(146 days)
The Tina-quant Hemoglobin A1cDx Gen.3 assay is intended for use as an aid in diagnosis of diabetes and as an aid in identifying patients who may be at risk for developing diabetes. It is an in vitro diagnostics reagent system intended for quantitative determination of mmol/mol hemoglobin A1c (IFCC) and % hemoglobin A1c (DCCT/NGSP) in hemolysate or venous whole blood on the cobas c 503 clinical chemistry analyzer. HbA1c determinations are useful for monitoring of long-term blood glucose control in individuals with diabetes mellitus.
Tina-quant Hemoglobin A1cDx Gen.3 assay is an in vitro diagnostics reagent system intended for quantitative determination of mmol/mol hemoglobin A1c (IFCC) and % hemoglobin A1c (DCCT/NGSP) in hemolysate or whole blood on the cobas c 503 clinical chemistry analyzer. The assay offers separate applications that are specific to the sample types whole blood and hemolysate. The Whole Blood Application differs from the Hemolysate Application in the hemolyzing step. For the Whole Blood Application, whole blood samples are placed on the analyzer and hemolysis occurs onboard the analyzer. For the Hemolysate Application, hemolyzed samples are placed on the analyzer and hemolysis occurs manually before placing the samples onboard the analyzer. The two applications yield the same results. Hemolyzing reagent is part of the test system and is either placed on board the analyzer for the Whole Blood Application or used manually for the Hemolysate Application. Anticoagulated whole blood is hemolyzed either manually or automatically prior to determination of HbAlc by a turbidimetric inhibition immunoassay. Liberated hemoglobin (Hb) in the hemolyzed sample is converted to a derivative having a characteristic absorption spectrum and measured bichromatically. The instrument calculates the % HbAlc from the HbAlc/Hb ratio according to a user selected protocol, either IFCC or NGSP protocols.
Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary for the Tina-quant Hemoglobin A1cDx Gen.3:
1. A table of acceptance criteria and the reported device performance
The document doesn't explicitly state "acceptance criteria" as a single, consolidated table with pass/fail thresholds. Instead, it presents various performance studies and their results. The implicit acceptance criteria are that the device's performance metrics are acceptable for its intended use and comparable to or better than the predicate device.
Here’s a table summarizing the reported device performance for key metrics:
| Performance Metric | Acceptance Criteria (Implicit) | Reported Device Performance (Tina-quant Hemoglobin A1cDx Gen.3) |
|---|---|---|
| Precision | Acceptable levels of repeatability and intermediate precision for clinical use. | Hemolysate Application: |
- Reproducibility (total CV%): Most samples/controls show CV% between 1.0% and 1.9%.
- Repeatability (CV%): Most samples/controls show CV% between 0.4% and 0.6%.
Whole Blood Application: - Reproducibility (total CV%): Most samples/controls show CV% between 1.2% and 1.6%.
- Repeatability (CV%): Most samples/controls show CV% between 0.4% and 0.8%. |
| Limit of Blank (LoB) | Detection limit sensitive enough for clinical application. | Hb LoB: 0.0530 mmol/L (0.085 g/dL)
HbA1c LoB: 0.0220 mmol/L (0.035 g/dL)
This corresponds to 15 mmol/mol (IFCC) and 3.5% HbA1c (DCCT/NGSP) at 13.2 g/dL Hb. |
| Limit of Detection (LoD) | Detection limit sensitive enough for clinical application. | Hb LoD: 0.119 mmol/L (0.192 g/dL)
HbA1c LoD: 0.0437 mmol/L (0.07 g/dL)
This corresponds to 22 mmol/mol (IFCC) and 4.2% HbA1c (DCCT/NGSP) at 13.2 g/dL Hb. |
| Linearity/Reportable Range | Linear response across the claimed measuring range. | Hemoglobin (Hb): 4 – 40 g/dL (2.48 – 24.8 mmol/L)
HbA1c: 0.3 – 2.6 g/dL (0.186 – 1.61 mmol/L)
This corresponds to a measuring range of 23-196 mmol/mol HbA1c (IFCC) and 4.2-20.1% HbA1c (DCCT/NGSP).
