(262 days)
For in vitro diagnostic use only
VITROS Chemistry Products HbA1c reagent is used on VITROS 5.1 FS Chemistry System, VITROS 4600 Chemistry System and the VITROS 5600 Integrated System for the quantitative determination of percent glycated hemoglobin Alc (DCCT/NGSP) and mmol/mol hemoglobin A1c (IFCC) in human whole blood.
The test is to be used as an aid in diabetes, as an aid in identifying patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus.
For in vitro diagnostic use only
VITROS Calibrator Kit 31 is used to calibrate the VITROS 5.1 FS Chemistry System. VITROS 4600 Chemistry System and the VITROS 5600 Integrated System for the determination of percent glycated hemoglobin (HbA1c) in human whole blood.
For in vitro diagnostic use only
VITROS Chemistry Products %A1c Performance Verifiers are assayed controls used on the VITROS 5.1 FS Chemistry System, the VITROS 4600 Chemistry System and the VITROS 5600 Integrated System to monitor performance of the VITROS d%A1c and VITROS HbA1c Reagent Kits.
The determination of % glycated hemoglobin (HbA1c) is performed using the VITROS Chemistry Products HbA1c Reagent Kit in conjunction with the VITROS Chemistry Products Calibrator Kit 31 on the VITROS 5,1 FS and VITROS 4600 Chemistry Systems and the VITROS 5600 Integrated System. The VITROS Chemistry Products HbA1c Reagents are two dual chambered packages containing ready-to-use liquid reagents. Whole blood samples are hemolyzed on the VITROS 5,1 FS and VITROS 4600 Chemistry Systems and the VITROS 5600 Integrated System. The concentration of HbA1c and total Hb are measured in the hemolyzed samples, controls and calibrators.
Hemoglobin A1c and Hemoglobin
Whole blood samples are hemolyzed on the VITROS 5,1 FS and VITROS 4600 Chemistry Systems and the VITROS 5600 Integrated System. Calibrators, controls and hemolyzed whole blood samples are mixed with Reagent 1 containing anti-HbA1c antibody to form a soluble antigen-antibody complex. Hemoglobin in the hemolyzed whole blood is converted with Reagent 1 to a hematin derivative that is measured bichromatically at 340 nm and 700 nm. Unbound anti-HbA1c antibody reacts with polyhapten (hexapeptide-glycan, A1c Reagent 2) to form an insoluble antibodypolyhapten immune complex, which is measured turbidimetrically at 340 nm. After a calibration has been performed for each reagent lot, the hemoglobin A1c and Hb concentrations in each unknown sample can be determined using the stored calibration curves and the measured absorbance obtained in the assay of the hemolyzed sample.
%A1c
% A 1c is a derived test calculated from the quantitative measurements of hemoglobin and hemoglobin A1c.
The VITROS® Chemistry Products Calibrator Kit 31 are prepared from a hemolysate derived from human and ovine blood to which surfactants, stabilizer, and preservative have been added. The calibrators are used to calibrate the VITROS 5,1 FS Chemistry System, VITROS 4600 Chemistry System and the VITROS 5600 Integrated System for the determination of percent glycated hemoglobin (HbA1c) in human whole blood.
VITROS %A1c Performance Verifiers I and II are prepared from a hemolysate derived from human and ovine blood to which surfactants, stabilizer, and preservatives have been added.
The VITROS® Chemistry Products FS Reconstitution Diluent is a common reagent that is used by multiple assays on VITROS® 5,1 FS Chemistry Systems, VITROS® 4600 Chemistry Systems, and VITROS® 5600 Integrated Systems. There are no active ingredients, the fluid is proceesed water and is supplied in a 5 mL vial for reconstitution of lyophilized materials.
The VITROS® 5,1 FS Chemistry System and VITROS 4600 Chemistry Systems are clinical chemistry instruments that provide automated use of the VITROS® Chemistry Products MicroTip® and MicroSlides® range of products. The VITROS® 5,1 FS System was cleared for market by 510(k) premarket notification (K031924). The VITROS® 4600 Chemistry System is commercialized under the FDA's Guidance for Industry and Staff: Reagent Replacement and Instrument Family Member Policy (December 11, 2003) as a family member of the VITROS 5,1 FS Chemistry System (K031924). The VITROS® 5600 Integrated Systems are clinical laboratory instruments that provide automated use of the VITROS® Chemistry Products MicroTip® and MicroSlides® range of products and VITROS® Immunodiagnostic Products MicroWells® range of products. The VITROS 5600® Integrated System was cleared for market by 510(k) premarket notification (K081543).
