(119 days)
The D-10™ Hemoglobin A1c Program 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 D-10TM Hemoglobin Testing System.
Hemoglobin Alc measurements are used as an aid in diagnosis of diabetes, as an aid to identify 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.
The D-10™ Hemoglobin A1c Program is intended for professional in vitro diagnostic use only.
The D-10™ Hemoglobin Testing System utilizes the principles of ion-exchange highperformance liquid chromatography (HPLC). A dual-piston, low pulsation HPLC pump and a proportioning value deliver the buffer solution to an analytical cartridge and detector. Whole blood samples undergo an automatic two step dilution process and then introduced into the analytical flow path. Pre-diluted samples are aspirated directly and introduced into the analytical flow path. Between sample injections, the sample probe is rinsed with Wash/Diluent Solution to minimize sample carryover.
A programmed buffer gradient of increasing ionic strength delivers the sample to the analytical cartridge where the hemoglobin species are separated based upon their ionic interactions with the cartridge material and the buffer gradient. The separated hemoglobin species then pass through the photometer flow cell where changes in the absorbance are measured at 415 nm and recorded as a digital chromatogram.
The software performs a reduction of raw data collected from each analysis that may indicate use of a calibration factor. A samples report and chromatogram are generated for each sample.
The D-10™ Hemoglobin A1c Program is designed to be used on the D-10™ Hemoglobin Testing System with or without a D-10 Rack Loader.
The provided text describes a 510(k) premarket notification for the D-10 Hemoglobin A1c Program. This device is an in vitro diagnostic (IVD) used for the quantitative determination of hemoglobin A1c (HbA1c) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
Here's an analysis of the acceptance criteria and the study that proves the device meets those criteria, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a single table, but rather presents performance characteristics derived from various studies. Based on the "Summary of Nonclinical Performance Data" and the conclusion that "The performance criteria as stipulated by the Special Controls requirements for HbA1c systems that diagnose diabetes have clearly been met," we can infer the acceptance criteria from the reported results. The critical performance metrics for an HbA1c assay for diabetes diagnosis typically include precision (CV%), linearity, and method comparison (bias).
| Performance Characteristic | Acceptance Criteria (Inferred from successful study results and regulatory requirements) | Reported Device Performance (D-10™ Hemoglobin A1c Program) |
|---|---|---|
| Precision (NGSP %) | Typically, CV% values are expected to be low, especially at clinical decision points. (Implicitly, the results demonstrate acceptable precision as per CLSI EP05-A2 guidelines). | Total Precision (Combined Instruments): |
| Patient 1 (5.2%): 2.0% CV | ||
| Patient 2 (6.7%): 1.6% CV | ||
| Patient 3 (8.3%): 1.6% CV | ||
| Patient 4 (12.7%): 2.2% CV | ||
| Control 1 (5.6%): 1.7% CV | ||
| Control 2 (10.3%): 2.2% CV | ||
| QC 1 (5.5%): 2.0% CV | ||
| QC 2 (9.9%): 1.8% CV | ||
| QC 3 (15.4%): 2.2% CV | ||
| Precision (IFCC mmol/mol) | Similarly, low CV% values are expected. | Total Precision (Combined Instruments): |
| Patient 1 (33 mmol/mol): 3.4% CV | ||
| Patient 2 (50 mmol/mol): 2.3% CV | ||
| Patient 3 (67 mmol/mol): 2.1% CV | ||
| Patient 4 (115 mmol/mol): 2.7% CV | ||
| Control 1 (37 mmol/mol): 2.8% CV | ||
| Control 2 (89 mmol/mol): 2.7% CV | ||
| QC 1 (37 mmol/mol): 3.2% CV | ||
| QC 2 (85 mmol/mol): 2.3% CV | ||
| QC 3 (145 mmol/mol): 2.5% CV | ||
| Linearity (NGSP %) | Maximum measured difference of ±0.1% between predicted 1st and 2nd order results across the reportable range. | Linear from 3.9 – 18.8% HbA1c, with a maximum measured difference of ±0.1%. |
| Linearity (IFCC mmol/mol) | Maximum measured difference of ±1 mmol/mol across the reportable range. | Linear from 19 – 182 mmol/mol, with a maximum measured difference of ±1 mmol/mol. |
| Method Comparison (Bias vs. NGSP SRL) | Biases at clinical decision levels should be within acceptable limits for diagnostic accuracy. (Implicitly, the reported biases are considered acceptable). | Bias Estimation: |
| 5.0±0.5% HbA1c: -0.05% (-0.96% Bias) | ||
| 6.5±0.5% HbA1c: 0.00% (0.03% Bias) | ||
| 8.0±0.5% HbA1c: -0.08% (-0.98% Bias) | ||
| 12.0±1.0% HbA1c: -0.10% (-0.87% Bias) | ||
| Total Error (TE) at Decision Levels | Should be below a specified threshold (e.g., as defined by CLIA or other regulatory guidelines for HbA1c testing). | Total Error Estimation: |
| 5.0% A1c: 4.9% TE | ||
| 6.5% A1c: 3.2% TE | ||
| 8.0% A1c: 4.1% TE | ||
| 12.0% A1c: 5.2% TE | ||
| Endogenous Interference | No significant interference (defined as a ± 7% change in %HbA1c value from the control) up to stated concentrations. | No significant interference observed for Lipemia (6000 mg/dL), Conjugated bilirubin (60 mg/dL), Unconjugated bilirubin (60 mg/dL), Glucose (2000 mg/dL), Rheumatoid factor (750 IU/mL), Total protein (21 g/dL). |
| Drug Interference | No significant interference (defined as a more than ± 7% change in %HbA1c value from the control) at therapeutic levels up to stated concentrations. | No significant interference observed for 15 common drugs (e.g., Acetylcysteine, Ampicillin-Na, Ascorbic acid, Cefoxitin, etc.) at specified concentrations. |
| Cross Reactivity with Hemoglobin Derivatives | No significant interference (defined as more than a ±7% change in HbA1c value from the control) at physiological levels. | No significant interference for Acetylated Hb (up to 49 mg/dL), Carbamylated Hb (up to 3.5%), and Labile A1c (up to 6%). |
