Common FAQ

In the clinical trial protocol, the basis for the determination of inconsistence between the investigational reagent and the comparator (similar product/reference methods etc.) in the clinical trial should be clearly explained. The inconsistent results should be comprehensively analyzed in the clinical trial to indicate whether it affects the evaluation of the clinical performance of the product. If samples with inconsistent results are confirmed using clinical reference standards or other appropriate methods, the confirmation results should not be used to change the original statistical analysis results. The clinical trial protocol should specify the clinical reference standards or other methods used for confirmation; the final confirmed result or judgment should be presented in the clinical trial report.

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In clinical trials of quantitative detection reagents, the results of the investigational reagent will be compared with the results from a similar NMPA-approved product or other reference methods. Regression analysis combined with Bland-Altman method can be used for consistence analysis of the results of quantitative detection.

Methods commonly used in regression analysis include Passing- Bland-Altman regression and Deming regression. In the statistical analysis, the regression coefficient and intercept, with confidence intervals, should be calculated. Hypothesis test can also be performed. Other evaluation parameters should be estimated at the same time, such as correlation coefficient or determination coefficient. If necessary, it is recommended to consider the difference in consistence performance for different concentration ranges, so as to perform stratified statistics.

Along with the regression analysis, the Bland-Altman method can be used to evaluate the consistency of the two test results by calculating the consistency limit. In particular, analysis is performed for consistency of test results near the level of medical decision. Consistency limits should be within clinically acceptable level.

In clinical trials of quantitative detection reagents, if the investigational reagent is compare

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After the type examination of the IVD reagents, the batch of the product used or not used in the type examination can be used for the clinical trials. There should be a clear statement in the report about the reagent lot number used in the clinical trial by each institution. If the clinical trial lasts a long time, or the number of reagents used for the clinical trial is large, more than one lot of the reagents may be needed to complete the clinical trial.

It should be noted that the products used for clinical trials, type examinations and analytical performance evaluations of IVD reagents should be produced under conditions that meet the requirements of the quality management system for medical device production, and the lot size should be sufficient.

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For the second and third category of IVD reagents, at least two or three clinical trial institutions should be included in the clinical trial. The distribution of samples among the institutions should be as even as possible, including the total sample size and subgroup sample size in each institution. If the product contains multiple indications for use, subjects for the evaluation of each intended use should be distributed as evenly as possible among the institutions; if the product covers multiple markers, positive samples of each marker should be distributed as evenly as possible among the institutions. The agreement study between different sample types from homologous subjects should be completed in at least two institutions in accordance with the regulations, and the distribution of samples between institutions should also be balanced. Samples from each institution for quantitative products should cover the testing range as much as possible, and for qualitative products, each institution should include a certain number of positive and negative samples.

If there are published technical guidelines applicable, clinical trials should also implement the requirements of corresponding guidelines. For example, it is required in the Technical Guidelines for the Registration of Pathogen-specific IgM Qualitative Detection Reagents that there should be no less than 30 patients infected by the pathogen in t

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In the clinical trials of IVD reagents, it is necessary to use samples of the subjects that meet the enrollment criteria for the clinical trial. At the same time, it should be noted that the sample collection, storage and transportation conditions should meet the requirements mentioned in the instructions for use. The operations of sample processing, testing, and data analysis in clinical trials should be as much as possible consistent with the clinical use process of the reagents after marketing. If the kit can only be tested on freshly collected samples in clinical use, freshly collected samples should be used for clinical trials. If there may be a sample preservation process during clinical use (such as frozen storage under certain conditions), and the corresponding sample storage conditions and expiry date are specified in the instructions for use, some samples under the corresponding storage conditions may be included in the clinical trial. It should be noted that the storage conditions and storage period of the samples in the clinical trial should be ensured to meet the requirements of the corresponding product instructions for use.

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 In the design of clinical trials, in addition to the total sample size, the sample number for positive group and negative group, the stratification and subgroup sample size should also be considered.

If the quantitative IVD kit has different reference intervals in different age groups, samples of the different age groups should be considered when enrolling subjects.

In the case where similar products have been approved, a certain number of subjects in each age group should be included in the clinical trial, and there should be a certain number of subjects in the normal range and abnormal range in each age group.

In the cases where there is not any similar product launched on the market, the number of subjects in each age group should meet the statistical requirements to confirm the established reference intervals.

