临床研究总结报告结构与内容

兆科药业(合肥)有限公司文件编号:版本号:V4.0 SOP-MW-006 Relevant File NO.1 Structure and Content of Clinical Study Summary Report Structure and Content of Clinical Study Summary Report: ●Page 1(the contents of each title in page 1 should be listed in separate page) 1.Title Page Title page should includes:Generic name of investigation product, drug registration applicant(with seal), research type, research number, study initiation date, study termination date, principal investigator(with signature), study site(with seal), signature of responsible leader of statistics and seal of statistical company, contact information of application, report date, source information retaining site. 2.Table of Contents Present the table of contents and corresponding page number of clinical trial summary report. 3.Synopsis of Study Report Briefly introduce the accomplished study, and describe the results with meaningful data rather than written description and P-value. 4.Ethics-related Information Declare that this completed clinical trial is conducted in compliance with the ethical principles of medical research of human that have their origin in the Declaration of Helsinki, and that has received independent ethics committee/institutional review board approval, as well as the revision application. The approval document of ethics committee, the clinical trial information which is provided to subjects and the sample of subjects’ informed consent form should be provided. 5.Clinical Investigators The clinical trial principal investigator’s name, site, duty in this study and CV (is given in appendix) should be provided, as well as the principal investigators, participants, director of statistical analysis and the writer of clinical study final report. 6.Abbreviations The full names of abbreviations in study final report. ●Main text 1.Introduction 1 / 10 Introduce the background, foundation, appropriateness, target population of the investigational product, along with the current therapies and therapeutic efficacy. To document the basic of the conduct of this study, and the cooperation between declarer and clinical study site. 2.Trial Objectives The objectives to achieve of this clinical study. 3.Trial Management Description of the management structure, management process and the status of conducting in accordance with GCP, should include the information of the training for the participants as well as monitoring/audit, regulations of reporting adverse events, quality control of laboratories, statistics/data management, appropriate action for the problems occur during this study. 4.Trial Design 4.1Description of the Trial Design and Protocol The description should be concise and clear, if required, relevant graphs can be used to describe directly. A description of the trial design should include: treatment(drug, dose and use), subjects and the sample size, blinding(un-blinded, single-blinded, double-blinded), control types, trial design(parallel and crossover),methods of assigning( random, stratified), duration of the trial and the sequence( the time period between pre-randomization to termination of treatment; the time of treatment interrupting., single-blinding or double-blinding, randomization; to illustrate time arrangement directly by schematic diagram as possible), processing plan and interim analysis for data auditing, problems of safety or special cases. 4.2Consideration of Trial Design and Choosing Control Group d To describe the deterministic accordance and rationality of setting the control group. If control group has not been set, an explanation should be provided; detailed explanations for overcoming selection bias should be provided if without using randomization. To declare the rational consideration of trial-related drug washout period and dose interval. 4.3Selection of Subjects Illustrate the indications, inclusion criteria, exclusion criteria and deletion criteria. 4.4Trial Process Describe the applicable process and related information of the investigational product in detail. The name, specification, dosage form, source(s), batch number (should record each batch number of the investigational product(s) if more than one batch number is used), date of expiration and preservation condition of the investigational product should be provided, as well as the detailed description for the investigational product administration (includes reference(s) for dose determination, route of administration, dosage and administration time). Provide detailed description of the method and procedure of random assignment. To describe the procedure of blinding(label, blind table, emergency document, double-dummy technique), situation of emergent unblinding. Appropriate measures should be taken to prevent distinguishing the investigational product and comparator, and to insure blinding could be administrated during data auditing or interim analysis. A specific statement of control bias should be provided, if blinding is inappropriate or permitted. In addition to the investigational product, information of the other drug should be provided, including administration, prohibition, record and guidelines, as well as the evaluation for the regarding results of any effects on investigational product. Provide the details of actions to secure compliance of the subjects, such as investigational products accoun tability, subjects’ diaries. 