| Hemoglobin Variant Interference | Acceptable bias for common variants (HbS, C, D, E, A2) and no significant interference for HbF up to 10%. | No significant interference for HbC (≤ 40%), HbD (≤ 43%), HbS (≤ 43%), HbE (≤ 32%), HbA2 (≤ 6%), and HbF (≤ 10%). Device has significant positive interference with HbF > 10%, rendering results invalid. |
| Traceability/Standardization | Traceable to IFCC reference calibrators and NGSP certified. | Traceable to IFCC reference calibrators. NGSP certified (certification expires annually). |
2. Sample Sizes Used for the Test Set and Data Provenance:
- Precision/Reproducibility: Four EDTA whole blood samples at target HbA1c concentrations (~5%, ~6.5%, ~8%, ~12%) and five quality control materials were used. Each sample/control was run in duplicate, in 2 runs per day, on 3 instruments for 20 days, and repeated with 3 different kit lots, yielding a total of 720 results per sample over 60 days. The data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective clinical samples), but it implies prospective collection for the study.
- Linearity: Low (3.9% HbA1c) and high (18.8% HbA1c) EDTA whole blood patient samples were mixed in varying ratios to create 11 sample pools. The exact number of individual patient samples generating the pools is not specified.
- Method Comparison: 128 variant-free whole blood K3 EDTA samples were evaluated. The range of HbA1c was from 3.9% to approximately 19.0% (19 to 184 mmol/mol). Data provenance is not explicitly stated for these samples, but they are referred to as "patient samples."
- Endogenous/Drug Interference & Hemoglobin Derivatives Interference: Two EDTA whole blood sample pools (low level ~6.5% HbA1c and high level ~8.0% HbA1c) were used for spiking experiments. Ten replicates of each pool with interferent and control were analyzed. The specific number of individual patient samples that formed these pools is not detailed.
- Hemoglobin Variant Study: A panel of normal and diabetic whole blood EDTA patent variant samples for HbS (n=22), HbC (n=20), HbD (n=22), HbE (n=23), HbA2 (n=20), and HbF (n=24) were used. These are patient samples with known variants.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
- For Method Comparison: The D-10™ Hemoglobin A1c Program results were compared to "testing performed at a secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." The NGSP SRL (National Glycohemoglobin Standardization Program Secondary Reference Lab) is itself a highly qualified reference standard, implying expert oversight and standardized methods for ground truth determination, though specific human experts are not named or qualified in this document.
- For Hemoglobin Variant Study: Comparison was made to a "NGSP reference method that has been demonstrated to be free from the hemoglobin interferent." Similar to the method comparison, this relies on a standardized reference method rather than individual expert adjudication for each sample.
4. Adjudication Method for the Test Set:
Not applicable in the traditional sense of image or clinical outcome adjudication by multiple experts. The ground truth for the method comparison and variant studies was established by comparison to a standardized NGSP reference method, which inherently provides a highly controlled and validated "truth" for HbA1c measurements.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done:
No, a MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) for laboratory use, not typically subject to 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 described are all standalone performance evaluations of the D-10™ Hemoglobin A1c Program device. The tests, such as precision, linearity, method comparison, and interference studies, assess the analytical performance of the algorithm and hardware without human interpretation in the loop determining the HbA1c value.
7. The Type of Ground Truth Used:
The ground truth for the performance studies primarily relies on:
- Reference Methods: For method comparison and variant studies, the ground truth was established by a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay" and an "NGSP reference method."
- Expected Values/Spiking: For precision, linearity, and interference studies, ground truth was based on preparing samples with known concentrations or by comparing to control samples without interferents.
- Consensus/Certification: The general standardization is traced to IFCC reference calibrators and NGSP certification.
8. The Sample Size for the Training Set:
This document describes premarket notification studies for an in vitro diagnostic device, not a machine learning algorithm. Therefore, there is no explicit "training set" in the context of machine learning model development. The device relies on established chemical and physical principles (ion-exchange HPLC) with programmed parameters, rather than learning from a large dataset. Calibration of the instrument is performed using calibrator materials, but this is distinct from a machine learning training set.
9. How the Ground Truth for the Training Set Was Established:
As there is no machine learning-based training set, this question is not applicable. The device's operational parameters and calibration are based on established analytical chemistry principles and reference materials. The value assignment for the calibrator materials "were previously reviewed under 510(k) submission K031043," indicating their ground truth was established through a separate, regulated process.
§ 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.