Here's the information about the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria (Stated) | Reported Device Performance | Device Met Criteria? |
|---|---|---|---|
| Accuracy (Total Error) | ≤6% Total Error | VITROS 5,1 FS Chemistry System: Range from 4.36% to 5.51% for controls and 3.99% to 5.14% for patients. | |
| VITROS 4600 Chemistry System: Range from 3.03% to 4.78% for controls and 2.95% to 4.94% for patients. | |||
| VITROS 5600 Integrated System: Range from 2.79% to 3.52% for controls and 2.77% to 3.88% for patients. | Yes | ||
| Accuracy (Correlation) | Not explicitly stated as a numerical criterion for approval. | VITROS Chemistry Products HbA1c assay vs. secondary reference laboratory method: Correlation coefficient (r) of 0.996. | |
| VITROS Chemistry Products HbA1c assay vs. NGSP Reference (Deming Fit Equations): |
- VITROS 5,1 FS: -0.08 + 1.01x
- VITROS 4600: -0.14 + 1.02x
- VITROS 5600: -0.06 + 1.00x | Not applicable (high correlation demonstrated) |
| Precision/Reproducibility | All acceptance criteria for precision were met. (Specific numerical criteria are not detailed in the summary but were likely internally defined and met based on the statement). | Total precision (%CV) for VITROS 5,1 FS: Controls (VITROS PV1 2.03%, BBI 5% 1.83%, BBI 6.5% 2.09%, BBI 8% 2.69%, BBI 12% 2.03%). Patients (5% 2.21%, 6.5% 2.01%, 8% 1.92%, 12% 2.52%).
Total precision (%CV) for VITROS 4600: Controls (VITROS PV1 1.32%, BBI 5% 1.19%, BBI 6.5% 1.62%, BBI 8% 1.43%, BBI 12% 2.01%). Patients (5% 1.10%, 6.5% 1.19%, 8% 1.66%, 12% 2.09%).
Total precision (%CV) for VITROS 5600: Controls (VITROS PV1 1.18%, BBI 5% 1.41%, BBI 6.5% 1.40%, BBI 8% 1.27%, BBI 12% 1.76%). Patients (5% 1.05%, 6.5% 1.12%, 8% 1.28%, 12% 1.94%). | Yes |
| Linearity/Measuring Range | Not explicitly stated as a numerical criterion for approval. | Linear range for % A1c: 3.034-15.444% (NGSP derived test).
Linear range for HbA1c: 9.6-145.3 mmol/mol (SI derived test).
(Specific r^2 values are given, all are >0.997). | Yes (linearity shown) |
| Detection Limit (LoD) | Claim of 2.580% NGSP for LoQ | LoB for %A1c: 2.396% NGSP (2.67 mmol/mol SI)
LoD for %A1c: 2.580% NGSP (4.68 mmol/mol SI)
LoQ for %A1c: 2.580% NGSP (4.68 mmol/mol SI) | Yes |
| Analytical Specificity (Interference) | Bias ≤ 0.5% A1c (≤ 5 HbA1c (mmol/mol)) at ~6.5% A1c; Bias ≤ 0.6% A1c (≤ 7 HbA1c (mmol/mol)) at ~8.5% A1c for listed substances. Hemoglobin variants HbA0, HbA1a, HbA1b, C, D, E, S should not interfere. | Listed Substances (e.g., Acetaminophen, Bilirubin, Glucose): Found not to interfere at specified concentrations.
Hemoglobin Variants: HbS up to 41%, HbC up to 38%, HbD up to 38%, HbE up to 26% of total hemoglobin do not interfere. Anti-HbA1c antibodies do not cross-react with HbA0, HbA1a, HbA1b at stated levels. HbF >7% may result in lower than expected values. | Yes (with a caveat for high HbF) |
| NGSP Certification | NGSP certification received. | NGSP certification was received for the VITROS HbA1c assay on all three noted systems. | Yes |
2. Sample Size Used for the Test Set and Data Provenance
- Accuracy (Method Comparison): 357 samples were used. The samples were distributed across the range of the assay.
- Precision/Reproducibility:
- Quality Control Materials (hemolysate and whole blood-based): 20-22 days of testing, samples per data point varied (e.g., 756 or 792 for controls for 3 lots across multiple analyzers).
- Intermediate Precision Study (whole blood patient samples): 4 days of testing, 144 samples per patient level.
- Linearity: Low and high pools were mixed to give 16 intermediate concentration pools.
- Detection Limit: 500 determinations based on 5 low-level samples.