4.5Parameters of Efficacy and Safety Detailed information should be provided about the parameters of efficacy and safety, laboratory examination, examination scheduling, examination methods, responsible staffs, flow chart, notes, definition of parameters and the tests results (including ECG, EEG, imaging tests and laboratory tests). The way of receiving adverse events data, criteria and handling of adverse events, should be provided. The primary criteria of endpoint for evaluating therapeutic effect should be illustrated clearly, the relevant evidence for determination (such as literatures, guidelines) should be provided, also, relevant evidence should be provided if substituted criteria is use, When measuring drug concentration, should specifies the sampling time of biological samples and the interval administration time, and the possible influence of diet, drug combination, cigarette, alcohol, coffee during the time the subjects receiving investigational product and sampling. Sample processing and measurement should be gone through by method validation, and explanation for special cases should be provided. 4.6Quality Assurance for Data Brief description of quality assurance procedure for guaranteeing the data is accurate and reliable should be provided, including the condition of monitoring/auditing, consistency of entered data, range of the values, logical checking, and the procedure of blind reviewing. When necessary, quality-control-related document should be provided, such as the source documents of consistency checking, range of values, rationality checking, blind reviewing, and the record of the communication of investigator(s) and monitor(s). 4.7Proposal of Statistics Handling and Sample Size Determination Should clearly describe the definition of analysis set(including Fully Analysis Set, Per Protocol Set(PPS), Safety Database Set, which are all determined by Intention To Treat Principle), types of trial (superiority, equivalence or non-inferiority), definition of primary indicator and secondary indicator, statistical analysis method for all kinds of parameters(the method and software should be recognized worldwide), the methods of evaluating therapeutic effects and safety. Should provide description which is focused on the way of analysis, comparison and statistical tests, and the handling of outliers and missing data, including descriptive analysis, parameter estimation, hypothesis testing, analysis of covariate (including the handling of central effect during multicentre trials). Should describe for the hypothesis of testing and treatment effect to be estimated, methods of statistical analysis and relevant statistical model. Treatment effect estimating should be provided with confidence interval along with calculation method. About the hypothesis testing, should specify to use whether one-side test or two-side test, the reasons for using one-side test should be provide. The definition of all kinds of primary and secondary indicators should be described clearly as well as the exclusion of some cases, along with reasons and detailed description. Calculation method of sample size, calculation procedure, the estimated value of statistics during calculating and its source. 4.8Amendment during Study Trial It is inadvisable to amend study protocol, if amendment is required, any amendments (such as changes of treatment groups, inclusion criteria, dosage, sample size), should be explained and has the approval of ethics committee. The amending time, reasons, procedure and whether it has filed should be described in detailed, as well as to demonstrate the effects for the evaluation for the results of the study. 4.9Interim Analysis To illustrate whether it has interim analysis, if has, should conduct in accordance with the definite study protocol and explain the calculation method of alpha spending function. 5.Results 5.1Subjects 5.1.1Inclusion of Subjects The number of the subjects involved could be described by chart, including the number of screening, randomization, subject completion and subject incompletion (including those withdraw, be removed, interrupt, and drop out). For the reasons of exclusion, incompletion(including visit missing, adverse effect, poor compliance), whether continue to visit after withdrawing, whether to conduct unbl inding when withdrawing, should be analyzed and described. Meanwhile, subjects’ demographic information and the other situation of drug combination should be described. 5.1.2Deviations From the Study Protocol Should describe all the deviations from inclusion criteria, exclusion criteria, subject management, subject evaluation and study procedure. Below should be listed in the report, summarized and analyzed: ?The subject(s) who is/are involved but not be eligible for inclusion in this study. ?The subject(s) who is/are eligible for the exclusion criteria but not yet to be excluded. ?The subject(s) who has/have received incorrect treatment or dosage. ?The subject(s) who take(s) prohibited medication(s) contemporarily. 