This software submission covers three assays with three different intended uses:
Hemoglobin A1c:
The VARIANT II Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
The VARIANT II Hemoglobin Alc Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.
Beta-thalassemia:
The VARIANT II Beta thalassemia Short Program is intended for the separation and area percent determinations of hemoglobin A2 and F, and as an aid in the identification of abnormal hemoglobins in human whole blood using ionexchange high-performance liquid chromatography (HPLC).
The VARIANT II Beta-thalassemia Short Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.
Total GHb:
The VARIANT II Total GHb Program is intended for the separation and area percent determination of total glycated hemoglobin (GHb) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
The VARIANT II Total GHb Program with is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.
Indications for Use:
This software submission covers three assays and has two different Indications for Use:
HbA1c & GHb: Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.
HbA2 and HbF: Measurement of the percent hemoglobin A2 and F are effective in screening of β-thalassemia (i.e. hereditary hemolytic anemias characterized by decreased synthesis of one or more types of abnormal hemoglobin polypeptide chains).
The VARIANT II Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II Hemoglobin A1c and Beta-thalassemia Short Program are based on chromatographic separation of hemoglobins on a cation exchange cartridge. The Total GHb Program is based on principles of boronate affinity high pressure liquid chromatography to separate glycated hemoglobin from non-glycated hemoglobin.
The new feature in this submission is the upgrade in CDM software. The current software (3.5) requires Windows NT and Object Store N.T. These products are nearing the end of their lifecycle. CDM 4.0 software is needed to transfer the CDM software to Microsoft XP Operating System and Object Store version 4.0.
Here's an analysis of the provided text regarding the acceptance criteria and study for the Bio-Rad VARIANTT II Hemoglobin Testing System with CDM 4.0.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria in this submission are implicit, established by demonstrating substantial equivalence to predicate devices (CDM 3.5 versions of the programs). The key performance metrics evaluated are accuracy (method correlation) and precision.
Here's the table:
| Device | Program | Performance Metric | Acceptance Criteria (Implicit - based on predicate performance) | Reported Device Performance (CDM 4.0 vs. CDM 3.5 Predicate) |
|---|---|---|---|---|
| VARIANT™ II Hemoglobin Testing System | Hemoglobin A1c Program | Accuracy (Method Correlation) | ||
| Least Squares Regression | r² close to 1, slope close to 1, intercept close to 0 (indicating good correlation with predicate) | r² = 0.9978 | ||
| Slope = 1.0119 | ||||
| Intercept = 0.0002 | ||||
| Precision (Within-run %CV) | Normal & Diabetic samples show comparable precision to predicate | Normal Sample: 1.1% (CDM 4.0) vs. 1.5% (CDM 3.5) | ||
| Diabetic Sample: 1.2% (CDM 4.0) vs. 0.7% (CDM 3.5) | ||||
| Precision (Total Precision %CV) | Normal & Diabetic samples show comparable precision to predicate | Normal Sample: 2.6% (CDM 4.0) vs. 2.1% (CDM 3.5) | ||
| Diabetic Sample: 2.7% (CDM 4.0) vs. 1.7% (CDM 3.5) | ||||
| VARIANT™ II Hemoglobin Testing System | Beta thalassemia Short Program (HbA2) | Accuracy (Method Correlation) | ||
| Least Squares Regression | r² close to 1, slope close to 1, intercept close to 0 | r² = 0.9924 | ||
| Slope = 1.0070 | ||||
| Intercept = -0.0034 | ||||
| VARIANT™ II Hemoglobin Testing System | Beta thalassemia Short Program (HbF) | Accuracy (Method Correlation) | ||
| Least Squares Regression | r² close to 1, slope close to 1, intercept close to 0 | r² = 0.9991 | ||
| Slope = 0.9806 | ||||
| Intercept = 0.0192 | ||||
| VARIANT™ II Hemoglobin Testing System | Beta thalassemia Short Program (Precision) | Precision (Within-run %CV) | (Data format unclear in provided text for direct comparison of specific %CV values for HbA2 and HbF for CDM 4.0 vs. 3.5, but overall statement is "equivalent") | Stated as "equivalent" between CDM 4.0 and CDM 3.5, though specific numbers are hard to extract due to formatting issues in the provided text. |
| Precision (Total Precision %CV) | (Data format unclear in provided text for direct comparison of specific %CV values for HbA2 and HbF for CDM 4.0 vs. 3.5, but overall statement is "equivalent") | Stated as "equivalent" between CDM 4.0 and CDM 3.5, though specific numbers are hard to extract due to formatting issues in the provided text. | ||
| VARIANT™ II Hemoglobin Testing System | Total GHb Program | Accuracy (Method Correlation) | ||
| Least Squares Regression | r² close to 1, slope close to 1, intercept close to 0 | r² = 0.9991 | ||
| Slope = 1.0054 | ||||
| Intercept = 0.042 | ||||
| Precision (Within-run %CV) | (Data format unclear in provided text for direct comparison of specific %CV values for CDM 4.0 vs. 3.5, but overall statement is "equivalent") | Stated as "equivalent" between CDM 4.0 and CDM 3.5, though specific numbers are hard to extract due to formatting issues in the provided text. | ||
| Precision (Total Precision %CV) | (Data format unclear in provided text for direct comparison of specific %CV values for CDM 4.0 vs. 3.5, but overall statement is "equivalent") | Stated as "equivalent" between CDM 4.0 and CDM 3.5, though specific numbers are hard to extract due to formatting issues in the provided text. |
2. Sample Size Used for the Test Set and Data Provenance
- Hemoglobin A1c Program (Accuracy): 40 EDTA whole blood samples.
