the occurrence of influenza outbreaks in the local area. The materials should state the intensity of the influenza outbreak and the composition of the influenza virus strains during the study period to demonstrate the authenticity of the influenza outbreak in the subject's area.

　　The requirements set forth in these guidelines are only the relatively consistent views and understanding of the drug regulatory authorities at present, and have a phased nature; except for those stipulated in drug regulatory regulations and technical requirements, mandatory implementation is not required. If applicants can provide sufficient scientific evidence to show that the clinical research is scientific and reasonable, using methods and standards other than those in these guidelines will also be accepted. At the same time, with the development of medical science and medical practice, the means of disease diagnosis and treatment will continue to improve, and the requirements for clinical trials will also be updated accordingly. Therefore, these guidelines will also be updated and revised in a timely manner based on the progress of medical science, on a more scientific, reasonable, and generally accepted basis.

　　These guidelines do not discuss general principles of clinical trial design or statistical analysis; relevant requirements for these aspects can be found in relevant regulatory documents and the "General Principles of Clinical Research of New Chinese Medicines".

　　II. Key Points of Clinical Trial Research

　　The main purpose of new drug clinical trials is to explore or confirm the safety and efficacy of new drugs for the target indication population through clinical trials. In clinical trials of new Chinese medicines for the treatment of influenza, attention should be paid to the purpose and positioning of clinical trials, disease diagnostic criteria, inclusion criteria, trial design and research methods, dosage regimen, course of treatment and efficacy observation time points, efficacy observation indicators, safety research and evaluation, and statistical requirements.

　　(1) Purpose and Positioning of Clinical Trials

　　Clinical trials of new Chinese medicines for the treatment of influenza should be a series of research processes with clear objectives, scientific design, controllable quality, and standardized implementation. The primary issue in conducting clinical trials is to formulate research objectives based on non-clinical research results, clarify TCM syndromes, and determine the clinical positioning of new drugs.

　　The goal of clinical treatment of influenza is to alleviate symptoms, prevent and treat complications, and reduce mortality.

　　The clinical positioning of new Chinese medicines for the treatment of influenza can generally be considered from the following aspects:

　　1. Improvement of clinical symptoms for the treatment of influenza (non-severe patients), observing the degree to which the test drug controls the course of influenza (such as shortening the course) and alleviates related symptoms. Control of the course of influenza (such as shortening the course) mainly refers to shortening the duration of influenza symptoms/signs, i.e., the time from medication to alleviation or cure of symptoms such as fever, nasal congestion, sore throat, cough, muscle aches, fatigue, headache, chills and/or sweating. The degree of alleviation of influenza-related symptoms/signs mainly refers to the degree of improvement of symptoms such as fever, headache, muscle aches, and fatigue.

　　2. Antipyretic: For trials treating specific manifestations such as high fever caused by influenza, the degree of intervention in specific manifestations such as high fever should be reasonably evaluated under the premise of ensuring the safety of the subjects.

　　3. Inhibition of influenza virus: This mainly targets trials that inhibit influenza viruses, evaluating the intensity of the test drug's intervention against influenza viruses.

　　(2) Diagnostic Criteria

　　1. Diagnostic criteria for influenza are based on the "Diagnostic Criteria for Influenza (WS285-2008)". See the appendix for influenza diagnostic criteria.

　　Confirmation of influenza is mainly based on epidemiological history, clinical manifestations, and laboratory pathogen testing.

　　The main technical requirements for the pathogen diagnosis of influenza are:

　　The etiological detection methods for influenza include virus isolation, viral nucleic acid, antigen, and antibody detection. Virus isolation is the "gold standard" for etiological detection; viral antigen and nucleic acid detection can be used for early diagnosis; antibody detection can be used as a retrospective auxiliary diagnosis.

　　The types and methods of specimen collection, specimen preservation and transportation, specimen detection timing and methods should all comply with generally accepted standards or the corresponding requirements put forward by the management department. Serological detection methods should use standardized methods and provide supporting information for the detection.

　　Generally accepted detection methods that can provide conclusive virological evidence should be used; influenza virus isolation or viral nucleic acid detection is recommended. Rapid viral antigen detection methods can be used for screening when subjects are enrolled, but they cannot be used as conclusive evidence of virological positivity and influenza virus typing, and nucleic acid detection or virus isolation confirmation is still required. Rapid test reagents should meet industry standards.

