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
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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
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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.
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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
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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.
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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
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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
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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.