- Beta thalassemia Short Program (Accuracy): 40 EDTA whole blood samples.
- Total GHb Program (Accuracy): 40 EDTA whole blood samples.
- Precision Studies (all programs): Although specific sample numbers are sometimes noted as
n=40orn=80for the combined precision data, it's important to note these refer to the number of individual measurements or patient samples, not necessarily distinct patients. The studies involved analyzing "duplicate aliquots of normal HbA1c and diabetic HbA1c patient samples and controls" over several days. - Data Provenance: The document states "EDTA whole blood samples" and "patient samples and controls." It does not specify the country of origin or if the data was retrospective or prospective. Given the context of method correlation and precision, it's likely these were carefully selected samples to cover the analytical range, and are prospective in nature for the purpose of the study.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
This submission is for an in vitro diagnostic device (IVD) that measures specific biomarkers (HbA1c, HbA2, HbF, GHb) using analytical techniques (HPLC). The "ground truth" for such devices is typically established through a reference method or a highly accurate existing method.
In this case, the device's performance is compared against its predicate device (the older CDM 3.5 version of the same program). The predicate device itself would have been validated against a reference method.
- No external human experts were explicitly used to establish "ground truth" for the test set in this particular comparative study. The ground truth is the measurement obtained from the predicate device (CDM 3.5).
- The standardization for HbA1c and GHb is stated as "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP) for HbA1c." This indicates that the values obtained by both the new and predicate devices are ultimately traceable to established clinical reference standards, which is how the "ground truth" of the concentration values is ensured.
4. Adjudication Method for the Test Set
Not applicable. This is not a study involving human interpretation of images or data that would require adjudication. It's a quantitative measurement device, and the comparison is statistical (regression and precision).
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
No. This is an in vitro diagnostic device for quantitative measurement, not an AI or imaging device requiring human reader interpretation or MRMC studies.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the studies presented are standalone performance evaluations of the device (system including software) in terms of its analytical accuracy and precision. There is no human-in-the-loop aspect being evaluated here, as the device is designed for automated measurement.
7. The Type of Ground Truth Used
The "ground truth" for the performance evaluation in this 510(k) submission is the measurements obtained from the predicate device (the Bio-Rad VARIANT II Hemoglobin Testing System running CDM 3.5). The new device (CDM 4.0) is compared directly to the predicate to demonstrate substantial equivalence, meaning it performs similarly.
Underlying this, the initial "ground truth" for quantitative values for HbA1c is linked to reference methods (DCCT and IFCC) and certification (NGSP). For HbA2 and HbF, the ground truth is also tied to established quantitative analysis using HPLC.
8. The Sample Size for the Training Set
The document does not describe a "training set" in the context of machine learning or AI. This device is an analytical instrument with associated software. The software (CDM 4.0) is an upgrade to manage the data and system on a new operating system, not a machine learning algorithm that is "trained."
9. How the Ground Truth for the Training Set was Established
Not applicable, as there is no "training set" in the machine learning sense for this device. The software update primarily concerns operating system compatibility and database management, not the underlying analytical algorithm itself.
§ 864.7470 Glycosylated hemoglobin assay.
(a)
Identification. A glycosylated hemoglobin assay is a device used to measure the glycosylated hemoglobins (A1a , A1b , and A1c ) in a patient's blood by a column chromatographic procedure. Measurement of glycosylated hemoglobin is used to assess the level of control of a patient's diabetes and to determine the proper insulin dosage for a patient. Elevated levels of glycosylated hemoglobin indicate uncontrolled diabetes in a patient.(b)
Classification. Class II (performance standards).