Empirical First Order Regression: Pearson's r for Hb = 0.9999, HbA1c = 0.9990. |
| Endogenous Interferences | No significant interference from common endogenous substances at specified concentrations. | Demonstrated claimed maximum concentrations without interference for: Bilirubin (60 mg/dL), Ditaurobilirubin (60 mg/dL), Lipemia (400 mg/dL), Rheumatoid Factors (750 IU/mL), Total Protein (21 g/dL), Albumin (60 g/L), Immunoglobulin (IgG) (60 g/L), Glucose (1000 mg/dL), Triglycerides (1584 mg/dL). A percent deviation criteria was used (not explicitly stated but implied to be within acceptable limits). |
| Cross-Reactivity | No significant cross-reactivity with specified hemoglobin fractions and glycated albumin. | Max Whole Blood Cross-Reactant Concentration with no Interference: HbA0 (120 g/dL), HbA1(a+b) (0.96 g/dL for Level 1, 1.6 g/dL for Level 2), Carbamylated Hb (2.0 g/dL), Acetylated Hb (2.0 g/dL), Glycated Albumin (10 g/dL), Labile HbA1c (1000 mg/dL).
Note: Specimens with >7% HbF may yield lower than expected HbA1c values. |
| Hemoglobin Variants | Accurate results for common hemoglobin variants (HbS, HbC, HbE, HbD, HbA2) within acceptable bias. | Relative % Bias from Reference Method at Low (around 6.5%) and High (around 9%) HbA1c: - HbS: -2.5% (Low), -4.0% (High)
- HbC: -3.9% (Low), -6.0% (High)
- HbE: -0.1% (Low), -1.2% (High)
- HbD: -1.8% (Low), -2.6% (High)
- HbA2: -1.0% (Low), 0.4% (High)
Note: Specimens with >7% HbF may yield lower than expected HbA1c values. |
| Exogenous Interferences (Drugs) | No significant interference from a list of commonly used drugs at specified concentrations. | No significant interference reported for 18 listed drugs (N-Acetylcysteine, Acetylsalicylic acid, Ampicillin-Na, Ascorbic acid, Cefoxitin, Heparin, Levodopa, Methyldopa + 1.5, Metronidazole, Doxycyclin, Rifampicin, Gammagard, Cyclosporine, Phenylbutazone, Acetaminophen, Ibuprofen, Theophylline, Tolbutamide) at tested concentrations. |
| Sample Matrix Comparison | Acceptable agreement across different anticoagulants and fill levels. | Mean Difference for K2-EDTA, K3-EDTA, Na Heparin, Li Heparin, NaF/Potassium oxalate, EDTA/Fluoride at full and half-full tubes indicate close agreement (e.g., -0.026 to 0.019). Upper and Lower 95% CIs are provided (e.g., -0.181 to 0.172). |
| Method Comparison | Good agreement with the NGSP reference method (Tosoh Automated Glycohemoglobin Analyzer HLC-723G8). | Whole Blood Application: Mean bias vs. NGSP TOSOH = -0.046%.
Hemolysate Application: Mean bias vs. NGSP TOSOH = 0.046%.
Bias at concentrations: (e.g., 5% HbA1c: WB -2.4%, Hemolysate 0.6%; 12% HbA1c: WB 0.7%, Hemolysate 1.2%). |
| Total Error (TE) | Total Error within clinical requirements, considering both bias and precision. | Hemolysate Application: TE ranging from 3.0% to 4.4% across HbA1c levels.
Whole Blood Application: TE ranging from 3.1% to 5.2% across HbA1c levels. |
2. Sample size used for the test set and the data provenance
-
Precision (Repeatability and Intermediate Precision):
- Sample Size: 10 samples (2 controls, 8 human samples) for each application (Hemolysate and Whole Blood). Measured for 21 days.
- Data Provenance: Human samples and controls mentioned. No specific country of origin is stated, but implied to be laboratory-based testing. Prospective study design.
-
Analytical Sensitivity (LoB, LoD):
- Sample Size:
- LoB: One analyte-free sample. 60 measurements per lot across 3 lots.
- LoD: Five unique human samples with low-analyte concentrations. 60 measurements per lot across 3 lots.
- Data Provenance: Human samples mentioned. Laboratory-based testing. Prospective study design.
- Sample Size:
-
Linearity/Assay Reportable Range:
- Sample Size: Separate dilution series (at least eleven levels) prepared from human hemolysate sample pools.
- Data Provenance: Human hemolysate samples. Laboratory-based testing. Prospective study design.
-
Endogenous Interferences:
- Sample Size: Pooled whole blood samples at two HbA1c levels, spiked with 9 different interferents. 18 spiked samples + interferent-free pools. Each tested in ten-fold.
- Data Provenance: Pooled whole blood samples. Laboratory-based testing. Prospective study design.