5.2Evaluation of Efficacy 5.2.1Effects Analysis Data Set Should provide specific definition for the subjects who are involved in effects analysis, including the subjects who have received investigational product, completed the study in accordance with study protocol,or all the subjects who have specific compliance. Should analyze the fully analysis set in general. Should provide detailed description for those subjects who have received investigational product but not yet to be involved to effects analysis data set. 5.2.2Demography and the other Baseline Data To conduct comparable analysis between the trial group by demographic parameter and baseline characteristic data, in general, including the analysis of the fully analysis set which is confirmed by Intention to Treat Principle, and the analysis which is in accordance with protocol set. In multicentre trial, the comparability of each center should be compared. The analysis should includes, age, gender, human race, target disease inclusion criteria, disease progress, severity, clinical specific symptoms, laboratory examination, important prognostic indicator, diseases combined, past history, the other trial-influent factors(such as weight, antibody level) and the other relevant index(such as smoking, alcohol, special diet and menstruation). 5.2.3Compliance To summarize and analyze the measured compliance of each subject(对每个受试者依从性测量的总结及分析。) Should describe the methods/parameters of assurance and recording compliance, such as calculation of medication administration, daily diary card. 5.2.4Analysis of Effects To compare the difference by comparing primary effect index, secondary effect index, pharmacokinetic parameter. Should conduct benefit/risk assessment on each subject when necessary. To perform FAS analysis and PP analysis according to the protocol as stipulated in trial design. Should analyze the classification indicator and numerical index of protocol, provide description of definition basic for newly-setting classification indicator, and if possible, time process which is produced by effect also should be provided. Each branch center of multicentre trial should provide descriptive analysis results(brief summary of branch center), and hypothesis testing may not need to conduct if the sample size is limited. Branch center brief summary should be written by its principal investigator, along with the seal of that branch center and writer’s signature in the title page. The contents should include the relevant information of that center, situation of subject inclusion, deviations from trial protocol, baseline of e.g., demography, descriptive analysis of data, statistical description of primary therapeutic effect index and secondary therapeutic effect index, handling and descriptive statistics of generated adverse effects, comments for the clinical trial of the principal investigator from corresponding branch center. 5.2.5Brief Summary of Efficacy Briefly summarize the efficacy and clinical significance of investigation product by analyzing the primary and secondary therapeutic effect index. 5.3Evaluation of Safety The subject, who has received investigational products at least once, should be included into safety analytic set. Evaluation of safety has three parts, Part 1: subjects’ level of administering investigational product/exposure, which refers to the dosage, treatment period(s), and number of receiving investigational product; Part 2: to classify the common adverse event and laboratory index in a rational way, compare the difference between each group by using appropriate statistical analysis method, and analyze the possible factors (such as time dependence, dosage, concentration, demographic characteristics) of affecting the frequency of adverse effects/events; Part 3, serious adverse events and the other important adverse event (refer to those adverse events which need clinical procedure, such as stop to receive investigation product, reduce dosage and the other medical treatment) are determined by analyzing the subject(s) who withdraw the trial because of adverse event(s). The causal relationship between all the adverse events and investigational product should be specified. The present adverse event can be summarized by chart, for the adverse events that need to focus on, should provide detailed description. The adverse events of investigational product and control drug should be reported. 5.3.1Level of Administering Investigational Product/Exposure Administering investigational product/exposure time may be described by mean and median, and the number of subjects in some specific period, meanwhile the number of subjects of each sub-group may be listed by the items, such as age, gender, disease, etc. Dose of administering investigational product/exposure may be described by mean and median, also can be expressed as the number of subjects of daily average dose. Administering investigational product/exposure time and dose may be described conjunctively (e.g., the number of subjects in a dose group if the administering investigational product time is at least one month), in the mean time the number of subjects of each sub-group should be listed by the items, such as age, gender, disease. The drug concentration which is related to adverse events or laboratory testing abnormalities should be provided. 