Under the COVID-19 crisis, China’s health regulators demonstrated unprecedented speed in providing approvals in mere weeks for needed medical devices, particularly for diagnostic test kits. Jiangsu provincial NMPA approved the first kit using nucleic acid detection on January 28, just two days after submission. Within two weeks, national NMPA had granted seven additional certificates, with 25 approved by April 1st (including 8 using antibody detection).
The criteria used to facilitate these expedited approvals could hold lessons for other diagnostics manufacturers seeking China entry. Much of that guidance comes from two documents the Center for Medical Device Evaluation (CMDE) published in February, “Technical Review Key Points for Registration of COVID-19 Nucleic Acid Detection Kit and “Technical Review Key Points for Registration of COVID-19 Antigen/Antibody Detection Kit.”(Editor’s Note: See earlier CMD articles on each of the above documents at the provided links.)
This article explores how the above documents served as a guide for both manufacturers and reviewers as NMPA balanced urgency with the need for IVD safety and efficacy.
NMPA approved two types of detection kits, each with features that affect how reviewers examine applications. One critical difference in these tests is how clinical samples are collected.
- For nucleic acid detection kits, samples are collected from the lower-upper respiratory tract, which includes pharyngeal swab, nasopharyngeal swab, alveolar lavage fluid, sputum, respiratory-tract lavage, respiratory-tract aspirate, and other respiratory secretions.
- The antigen/antibody detection kits use respiratory-tract samples (pharyngeal swab, alveolar lavage fluid, sputum, and other respiratory secretions); serum and plasma can also be used for virus detection.
Registration material must include all of the research data related to performance evaluation/verification, such as specific research methods, study plans, experimental data, statistical analysis, etc. The required registration documents for detection limit, compatibility of virus samples from different regions, analytical specificity, precision, verification material for in-house reference standards are described in detail in these two guidance documents. Review details at the R&D stage to make ensure necessary data is on file before the application process starts. Some of the key points include.
- To verify the detection limit, at least 3 different types of samples should be used and at least 90%-95% of the tested samples should show positive results.
- To verify the compatibility of virus samples, include samples from patients at different clinical stages as well as from different geographic regions
- For nucleic acid detection kits:
- Provide data about human genomic DNA to evaluate the analytical specificity
- Not only the substance originally in the sample such as blood, nasal secretions but also the nasal medications that possibly be used by the patients should be included for specificity verification.
- For antigen/antibody detection kits:
- Provide data about verification of cross-reactivity of human COVID-19 specific IgM and IgG antibodies at high concentration
- Include research data about the Hook Effect causing false results if the antibody/antigen concentrations are too high
- Include data about blood components for specificity verification if a blood sample is used
Study data for main raw materials
To meet NMPA requirements, applications must include research data about selection/source, preparation process and quality standards of main raw materials, as well as target value determination of quality controls.
If the applicant produces the materials, it should provide detailed information about the production process. If materials are sourced from suppliers, required documents include (though are not limited to) the determination basis for raw material selection, the quality standards provided by the supplier, the product COA, and quality inspection data after the raw material is delivered.
For both types of detection kits, the clinical evaluation shall be conducted in three or more clinical trial institutions (including the CDC at all levels). In addition, the verification process for test kits produced by different manufacturers ideally should be performed by the same clinical trial institution. Include patients at different clinical stages in clinical evaluation. For nucleic acid and antigen detection kits, only upper and lower respiratory tract samples are involved. For antigen/antibody detection kits, applicable samples can be whole blood, serum or plasma. Data from different sample types can be analyzed together only the manufacturer can prove no difference between sample types; otherwise, the statistical analysis should be performed separately.
The major difference between nucleic acid and antigen/antibody detection kits are summarized in Table 1.
Clinical sample size determination
As long as minimum sample-size requirements are met, applicants can estimate the sample size according to the characteristics of the products.
The recommended minimum sample size is:
- Confirmed cases: ≥200
- Excluded cases: ≥300
Calculation of the minimum sample size should be based on:
- Preset clinical evaluation indexes, such as clinical sensitivity and specificity
- Relevant statistical parameters
- Reasonable statistical models
The minimum sample size can be used only if the kit is for a single sample type (e.g. whole blood or serum). If the kit is for multiple sample types, and the manufacture cannot provide sufficient data to prove their equivalence, the clinical experiments need to be performed separately. For each experiment, the minimum sample size should be met.
Table 1. Differences Between COVID-19 Detection Kits: Nucleic Acid versus Antigen/Antibody