Guideline For Clinical Trials Of In Vitro Diagnostic Reagents (draft)
2021-06-22
Table of Contents I. Scope of Application …………………………………………………………………..2 II. Basic Principles………………………………………………………………………….2 (i) Ethical principle……………………………………………………………………2 (ii) Scientific principles ……………………………………………………………..3 (iii) Compliance principles…………………………………………………………3 III. Design of the Clinical Trial ………………………………………………………….6 (i) Clinical trial methods ……………………………………………………………6 (ii) Control of bias…………………………………………………………………….9 (iii) Subject selection ………………………………………………………………10 (iv) Number and requirements of clinical trial institutions……………13 (v) Selection of clinical evaluation indicators………………………………14 (vi) Statistical analysis of clinical trial…………………………………………15 (vii) Sample size requirements …………………………………………………18 IV. Clinical Trial Quality Management……………………………………………..22 (i) Pre-trial management…………………………………………………………22 (ii) Protection of rights and interests of subjects…………………………23 (iii) Clinical trial protocol …………………………………………………………23 (iv) Duties of all parties …………………………………………………………..24 (v) Records and reports…………………………………………………………..24 (vi) Management of reagents and equipment for clinical trials……..26 (vii) Document management……………………………………………………26 V. Others……………………………………………………………………………………27 2 /33 I. Scope of Application Clinical trial of the vitro diagnostic reagent is a systematic study of the clinical performance of the in vitro diagnostic reagent in the corresponding clinical environment.The objective of clinical trials is to determine the acceptability of the risk/benefit ratio of the product and the applicable population and indications of the product by examining whether the clinical performance of the product meets the use requirements or intended use. This Guidelines is applicable to clinical trials conducted in China with in vitro diagnostic reagents administered as medical devices and applied for registration in China. This Guidelines aims to clarify the basic principles of clinical trials, make principled recommendations for clinical trial design, identify the key factors to be considered in clinical trials, and put forward basic requirements for clinical trial management to guide the sponsor to conduct the clinical trial, and to provide reference for the review of clinical trial data by technical review departments. Because in vitro diagnostic reagent products have the characteristics of rapid development, large professional span and different intended clinical uses, the clinical trial methods and contents of different products are different.The sponsor should formulate a reasonable clinical trial protocol according to the specific conditions of the product. The contents of this Guidelines will also be revised in time according to the needs of the development of in vitro diagnostic reagents. II. Basic Principles (i) Ethical principle Clinical trials must follow the ethical guidelines set out in the Declaration of Helsinki made at the World Medical Congress. They should be examined and agreed by the ethics committee of the clinical trial institutions. If a clinical trial institution does not meet the ethical review requirements, the clinical trial should be 3 /33 examined and agreed by the regional ethical committee. The investigator should consider the risk of acquisition and test results of samples for clinical trials, such as blood, amniotic fluid, pleural fluid, ascites, tissue effusion, pleural effusion, tissue sections, bone marrow, etc. to the subjects and submit them to the ethics committee for review to ensure that the clinical trials do not place the subjects at unreasonable risk. (ii) Scientific principles The investigator should design clinical trials scientifically according to the intended clinical use of products, epidemiological background of related diseases and statistical requirements, and at the same time control test errors to the greatest extent, improve test quality and make scientific and reasonable analysis of test results.While ensuring that the test results are scientific, accurate and credible, we should try our best to ensure they are efficient, fast and economical. (iii) Compliance principles This Guidelines has been formulated within the framework of the Regulations for the Supervision and Administration of Medical Devices (Decree No. 680 of the State Council) and the Provisions for In-vitro Diagnostic Reagent Registration (Decree No. 5 of China Food and Drug Administration).Clinical trials of in vitro diagnostic reagents should meet the requirements of relevant regulations.
Clinical trial intuitions and personnel The clinical trial sponsor should choose the medical device clinical trial institutions that have filed in the “Medical Device Clinical Trial Institution Filing Management Information System” according to the requirements of the “Announcement of China Food and Drug Administration and National Health Commission on Issuing the Conditions of and Measures for the Administration of Filing of Medical Device Clinical Trial Institutions (No. 145 of 2017) for clinical trials. 4 /33 Clinical trials of in vitro diagnostic reagents should be carried out in several clinical trial institutions at the same time, and one clinical trial institution should be identified as the leader unit. The investigator in the leader unit is the coordinating investigator responsible for the coordination of the work among clinical trial institutions in the course of clinical trials, organizing investigator meetings in the early, middle and late stages of clinical trials and implementing the whole trial together with the sponsor. In vitro diagnostic reagent clinical trial institutions should possess the required professional and technical level, organizational and managerial competence, ethical review competence, test conditions, facilities and equipment for clinical trials.Specifically, it includes but is not limited to: routinely carrying out relevant testing and disease diagnosis and treatment items, having the ability to interpret the relevant diagnostic results and treat diseases, having the emergency mechanism and ability to prevent and deal with emergencies and serious adverse events in clinical trials, and having the subjects who meet the needs of clinical trials; having necessary laboratory testing conditions and facilities and equipment and meeting the relevant qualification requirements for testing laboratories (if any). The sponsor should select institutions with relevant disciplinary advantages to carry out clinical trials according to the characteristics of products and their intended uses, taking into account the population differences, epidemiological background and the characteristics of pathogenic microorganisms in different regions.Clinical trial institutions should be able to represent the type of institutions expected to use the product. Clinical trial investigators and participants should have the ability to design and implement relevant clinical trials, be familiar with relevant testing techniques, and be able to correctly interpret the test results.The person in charge of clinical trial statistics shall be a practitioner with relevant professional background and 5 /33 competence. Clinical trial investigators should understand the necessary clinical trial regulations and requirements.Clinical trial institutions should be able to ensure that relevant clinical trials are carried out in strict accordance with the scheduled protocol, and be able to cooperate in the product registration application process, including conducting necessary supplementary tests, cooperating in the authenticity verification of clinical trials, etc.
