(203 days)
The VARIANT™ II TURBO HbA1c Kit- 2.0 is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/mol and NGSP %) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the VARIANT II TURBO Hemoglobin Testing System and VARIANT II TURBO Link Hemoglobin Testing System.
This test is to be used as an aid in diagnosis of diabetes and as an aid in identifying patients who may be at risk for developing diabetes.
The VARIANT II TURBO HbA1c Kit- 2.0 is intended for Professional Use Only.
The Hemoglobin Capillary Collection System (HCCS) is intended for the collection of human whole blood for the percent determination of hemoglobin A1c using Bio-Rad HPLC methods.
The VARIANT™ II TURBO HbA1c Kit - 2.0 utilizes principles of ion-exchange highperformance liquid chromatography (HPLC). The samples are automatically diluted on the VARIANT™ II TURBO Sampling Station (VSS) and injected into the analytical cartridge. The VARIANT™ II TURBO Chromatographic Station (VCS) dual pumps deliver a programmed buffer gradient of increasing ionic strength to the cartridge, where the hemoglobins are separated based on their ionic interactions with the cartridge material. The separated hemoglobins then pass through the flow cell of the filter photometer, where changes in the absorbance at 415 nm are measured. An additional filter at 690 nm corrects for background absorbance.
The VARIANT™ II TURBO Clinical Data Management (CDM™) software performs reduction of raw data collected from each analysis. Two-level calibration is used for adjustment of the calculated HbA1c values. A sample report, including retention times of detected peaks and a chromatogram, is generated by the CDM for each sample. The A1c peak is shaded for ease of identification. The area is calculated using an exponentially modified Gaussian (EMG) algorithm and the result printed in either mmol/mol or % HbA1c format as selected by the user.
The VARIANT™ II TURBO HbA1c Kit – 2.0 is designed to be used on the standalone VARIANT™ II TURBO and the VARIANT™ II TURBO Link Hemoglobin Testing Systems. VARIANT™ II TURBO and the VARIANT™ II TURBO Link Hemoglobin Testing Systems are identical with respect to all operational and system components. Physically, the VARIANT™ II TURBO Link VSS outer case is modified for compatibility with a track Functionality of the VARIANT™ II TURBO Link has not changed, just the system. physical orientation to accommodate sample tube management on a track system.
This document describes the performance of the VARIANT™ II TURBO HbA1c Kit - 2.0, an in vitro diagnostic device used for quantitative determination of hemoglobin A1c.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are derived from the "Special Controls Requirements for HbA1c for Diabetes Diagnosis" as outlined in Table 17 of the document (though it's mislabeled and actually on page 14 of the PDF). The device performance is reported in various sections of the "Summary of Performance Data."
| Requirement (Acceptance Criteria) | Reported Device Performance and Section in Document | Does Device Meet Criteria? |
|---|---|---|
| Device must have initial and annual standardization verification by a certifying glycohemoglobin standardization organization deemed acceptable by the FDA. | Section 8.d Traceability: "The assigned HbA1c values... are certified with the National Glycohemoglobin Standardization Program (NGSP)." (p. 10) | Yes |
| Performance testing of device precision must, at a minimum, use blood samples with concentrations near 5.0%, 6.5%, 8.0%, and 12% hemoglobin A1c. Testing must evaluate precision over a minimum of 20 days using at least 3 lots of the device and 3 instruments, as applicable. | Section 8.a Precision/Reproducibility: Evaluated based on CLSI EP05-A2 using four EDTA whole blood samples at ~5%, ~6.5%, ~8%, and ~12% HbA1c. Precision evaluated using three reagent lots, three instruments, for 20 days. (p. 6) | Yes |
| Performance testing of accuracy must include a minimum of 120 blood samples that span the measuring interval of the new device and compare results of the new device to results of the standardized method. Results must demonstrate little or no bias versus the standardized method. | Section 8.c Method Comparison: 130 variant-free whole blood EDTA samples (3.4% to 20.0% HbA1c) were evaluated. Deming and Passing-Bablok regression analyses performed against an NGSP SRL reference method. Bias estimation (Table 11) shows low bias. (p. 8-10) | Yes |
| 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%. | Section 8.c Total Error Decision Levels: Total Error (TE) calculated at 5.0%, 6.5%, 8.0%, and 12.0% HbA1c. All reported TE values (5.2%, 3.4%, 2.6%, 3.2% respectively) are less than 6%. (Table 12, p. 10) | Yes |
| 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. | Section 8.e.iv Hemoglobin Variant Study: Specific variant samples (HbS, HbC, HbD, HbE, HbA2, HbF) were tested. Relative % Bias from Reference Method observed for each variant reported in Table 16 (p. 13). All biases are within acceptable limits, indicating little to no interference. | Yes |
| 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 population. | Section 8.e.iv Hemoglobin Variant Study: HbF was included in the study, and its bias was reported. No warning statement recommendation is mentioned, implying no significant interference was observed that would require such a warning. (p. 13) | N/A (No significant interference observed) |
Detailed Study Information:
2. Sample Size Used for the Test Set and the Data Provenance
- Precision/Reproducibility Study:
- Sample Size: 4 EDTA whole blood samples (at ~5%, ~6.5%, ~8%, and ~12% HbA1c) and 5 quality control materials. Each sample had 720 measurements (run in duplicate, 2 runs/day, for 20 days across 3 instruments).