-
Cross-Reactivity:
- Sample Size: Not explicitly stated as a number of unique samples, but rather a "series of experiments" with specific cross-reactants. Ten replicates of each sample were analyzed for each dilution level.
- Data Provenance: Laboratory-based testing using prepared samples to introduce cross-reactants. Prospective study design.
-
Hemoglobin Variants:
- Sample Size: 30 HbS, 30 HbC, 30 HbE, 29 HbD, 15 HbA2, 19 Elevated HbF. Total = 153 samples.
- Data Provenance: Not specified, but implied to be characterized patient samples containing the variants. Laboratory-based testing. Prospective.
-
Exogenous Interferences (Drugs):
- Sample Size: Hemolysate samples at two HbA1c levels, spiked with 18 common drugs at two concentrations. Each drug/concentration combination tested in ten-fold.
- Data Provenance: Hemolysate samples and spiked drugs. Laboratory-based testing. Prospective study design.
-
Sample Matrix Comparison:
- Sample Size: At least 40 samples of each anticoagulant type (e.g., K2-EDTA, K3-EDTA, Na Heparin, Li Heparin, NaF/Potassium oxalate, EDTA/Fluoride) at full and half-filled tubes. Samples from one donor for full/half-filled comparisons.
- Data Provenance: Human donor samples. Laboratory-based testing. Prospective study design.
-
Method Comparison:
- Sample Size: 171 whole blood samples and 173 hemolysate samples.
- Data Provenance: Samples from a "secondary NGSP reference laboratory." This suggests these are clinical samples that have been previously characterized by a gold standard (NGSP certified) method. The nature (retrospective/prospective clinical samples) is not explicitly stated but is consistent with a clinical validation using real patient samples.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The document does not describe the use of human experts to establish ground truth in the way one would for image-based diagnostic AI. This device is an in vitro diagnostic (IVD) reagent system for quantifying a biomarker (HbA1c).
- Ground truth for the performance studies (e.g., precision, linearity, interferences) is established through:
- Reference materials (e.g., controls like PreciControl HbA1c norm/path).
- Dilution series from characterized sample pools.
- Spiking experiments with known concentrations of interferents or cross-reactants.
- For Hemoglobin Variants and Method Comparison:
- The "ground truth" or reference method is the NGSP Tosoh HPLC system. This system undergoes certification by the National Glycohemoglobin Standardization Program (NGSP) and is considered a highly accurate laboratory assay method, not dependent on human expert interpretation of a result. No individual human expert counts or qualifications are reported for establishing these reference values.
4. Adjudication method for the test set
Not applicable. This is an IVD device, not an AI or imaging diagnostic device that typically requires expert adjudication for ground truth establishment. The performance is assessed by comparing results to established reference methods, spiked concentrations, or statistical analysis of replicates.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
Not applicable. The Tina-quant Hemoglobin A1cDx Gen.3 assay is an in vitro diagnostic (IVD) device for quantitative determination of HbA1c. It does not involve human readers interpreting images or data with or without AI assistance. It provides a numerical result.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the studies described are all standalone (algorithm only) performance evaluations. The device autonomously measures HbA1c and Hb concentrations, calculates the ratio, and reports the final HbA1c result. There is no human intervention in the result generation process once the sample is loaded onto the analyzer.
7. The type of ground truth used
The ground truth used in various parts of the study consists of:
- Reference Methods: The NGSP Tosoh HPLC system for method comparison, which is a recognized standardized method for HbA1c determination.
- Certified Reference Materials/Controls: PreciControl HbA1c norm and path with assigned values.
- Known Concentrations: For linearity, LoB, LoD studies, the "truth" is derived from preparing samples with known concentrations or by statistical analysis of repeat measurements of low/negative samples.
- Spiked Samples: For interference and cross-reactivity studies, the "truth" is the un-spiked sample value, and the effect is measured by deviation after adding a known amount of interferent.
- Characterized Patient Samples: For hemoglobin variant testing, samples from patients known to carry specific hemoglobin variants were used.
8. The sample size for the training set
This document does not describe a "training set" in the context of machine learning or AI. The Tina-quant Hemoglobin A1cDx Gen.3 is a reagent system for a well-established immunoassay technique. Its development involved chemical and assay optimization, not machine learning model training.
9. How the ground truth for the training set was established
Not applicable, as there is no mention or indication of a machine learning "training set" for this IVD device. The assay's analytical principles are based on turbidimetric inhibition immunoassay (TINIA) and bichromatic photometric determination, which are traditional chemical analysis methods, not AI-driven algorithms requiring training data.
§ 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.