Clinical trial protocol and report Before the start of clinical trials, the sponsor should work with investigators from various clinical trial institutions to formulate a scientific and reasonable clinical trial protocol, which shall be strictly followed in the whole process of clinical trials after approval by the ethics committee.Once approved, the clinical trial protocol shall not be changed at will.Refer to Appendix 1 for the requirements for the contents of the clinical trial protocol.Each clinical trial institution should follow a unified clinical trial protocol, including clinical trial methods, subject selection, evaluation indicators, estimated sample size, statistical analysis methods and quality control requirements.In the protocol, the allocation plan of sample size is determined according to the situation of each institution. After the end of the clinical trial, the investigators in each clinical trial institution should summarize their own clinical trial data, provide a summary of the clinical trial, and attach the clinical trial data sheet and so on. See Appendix 2 for the summary and content requirements of the clinical trial. Leader unit should be responsible for collecting all clinical trial data, forming a clinical trial data summary table (content requirements are the same as the “clinical trial data table”), completing data statistical analysis, and issuing clinical trial reports.See Appendix 3 for the format and content of the clinical trial report. 6 /33 III. Design of the Clinical Trial Clinical trials should be designed scientifically according to the intended use of the product, the applicable population, the characteristics of the tested object and the method of using the product (e.g. user, result interpretation, sample type), including the selection of appropriate clinical trial methods, the determination of suitable criteria for selecting subjects and clinical evaluation indicators, etc.The conclusion of the clinical trial should be able to demonstrate that the clinical performance of the product meets the requirements of the intended use, and supports the relevant contents described in the instructions. At the same time, the clinical trial is the process of making statistical inferences about the subjects with similar conditions in the future based on the results of a limited number of samples collected from subjects.Therefore, in the design of the clinical trial, it is necessary to apply statistical principles to make reasonable and effective arrangements for the factors related to the trial, and to make a scientific and rational analysis of the trial results. Before conducting the clinical trial, consideration should be given to designing a pre-test of a small sample size. Especially for new in vitro diagnostic reagents or products with significant differences compared with similar products already on the market, pre-tests can be used to determine possible intended uses, applicable populations, clinical evaluation indicators, etc., and also to conduct a limited evaluation on the factors that may lead to bias and help to reduce the possibility that unexpected results will lead to changes in key design in clinical trials.Generally speaking, in order to make scientifically valid corroborative reasoning, pre-test data cannot be merged with research data in the clinical trial stage. (i) Clinical trial methods In general, clinical trials of in vitro diagnostic reagents should adopt the method of comparative study between in vitro 7 /33 diagnostic reagents and clinical reference criteria to evaluate the clinical sensitivity and specificity of in vitro diagnostic reagents, so as to prove that their clinical performance meets the requirements of intended uses.Clinical reference standards refer to the best methods available clinically under existing conditions to determine the target state of a subject (health status, disease status, disease progression, disease or health status guiding clinical management), usually from clinical and laboratory medical practice, including recognized under existing conditions, reliable and authoritative diagnostic criteria for diseases (such as histopathological examination, imaging examination, pathogen isolation, culture and identification, conclusions from long-term follow-up, etc.), diagnostic methods identified in disease diagnosis and treatment guidelines, consensus of experts in the industry or clinically recognized and reasonable reference methods, etc.The clinical reference standards may be a method or a combination of various methods. For an in vitro diagnostic reagent that has a similar product already marketed, in the clinical trial, the in vitro diagnostic reagent for testing and the similar product (contrast reagent) can be comparatively studied to prove that they are equivalent, thus indirectly proving that the clinical performance of the in vitro diagnostic reagent for testing meets the requirements of the intended uses.The contrast reagent should be comparable with the in vitro diagnostic reagent in the intended use, applicable population, sample type and testing performance. In order to evaluate the clinical performance of in vitro diagnostic reagents more comprehensively, the comparative study with clinical reference standards and the comparative study with similar products on the market can be combined in clinical trials to evaluate the intended use of the products and the testing accuracy of the tested object. For some cases where there is no clear clinical reference standard or similar products on the market at present, clinical 8 /33 trial investigators should establish a generally accepted and reasonable method for comparative study based on the existing clinical practice and theoretical basis. The selection of clinical trial methods should be based on the intended use of products, the nature of test results (qualitative or quantitative), and the availability of clinical reference standards and contrast reagents. The conclusions of clinical trials should be able to support the contents of the intended use description.For products with high risk, it is suggested that priority should be given to comparative study with clinical reference standards. The selection and basis of clinical reference standard or contrast reagent should be described in detail in the clinical trial protocol. The clinical trials of in vitro diagnostic reagent change registration generally adopt a comparative study between the products before and after the change; for cases where the performance of the product has changed significantly or the clinical indications have been added before and after the change, the method of comparative study with clinical reference standards or similar products on the market can also be used to prove the clinical performance of the product after change. For some in vitro diagnostic reagents, clinical trials may encounter situations requiring special consideration, such as:
For in vitro diagnostic reagents used by consumers, in clinical trials, besides evaluating the clinical performance of the test reagent, it is also necessary to evaluate the cognitive ability of users without medical background to the product instructions, and to prove the consistency of the test results between users without medical background and professional examiners.
