The NMPA granted Class II approvals to Roche’s Vitamin K Antagonist Self-Test, the combination of CoaguChek INRange and CoaguChek XS PT Test PST, and issued two review reports.
The published review reports like this one serve as important references for you to understand what the regulatory authorities are thinking and evaluating during their review process. We have been following the list for the past several years and review the relevant ones for our clients’ specific products to gain more clarity and be more efficient in their submission and approval process. As NMPA standardizes and streamlines the review process for fast-track approval, domestic and overseas players can benefit from our expertise and experience.
Below report is for CoaguChek XS PT Test PST, the IVD reagent.
Product overview
- Product structure and composition
- Intended Use
The product is intended for in vitro detection of prothrombin time (PT) in fresh capillary blood samples from humans. It is suitable for monitoring the treatment of vitamin K antagonists and is intended solely for patients to perform self-testing of prothrombin time.
CoaguChek XS PT Test PST is an in vitro diagnostic method that uses the CoaguChek INRange coagulation meter for in vitro determination of prothrombin time (PT), utilizing fresh capillary blood samples.
This product should be used for monitoring after medication has been administered and the INR values have stabilized. It is not for patients to self-adjust their medication. If results are abnormal, patients should immediately contact their doctor.
- Model/Specification
- Working principle
Pre-clinical
- Main Raw Materials
The test card contains recombinant human tissue factor as an activator, stabilizers, and preservatives. The primary raw materials are procured by the applicant from third parties. The suitability of these raw materials is determined through functional testing, and quality standards are established for each primary raw material, ensuring they meet the required inspection standards.
- Production Process and Reaction System Research
The applicant has determined the optimal production process for the test card through research on the main production techniques. The reaction system was optimized by adjusting the sample volume, recombinant human tissue factor, stabilizers, and preservatives, ultimately establishing the best reaction system.
- Analytical Performance Evaluation
The analytical performance includes accuracy, intermediate precision, repeatability, batch-to-batch variability, and interference studies.
Accuracy Study: The applicant compared the measurements of three batches of test cards and 1020 fresh capillary blood samples with reference laboratory methods using citrated plasma samples. All results met acceptable standards.
Intermediate Precision Study: The applicant conducted three trials. The first study involved four clinical institutions in Europe, with at least four operators and two test instruments per institution, performing daily quality control tests for 20 days. The second study was conducted in four clinical trial institutions in the USA, with at least one operator per institution using nine test instruments, performing daily quality control tests for 25 days. The third study was conducted in a laboratory with one operator using six test instruments and three batches of test cards, performing daily quality control tests for 25 days. The mean, standard deviation, and coefficient of variation were calculated, and all results met acceptable standards.
Repeatability Study: The applicant used three batches of test cards, measuring two fresh capillary blood samples from each of 686 subjects twice. The mean, standard deviation, and coefficient of variation were calculated, and the results were within the acceptable range.
- Batch-to-Batch Variability Study: The applicant used three batches of test cards, measuring fresh capillary blood on the instrument twice daily. The relative mean bias between batches was calculated to determine batch-to-batch variability. All results met acceptable standards.
- Interference Study: Interference Study Summary
A study examined common interfering substances and found that ascorbic acid (≤ 170 μmol/L), bilirubin (≤ 513 μmol/L), hemolysis (≤ 0.62 mmol/L), and triglycerides (≤ 5.7 mmol/L) did not significantly affect test results. Hematocrit levels between 25% and 55% also had no significant impact. The test was insensitive to unfractionated and low-molecular-weight heparin (≤ 2 IU/mL). However, direct oral anticoagulants (DOACs) and other non-vitamin K antagonist anticoagulants affected prothrombin time (PT). Medications like protamine sulfate, olmesartan, calcium dobesilate, and fondaparinux impacted results. Coumarin derivatives’ effects varied with other medications, affecting PT/INR. β2-glycoprotein I antibodies prolonged PT.
- Positive Judgment Values or Reference Interval Studies
Not applicable
- Stability Study
Real-time Stability Study: Three batches of test cards were stored at 2-8°C and 26-30°C, tested at 3, 6, 16, and 25 months. The deviation of quality control measurements was calculated by comparing them with the initial measurements (0 months) of non-stressed test cards. For blood sample measurements, deviations were calculated by comparing them with non-stressed test cards stored at -20°C. Results indicated that the test cards remained stable for 25 months at 2-30°C, supporting a claimed storage period of 21 months under these conditions.
Additionally, the applicant conducted transport stability, open vial stability, outside-vial stability, and sample stability studies.
Clinical
The applicant conducted clinical trials at three institutions: the First Affiliated Hospital of Dalian Medical University, the First Affiliated Hospital of Bengbu Medical College, and Zhejiang Provincial People’s Hospital. These trials aimed to compare an experimental in vitro diagnostic reagent with standard clinical laboratory methods. The study population consisted of patients undergoing anticoagulant therapy with oral vitamin K antagonists, and the sample type was fingertip capillary blood.
Professional vs. Professional Use
In the study comparing the experimental reagent used by professionals to the comparator reagent used by professionals, 205 cases were included. The results indicated that for the INR (International Normalized Ratio) evaluation:
The correlation coefficient was 0.94 (95% CI: 0.92, 0.96), with a regression equation of y = 1.17x – 0.25.
When INR < 2.0, 98.8% of the differences between the experimental and comparator reagent results were within ±0.5 INR.
When 2.0 ≤ INR < 4.5, 97.6% of the differences were within ±30%.
The bias between the two methods was 0.104 INR, meeting relevant standards.
For the seconds value evaluation, the correlation coefficient was 0.95 (95% CI: 0.94, 0.96), with a regression equation of y = 1.38x – 3.99. Bland-Altman (BA) analysis for both indices showed that the absolute bias met the requirements.
Non-Professional vs. Professional Use
The study comparing non-professional use of the experimental reagent to professional use included 33 cases. For the INR evaluation:
The correlation coefficient was 0.89 (95% CI: 0.78, 0.94), with a regression equation of y = 1.000x.
When 2.0 < INR < 4.5, 95.6% of the differences between non-professional and professional results were within ±0.5 INR, meeting relevant standards.
For the seconds value evaluation, the correlation coefficient was 0.89 (95% CI: 0.79, 0.95), with a regression equation of y = 1.03x – 0.29. BA analysis for both indices showed that the absolute bias met the requirements.
Non-Professional vs. Professional Comparator
In another study comparing non-professional use of the experimental reagent to professional use of the comparator reagent, 33 cases were included. For the INR evaluation:
The correlation coefficient was 0.89 (95% CI: 0.77, 0.94), with a regression equation of y = 1.42x – 0.87.
For the seconds value evaluation, the correlation coefficient was 0.92 (95% CI: 0.84, 0.96), with a regression equation of y = 1.62x – 10.50. BA analysis for both indices showed that the absolute bias met the requirements.
Usability Evaluation of Instructions
The usability evaluation of the instructions involved 31 participants, assessing their understanding of the associated instruments and the experimental in vitro diagnostic reagent instructions. The results showed an overall satisfaction rate of 93.7% (64.4% strongly agree and 29.4% agree), meeting the requirements.
Overall, the clinical performance of the experimental in vitro diagnostic reagent was found to be good, meeting clinical use needs and technical review requirements.
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