What Are The Common Problems About The Subject Enrollment And Sample Size In Clinical Trials Of IVD Reagents?
2023-03-10
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 collected prospectively in accordance with the clinical trial protocol. If necessary, the retrospectively collected samples can be partially included under the premise of strict control of selection bias, for which relevant information of the subjects should also be ensured to be complete and traceable. Explanation of reasons for using retrospective samples in the clinical trial protocol is recommended.
General requirements for the sample size of IVD clinical trials. The sample size of IVD clinical trials should meet the statistical requirements and the basic requirements in the Technical Guidelines for the Clinical Study of In-Vitro Diagnostic Reagents. If there are applicable technical review guidelines for special products, the requirements in them for the sample size should also be met. For quantitative detection reagents, there should be a certain number of samples at different concentrations in the reporting range, especially the samples at the medical decision level. For qualitative detection reagents, a certain number of samples near the cutoff value should be included.
Sample size for a multi-marker assay. For a multi-marker assay, the clinical performance of each marker should be evaluated separately. In the clinical trial report, statistical analysis should be made separately for each marker, so the total number of samples for each marker must meet the statistic requirements. The specific requirements for the number of samples may be mentioned in the relevant guidelines which should be referred to. For each subject sample, test results for all markers should be obtained at the same time. Therefore, each sample test can produce a positive or negative result for different markers.
Sample size for multi-genetic-mutation detection products. For multi-genetic-mutation detection products, the total sample size must meet the minimum statistical requirements and related technical guidelines. Depending on the product designs and the specific purpose of the clinical trial, the positive sample size for specific mutation types may vary. For the purpose of detection performance evaluation for gene mutation detection, if the diagnostic reagent can detect multiple gene mutations at the same time, but cannot identify each mutation, the total number of positive subjects should meet the statistical requirements, of which, each type of mutations (identified by appropriate methods) should have some positive cases. If the diagnostic reagent can identify different genetic mutation types, the number of positive subjects for each type should meet the statistical requirements. For the purpose of confirming the clinical significance for the genetic mutation test (i.e., the evaluation of the correlation between genetic mutations and the target condition of the subject), in principle, the clinical significance of each mutation type should be confirmed separately and the sample size should meet statistical requirements separately. If some genetic mutations have the same biological function (e.g., various deletion mutations in the same exon), the total number of these genetic mutations should meet the statistical requirements.
About the sample size for different sample types in clinical trials. For the IVD products applicable to different sample types, if the different sample types claimed by the product have good comparability, such as serum and plasma, one sample type (the main sample type) of them can be chosen for a complete clinical performance evaluation, of which the sample size should meet the requirements of statistics and the Technical Guidelines for the Clinical Study of In-Vitro Diagnostic Reagents. At the same time, other comparable sample types should be used to conduct agreement study with the homologous main sample type in at least 2 clinical trial institutions, in which the number of samples should meet the requirements of at least 200 for the products of the third category and at least 100 for the products of the second category. If there are significant differences between sample types, for example, differences in clinical performance, target population, indications for use, expected value, etc., clinical trials should be completed for each sample type separately, and the sample size should meet the statistical requirements separately.