5.3.2Analysis of Adverse Event Should analyze all the adverse events of investigational product and control drug, and be illustrated directly by using graphs and charts, which should reveal the frequency, severity of adverse events, also the causal relationship of adverse events and drug administration, adverse events of each system. To compare the frequency of adverse events of treatment group and control group, preferably to compare separately in combination with the severity and causal judgment, if necessary, should analyze the relevance between adverse events and dose of administration, time of administration, feature of baseline and demographic characteristic, respectively. Serious adverse event and the important adverse event that principal investigator consider need to be reported, should be reported and analyzed additionally and attached with case report.. The attachment would provide the case report of each subject who has serious adverse event and important adverse event, including case number, demographic characteristic, details of the occurrence of adverse event (initiation time, duration, severity, treatment and the result) and judgment for causal relationship, etc. 5.3.3Safety-related Laboratory Examination According to professional judgment, it would eliminate the non-significant abnormalities that have not relationship with safety, besides, description for significant abnormalities of laboratory examination will be provided. Also, it would supply abnormal items list and the form for the analysis and statistics of treatment group and control group, and the discussion of the changing clinical significance as well as the relationship with investigational product. 5.3.4Brief Summary of Safety Provide overall summary to safety of investigational product, and focus on the adverse event that results in dose adjustment, requiring other treatments, investigational product discontinuation or death. Would present the possible significance of safety for the widely use in clinic of investigational product. 5.4Discussion and Conclusion Summarize the result of safety and efficacy of clinical study, also, discuss and measure the risk and benefit of investigation product. Briefly and repeatedly report the results are not permitted, as well as raise new result(s). The conclusion should provide evaluation of its significance and possible problems, description for the individual or population obtained benefits during treatment of and problems need to be noticed, and the significance for further study. 5.5Statistical Analysis Report Statistical analyses report, which is provided in appendices, includes, 1. Brief description for the information collection and arrangement of the procedure of the whole clinical trial, which includes objectives, study design, randomization, blinding, blinding review, definition of primary object and secondary objective, regulations of statistical analyses set, handling for missing values and outliers. 2.Accurate and complete description of statistical model, which includes, choosing statistical analysis software (should provide the full name and version of the statistical analysis software), the contents of statistical description, regulation for significant level, the choice its reasons for conducting hypothesis testing and establishing confidential interval. If data transformation has been conducted during the process of statistical analyses, rationale of data transformation, and explanation for the assessment of treatment response (base on the transformational data), would be provided. 3. Description of the characteristics of baseline for subject inclusion of each group, also the results of statistical tests. 4. Statistical description for each observation index (primary index, secondary index and composite index, index of comprehensive evaluation and substituted index) for each group and the results of hypothesis testing. Statistical description results of each observation time; also the test statistics and p-value of hypothesis testing would be provided; for instance, the results of t-test (which can be used to determine if two sets of data are significantly different form each other) should include the case number of each sample, mean value, minimum value, maximum value, t-value and p-value. When conducing analysis of variance for efficiently analyzing the primary index, at least should includes mean value and standard deviation of each site and analysis of covariance form (which would take each treatment, the factor of each site and baseline into analyzing). For the information of crossover design, including the information of treatment sequence and its number of subjects, each baseline at the beginning of each phase, washout period and its duration, the situation of drop-out in each phase and ANOV A table( for analyzing treatment, phase and the interaction of treatment and phase). 5. The safety evaluation of each group is mainly described by statistical description, including situation of administrating medication (duration, dosage and medication concentration), adverse event rate, detailed description of adverse event, the changes of laboratory tests results before and after the trial, abnormal changes and its relationship with investigational product. The results above should be indicated by statistical table and chart as much as possible, and the conclusion of statistical analyses should be illustrated by accurate statistics glossary. All the statistical calculation procedure should be save as a file so as to audit. 6.References Relevant references should be listed in accordance with V ancouver Style, and the copy of principal references should provide in appendix.