　　In principle, all specimen testing should be conducted in the same laboratory. If testing needs to be conducted at a different location, it should be reviewed in a designated laboratory. The laboratories conducting the testing and review should have industry-recognized qualifications.

　　2. Traditional Chinese medicine syndrome diagnostic standards and compound preparations should conform to the basic principle of "syndrome-prescription correspondence", and generally accepted syndrome diagnostic standards should be selected. The more common traditional Chinese medicine syndromes for influenza are mainly wind-heat invading the exterior syndrome, wind-cold binding the exterior syndrome, exterior cold and interior heat syndrome, damp-heat stagnation syndrome, etc., however, due to the different types of influenza viruses (strains), seasons, and regions, there are certain differences in the types of clinical syndromes. Researchers can refer to clinical guidelines or expert consensus issued by health management departments based on the type of influenza prevalent at the time, clinical manifestations, the functions and indications of the experimental drug, and the characteristics of the target indication.

　　Traditional Chinese Medicine Syndrome Diagnostic Standards:

　　Wind-heat invading the exterior syndrome: In the initial stage of the disease, fever or no fever, sore throat, mild cough with little phlegm, slight sweating; red tongue, thin or slightly greasy coating, floating and rapid pulse.

　　Wind-cold binding the exterior syndrome: In the initial stage of the disease, aversion to cold, fever or no fever, body aches and headache, clear nasal discharge, no sweating; light red tongue, thin and moist coating, floating and tight pulse.

　　Exterior cold and interior heat syndrome: Aversion to cold, high fever, headache, body aches, sore throat, nasal congestion, runny nose, thirst, red tongue, thin or yellow coating, rapid pulse.

　　Damp-heat stagnation syndrome: Fever, thirst, fatigue and soreness of limbs, headache, chest tightness, abdominal distension, fullness and nausea, loose stools, red tongue with yellow greasy coating, slippery and rapid pulse.

　　(3) Subject Selection

　　Because influenza epidemics have seasonal and regional characteristics, subject selection should consider different regions and ensure representativeness.

　　1. The inclusion criteria are confirmed cases of influenza, and the diagnostic standards for traditional Chinese medicine syndromes corresponding to the prescription are selected. For age selection, researchers can determine the age range of enrolled subjects according to research needs. If studying special effects such as antipyretic effects, the appropriate subject body temperature characteristics or disease conditions should be determined based on the specific situation of the subjects. Because influenza is a self-limiting disease, the duration of the included cases should be specified.

　　2. Exclusion criteria Exclusion criteria should be reasonably formulated based on the characteristics of the drug, the target indication, and ethical factors. Subjects with complications and other systemic diseases should be excluded. Pregnant or lactating women, those with allergic constitutions or a history of drug allergies, and those who have received influenza vaccinations within one year should not participate in the study.

　　3. Placebo control Because influenza is a self-limiting disease, for influenza patients (non-severe patients), placebo-controlled clinical trials are recommended based on medical ethics.

　　If a positive drug control is used, the drug must have sufficient evidence of efficacy and comparability with the experimental drug in terms of functions and indications.

　　(4) Withdrawal or Termination Criteria

　　Subject withdrawal: Based on the clinical characteristics of influenza, strict termination criteria and emergency handling measures should be established. If the subject's condition worsens or complications occur during the trial, or if a serious adverse event occurs, the subject should generally withdraw from the trial and necessary treatment measures should be taken. Before the start of the trial, the sponsor should formulate specific criteria for deciding whether a subject should withdraw if their condition deteriorates, and discuss and approve them with the researchers. In addition, according to the informed consent form, the subject has the right to withdraw from the trial midway, or if the subject does not explicitly withdraw from the trial but no longer receives medication and testing and is lost to follow-up, this also constitutes "withdrawal" (or "dropout"), and the reasons for withdrawal should be understood and recorded as much as possible. Regardless of the reason, for cases where the researcher or subject decides to withdraw from the trial, the original medical records and case record forms should be retained, and the results of the last test should be used as the final results, and the efficacy and adverse reactions should be analyzed using the full dataset.

　　Trial termination: The clinical trial should be terminated immediately under the following circumstances: serious safety issues occur during the clinical trial, the researcher believes that the safety of the subjects may be at risk; major errors are found in the clinical trial protocol during the trial, making it difficult to evaluate the drug effect; the clinical protocol design is good, but important deviations have occurred during implementation, making it difficult to evaluate the drug effect, etc.