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1. Requirements for subject selection.
   The subjects for IVD reagent clinical trials should come from the target population claimed for the intended use of the product. For example, an IVD reagent is intended to be used as an auxiliary diagnosis of a certain disease, so the subjects of the clinical trial should be a group of people suspected of having certain disease- related symptoms, signs, physiology, and pathological conditions or with an epidemiological background, including those people susceptible to confusing diseases. The enrolled subjects should be able to represent various characteristics of the target population, including people of all ages, different sexes, people with different symptoms, signs (such as typical and atypical symptoms), and in different disease stages. Consideration may also be given to including samples that may introduce interferences. As for the apparently healthy asymptomatic people, if they are not the target people for the intended use of the product, they should not be enrolled in large numbers except for the necessary specificity evaluation.
   It is recommended to briefly summarize the numbers of the subjects with different characteristics in the clinical trial report to indicate whether the test population can represent the target population well.
   All enrolled subjects should be unique and traceable.
   Samples in clinical trials should, to the extent possible, be collecte

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For some situations where a clinical reference standard does not exist or is not available, and, at the same time, there is still not any similar product approved in China, when designing a clinical trial, a widely accepted and reasonably used laboratory reference method may be chosen to be the comparator, such as DNA sequencing, GC-MS/MS and so on. These methods are not routine laboratory assays, requiring special equipment, instruments and test conditions which clinical trial institutions may not have.

In such cases, the sponsors should try to choose a clinical trial institution with appropriate conditions to perform the tests as much as possible. Some clinical trial institutions that do not have the testing conditions can entrust this part of the study to a specialized testing institution or a laboratory with a certain qualification, and verify if the test results can be accepted. All of the related dossiers should be submitted for registration, including certificate documents for the commission, methodological research data and quality control data of comparison methods. The laboratory of the sponsor should not be chosen to carry out the tests.

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 In clinical trials of IVD reagents, if Sanger sequencing is used as a comparator, the detailed information and data for the establishment and verification of Sanger sequencing methods should be provided as attachment to the clinical trial report. The specific content includes:

1. Informational content
   • Brief introduction of the principle of the sequencing method, sequencing instrument, sequencing reagent and other reagents needed.
   • Detailed description about the primers used in the sequencing, including selection of target gene sequence, primer design, etc., and the trial data for primer molecular weight confirmation, purity­evaluation, and functional verification.
2. Validation data
   • Evaluate the analytical performance of the established Sanger sequencing method, especially the LoD. It is recommended that the analytical performance of the established sequencing method and the investigational reagent should be compared and analyzed to confirm the established sequencing method being suitable as a comparator for the clinical trial.
   • Proper positive and negative controls

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 In order to confirm the clinical significance and testing performance of an IVD reagent, and to provide sufficient supporting evidence for the intended use of the product, ideally, in a clinical trial, the investigational IVD reagent should be compared with clinical reference standards for performance evaluation of the correlation between the test results of the in vitro diagnostic reagent and the target status of the subjects.

A clinical reference standard should be the best available method for establishing a subject's true status with respect to a target condition. Generally, the recognized, reliable and authoritative disease diagnosis standards under the existing conditions (e.g., the pathological result of a biopsy sample, imaging examination result, bacterial isolation and identification, conclusions from long-term follow-up, etc.) should be adopted. In the case of new detection indicators or other circumstances where there is no clear disease diagnosis standard that can be referred to, the disease diagnosis method specified in the disease diagnosis and treatment guidelines, or the consensus of experts in the industry or the clinically recognized and reasonable reference method, etc., can also be considered.

For clinical trials of IVD reagents with similar products already approved to be marketed in China (comparator product), the meth

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Clinical trials of IVD reagents should follow the ethical principles determined in the Helsinki Declaration of the World Medical Association and be reviewed and agreed by the ethics committee. For the registration of IVD reagents, the review document of the ethics committee to agree with the conducting of the clinical trial and the manuscript of the subject informed consent form (if any) should be submitted.

The original review document (but not a copy) of the ethics committee should be submitted, in which the following information must be made clear, including the approval of the conduct of the clinical trial according to the approved protocol, the version number and date of the approved protocol and the manuscript of the subject informed consent form, the principal investigator and the date permitting the clinical trial to be conducted. It should be noted that in the review document of the ethics committee the information about the product and clinical trial should be consistent with the actual situation, including the product name, sponsor, investigator and the version of the protocol and the manuscript of the subject informed consent form. If the clinical trial is exempted from the subject's informed consent after being reviewed, it should be clearly mentioned in the opinion of the ethics committee, and should be consistent with the actual situation of the clinical trial, avoiding situations, fo

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