- Data Provenance: Not explicitly stated regarding country of origin, but it involves patient samples and quality control materials, which are typically retrospective or derived from clinical settings.
- Method Comparison Study:
- Sample Size: 130 variant-free whole blood EDTA samples.
- Data Provenance: Not explicitly stated regarding country of origin. The samples ranged from 3.4% to 20.0% HbA1c, suggesting prospective collection covering a diagnostic range. It mentions comparison to a "secondary NGSP SRL reference laboratory," implying real-world clinical samples.
- Linearity Study:
- Sample Size: Low (3.4%HbA1c) and high (20.6%HbA1c) EDTA whole blood patient samples mixed at varying ratios, creating 11 distinct levels (Level 1 to Level 11).
- Data Provenance: Patient samples, likely retrospective.
- Analytical Specificity (Interference) Studies:
- Endogenous Interference: Two EDTA whole blood sample pools (~6.5%HbA1c and ~8.0%HbA1c) were used. 10 replicates of each pool with test and control samples.
- Drug Interference: Two EDTA whole blood sample pools (~6.5%HbA1c and ~8.0%HbA1c) were used. 10 replicates of each drug with test and control samples.
- Hemoglobin Derivatives Interference: Low (~6.5%HbA1c) and high (~8.0%HbA1c) whole blood EDTA samples. Ten replicates each.
- Hemoglobin Variant Study: Specific variant samples (HbS, HbC, HbD, HbE, HbA2, HbF), with n=21-29 for each variant (e.g., 26 for HbS, 25 for HbC). Tested in duplicate.
- Data Provenance: Not explicitly stated regarding country of origin. "Patient samples" were used for some, and pure substances/serum samples for others.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
- The document does not explicitly state the number or qualifications of experts for establishing ground truth.
- For the Method Comparison Study, the device's results were compared to a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." The NGSP (National Glycohemoglobin Standardization Program) provides certification for laboratories and methods to ensure traceability to the DCCT (Diabetes Control and Complications Trial) reference method. This implies the ground truth is established by a highly standardized and validated reference method in an accredited laboratory, rather than by individual experts' consensus.
- For the Hemoglobin Variant Study, the comparison was against "a NGSP reference method that has been demonstrated to be free from the hemoglobin interferent," again pointing to a high-standard reference method as the ground truth.
4. Adjudication Method for the Test Set
- No explicit adjudication method (like 2+1 or 3+1 consensus) is described. The ground truth relies on established reference methods (NGSP-certified HPLC for HbA1c, and specialized NGSP reference methods for variant studies) as opposed to human adjudication of ambiguous cases. This is typical for quantitative analytical devices where a measurable reference standard exists.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done
- No, an MRMC comparative effectiveness study was not done. This type of study typically evaluates the effectiveness of a diagnostic aid (like AI) on physician performance in interpreting medical images or making diagnoses. The VARIANT™ II TURBO HbA1c Kit - 2.0 is an automated in vitro diagnostic device for quantitative chemical analysis, not an image interpretation or diagnostic aid that involves human "readers." Its performance is measured directly against reference methods and statistical criteria.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was Done
- Yes, the studies evaluate the standalone (algorithm only) performance. The device is an automated system (ion-exchange HPLC) that processes samples and produces quantitative HbA1c results. The performance data presented (precision, linearity, method comparison, interference studies) directly assesses the accuracy and reliability of this automated system in determining HbA1c values, without human intervention in the interpretative step. The "Human-in-the-loop" aspect would primarily involve sample collection and loading the instrument, not interpretation of the results themselves.
7. The Type of Ground Truth Used
- Primarily reference method comparison, traceable to international standards.
- For HbA1c quantification, the ground truth is established by comparison to NGSP-certified reference methods, which are themselves traceable to the DCCT (Diabetes Control and Complications Trial) reference method and IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) units. This is stated under "Traceability" (Section 8.d) and in the method comparison and variant studies.
- For interference studies, the ground truth is based on the expected values of spiked samples without the interferent, as measured by the device itself or a control.
8. The Sample Size for the Training Set
- The document does not explicitly mention a "training set" in the context of machine learning or algorithm development. This device is based on established HPLC principles and data reduction algorithms, which are typically designed and validated, rather than "trained" in the machine learning sense. The performance studies described serve as validation/verification of the final device.
9. How the Ground Truth for the Training Set Was Established
- As a traditional in vitro diagnostic device based on HPLC, there isn't a "training set" in the machine learning paradigm. The device's underlying principles (ion-exchange chromatography, spectrophotometry, and specific algorithms for peak detection and calculation) are built upon scientific understanding and engineering. The "ground truth" for developing and calibrating such systems would come from well-characterized reference materials and methods, likely through extensive internal R&D and calibration procedures following international standards, but this is not detailed as a "training set" in the document.
§ 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.