　　(5) Treatment Duration and Observation Time Point Design

　　Set a reasonable treatment duration and observation time points based on the purpose of the clinical trial, the characteristics of the drug prescription, and the characteristics of the changes in the main efficacy indicators.

　　For trials aimed at improving clinical symptoms, the duration of the enrolled subjects should be within 48 hours. With the degree of relief of related symptoms as the main objective, the treatment duration is 3-5 days. If the main objective is to control the course of influenza (such as shortening the course), the medication duration can be appropriately extended. Subjects complete diary card registration during the trial.

　　For trials aimed at antipyretic effects, the body temperature of enrolled subjects should be above 39°C, generally considering the course of the disease to be within 24 hours, the treatment duration is 1-3 days, and the immediate antipyretic time and the time for body temperature to return to normal can be observed. Reasonably formulate body temperature monitoring time points.

　　For trials aimed at etiological observation, the treatment duration should be determined based on the etiological and onset characteristics of influenza that year, generally 3-6 days, with a 3-day follow-up. It can also be reasonably determined based on the actual situation.

　　Subject symptoms/signs, degree of relief, etc., should be recorded in the subject's diary card.

　　(6) Efficacy Evaluation

　　Determine the primary and secondary efficacy indicators based on the purpose and positioning of the clinical trial.

　　1. For trials aimed at improving clinical symptoms, if the control of influenza course (e.g., shortening the course) is observed, the primary efficacy endpoint is the time required for influenza recovery or relief, i.e., the time required for the disappearance or alleviation of symptoms such as fever, nasal congestion, sore throat, cough, muscle aches, fatigue, headache, chills and/or sweating. If the degree of relief of related symptoms is observed, the primary efficacy endpoint is the degree of relief of the main symptoms in different syndromes.

　　Symptom relief assessment: Represented by the area under the curve (AUC) of the symptom score decrease from the patient's diary card. The daily decrease in the total score of observed symptoms is calculated, plotted against time (h) using the median, and the AUC is calculated for subsequent statistical comparison.

　　2. For clinical trials focused on high fever, the time to defervescence should be used for evaluation.

　　3. For trials focused on pathogen observation, the nucleic acid test index turning from positive to negative is used as the primary efficacy evaluation index.

　　4. For trials focusing on other special manifestations, corresponding evaluation indicators should be designed, such as reducing the incidence of complications and hospitalization rates.

　　5. For the efficacy evaluation of Traditional Chinese Medicine (TCM) syndromes, the integral value calculation of TCM main symptoms + secondary symptoms can be considered. That is, the syndrome efficacy judgment standard integral value decrease: clinical cure: ≥95%, marked effect: ≥70%, effective ≥30%, ineffective: less than 30%.

　　(7) Safety evaluation

　　For safety evaluation, attention should first be paid to general condition, vital signs (body temperature, respiration, heart rate, blood pressure), routine blood, urine, and stool tests, liver and kidney function, and electrocardiogram. Second, in addition to the above indicators, corresponding safety indicators should be designed according to the purpose of the trial and the potential safety issues of the test drug, and reasonable visit time points should be set.

　　If adverse reactions or abnormal laboratory indicators occur during the trial, the patient's condition should be observed promptly, and re-examination and follow-up should be carried out for comprehensive analysis.

　　Adverse events should be reported seriously. At the same time, attention should be paid to the contraindications, precautions and dietary aspects of the test drug.

　　(8) Concomitant medication

　　It should be noted that during clinical trials, symptomatic treatment and medication should be selected purposefully based on the different research objectives. Drugs that interfere with the research objectives should be avoided. If therapeutic drugs that affect efficacy evaluation are used, it is recommended to statistically count the efficacy as invalid cases, and the therapeutic effect should be "ineffective".

　　If the subject has previously taken drugs to control chronic diseases, such as antihypertensive or antidiabetic drugs, the medication situation should be truthfully recorded during the trial, and the impact of concomitant medication on the safety and efficacy evaluation of the trial drug should be minimized or avoided in the study.

　　(9) Quality control of the trial

　　In order to ensure the consistency of the study, blinding operation is implemented during the study, subjects are randomly assigned to groups to reduce selection bias, and balance and comparability are achieved. Attention should be paid to dropouts and loss to follow-up. Investigators should truthfully report the actual situation of dropouts and loss to follow-up, and should not arbitrarily exclude corresponding cases, as the changes in the condition of these subjects may include adverse reactions to the trial drug.