- Analytical Specificity (Interference): Specific numbers of patient samples for Hb variants were tested (e.g., 70 for HbA1a/A1b, 22 for HbA2, 31 for HbC, 21 for HbD, 30 for HbE, 40 for HbS, 43 for HbF). The list of interfering substances does not specify sample size per substance but indicates testing was done “for each substance tested” on control and test substance pools.
- Data Provenance: The document implies the data was generated specifically for this 510(k) submission (prospective), likely from internal studies or contract research organizations. The country of origin for the data is not explicitly stated, but the submission is to the US FDA by Ortho-Clinical Diagnostics, Inc. in Rochester, New York, suggesting US-based studies unless otherwise specified. The reference method for accuracy was a "secondary reference laboratory of the NGSP," implying a credible, standardized source.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
- The ground truth for the accuracy study was established using a "secondary reference laboratory of the NGSP." The number and specific qualifications of experts within this laboratory are not specified in this document. However, the NGSP (National Glycohemoglobin Standardization Program) implies adherence to a highly standardized and validated reference method for HbA1c, which inherently involves expert-level procedures and validation.
4. Adjudication Method
- For the analytical performance studies (accuracy, precision, linearity, detection limits, analytical specificity), an adjudication method is not typically described as it would be for clinical image interpretation or diagnostic performance involving human assessment. The "ground truth" is established by highly controlled and validated laboratory reference methods. The comparison is quantitative against these reference methods.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is relevant for diagnostic imaging AI devices where human reader performance is being assessed and compared with and without AI assistance. The VITROS Chemistry Products HbA1c Reagent Kit is an in vitro diagnostic assay, not an imaging AI device with a human-in-the-loop component for interpretation.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
- Yes, the performance data presented is for the standalone device (the VITROS Chemistry Products HbA1c Reagent Kit and associated systems/calibrators/verifiers) without human-in-the-loop performance being a variable. The studies assess the analytical performance of the assay itself.
7. Type of Ground Truth Used
- The ground truth used for relevant studies (e.g., accuracy) was:
- Reference Method: Traceability to the IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) Reference Method, and certification by the National Glycohemoglobin Standardization Program (NGSP) which is traceable to the Diabetes Control and Complications Trial (DCCT) Reference Method. This represents a highly standardized and validated laboratory-based reference standard.
8. Sample Size for the Training Set
- This information is not provided. For an in vitro diagnostic reagent kit, there isn't typically a "training set" in the machine learning sense. The device's "training" or optimization would happen during its development phase using various experimental designs and samples, rather than a distinct, documented "training set" like in AI/ML performance studies. The document focuses on the validation or test set performance.
9. How the Ground Truth for the Training Set Was Established
- As mentioned above, a "training set" in the AI/ML context isn't directly applicable here. The development of the assay (analogous to "training") would involve extensive R&D, chemical optimization, and preliminary testing against known samples and reference methods. The ground truth for these developmental internal studies would be established using similar highly accurate and traceable laboratory reference methods.
§ 862.1373 Hemoglobin A1c test system.
(a)
Identification. A hemoglobin A1c test system is a device used to measure the percentage concentration of hemoglobin A1c in blood. Measurement of hemoglobin A1c is used as an aid in the diagnosis of diabetes mellitus and as an aid in the identification of patients at risk for developing diabetes mellitus.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The device must have initial and annual standardization verification by a certifying glycohemoglobin standardization organization deemed acceptable by FDA.
(2) The premarket notification submission must include performance testing to evaluate precision, accuracy, linearity, and interference, including the following:
(i) Performance testing of device precision must, at a minimum, use blood samples with concentrations near 5.0 percent, 6.5 percent, 8.0 percent, and 12 percent hemoglobin A1c. This testing must evaluate precision over a minimum of 20 days using at least three lots of the device and three instruments, as applicable.
(ii) Performance testing of device accuracy must include a minimum of 120 blood samples that span the measuring interval of the device and compare results of the new device to results of a standardized test method. Results must demonstrate little or no bias versus the standardized method.
(iii) Total error of the new device must be evaluated using single measurements by the new device compared to results of the standardized test method, and this evaluation must demonstrate a total error less than or equal to 6 percent.
(iv) Performance testing must demonstrate that there is little to no interference from common hemoglobin variants, including Hemoglobin C, Hemoglobin D, Hemoglobin E, Hemoglobin A2, and Hemoglobin S.
(3) When assay interference from Hemoglobin F or interference with other hemoglobin variants with low frequency in the population is observed, a warning statement must be placed in a black box and must appear in all labeling material for these devices describing the interference and any affected populations.