　　(10) Statistical methods

　　It should meet the general requirements of statistics. The sample size design should be calculated according to the requirements of statistics and regulations (if any), and there should be relevant data on the efficacy of the research drug in advance. It can refer to the efficacy of the drug in treating other types of influenza before, or the data of pilot tests of the drug efficacy.

　　(11) Follow-up

　　Depending on the purpose of the trial, the method, time point, and content of follow-up will be determined.

　　Three, References

　　1. Diagnostic criteria for influenza, People's Republic of China health industry standard (WS285-2008)

　　2. Guiding principles for clinical research of new Chinese medicines (trial), China Medical Science and Technology Press, 2002

　　3. Guidelines for the diagnosis and treatment of influenza (2011 edition). Chinese Journal of Tuberculosis and Respiratory Diseases, 2011, 9(5): 725-734

　　4. Treatment plan for influenza A H1N1 (2010 edition). International Journal of Respiratory Diseases, 2011 31(2): 81-84

　　5. GB/T 16751.2-1997 TCM clinical diagnosis and treatment terminology

　　6. Li Longyun, Cai Baiqiang, Wang Mengzhao, Zhu Yuanjue. Multicenter clinical study of oseltamivir phosphate in the treatment of influenza. Chinese Journal of Internal Medicine, 2001, 40(12): 838-842

　　Four, Appendix

　　Diagnostic criteria for influenza [Diagnostic criteria for influenza (WS285-2008)]

　　1. Diagnostic basis

　　(1) Epidemiological history

　　During the local epidemic season (such as winter and spring in northern China, winter and spring and summer in southern China), a large number of upper respiratory tract infection patients appear in a unit or region, or there is a significant increase in upper respiratory tract infection patients in outpatient and emergency departments of hospitals.

　　(2) Clinical manifestations

　　① Usually manifested as sudden high fever (axillary temperature ≥38℃), chills, headache, dizziness, body aches, fatigue and other toxic symptoms, and pharyngalgia and dry cough, but catarrhal symptoms are often not obvious.

　　② A few cases have decreased appetite, accompanied by abdominal pain, abdominal distension, vomiting and diarrhea.

　　③ A few cases may also develop complications such as sinusitis, otitis media, laryngitis, bronchitis, pneumonia, and even respiratory and circulatory failure leading to death.

　　④ In children under two years old, or those with pre-existing chronic underlying diseases, there may be decreased breath sounds, moist rales or wheezing in both lungs, but no signs of pulmonary consolidation.

　　⑤ Chest X-ray examination in severe patients may show unilateral or bilateral pulmonary parenchymal lesions, and a few may be accompanied by pleural effusion.

　　⑥ The total number of white blood cells in peripheral blood is not high or low, with a relative increase in lymphocytes. Severe patients often have decreased total number of white blood cells and lymphocytes.

　　(3)Laboratory Tests

　　① Influenza virus isolated and identified from respiratory specimens of the subject.

　　② Antibody titer against influenza virus in the convalescent-phase serum of the subject is 4 times or more higher than that in the acute-phase serum.

　　③ Positive nucleic acid test specific for influenza virus or detection of specific virus in the respiratory specimens of the subject.

　　④ After virus propagation for one generation in sensitive cells from the collected specimens, positive nucleic acid test specific for influenza virus or detection of specific antigen.

　　2. Diagnostic Principles

　　During the non-epidemic season of influenza, it is difficult to distinguish influenza from diseases caused by other pathogens, especially respiratory pathogens, based on clinical manifestations alone. Confirmation of influenza cases often requires laboratory diagnostic evidence. However, during the influenza epidemic season, when a large number of subjects with upper respiratory tract infections appear in a local unit or area, or when there is a significant increase in subjects with upper respiratory tract infections in hospital outpatient or emergency departments, those with corresponding clinical manifestations can be considered as clinically diagnosed influenza cases.

　　3. Diagnosis

　　(1) Clinically Diagnosed Cases

　　Subjects with any of the clinical manifestations in diagnostic criteria (1) and (2).

　　(2) Confirmed Cases

　　① Influenza-like illness and any of the diagnostic criteria in (3).

　　② Clinically diagnosed cases with any of the diagnostic criteria in (3).

　　State Food and Drug Administration

　　September 29, 2016