(434 days)
The Hemoglobin Alc assay is used in clinical laboratories for the quantitative in vitro measurement of percent hemoglobin A 1c (NGSP) or HbA1c fraction mmol/mol (IFCC) in human whole blood and hemolysate on the ARCHITECT c 4000 System.
Hemoglobin A1c measurements are used as an aid in the diagnosis of diabetes mellitus, 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 Hemoglobin Alc Calibrators are for use in the callbration of the Hemoglobin A1c assay on the ARCHITECT e 4000 System.
The Hemoglobin A 1c Controls are used for the estimation of test precision of systematic analytical deviations of the Hemoglobin A1c assay on the ARCHITECT c 4000 System.
The Hemoglobin A1c assay consists of two separate concentration measurements: glycated hemoglobin (HbA1c) and total hemoglobin (THb). The two concentrations are used to determine the percent HbA1c (NGSP units) or the hemoglobin fraction in mmol/mol (IFCC units). The assay utilizes an enzymatic method that specifically measures N-terminal fructosyl dipeptides of the ß-chain of HbA1c. The total hemoglobin is determined by measuring absorbance. The final result is expressed as %HbA1c (NGSP) or mmol/mol HbA1c (IFCC) and is automatically calculated by the system from the HbA1c/THb ratio. The device also includes Hemoglobin A1c Calibrators and Hemoglobin A1c Controls.
This document describes the Hemoglobin A1c Assay, Calibrators, and Controls, a device used for the quantitative in vitro measurement of percent hemoglobin A1c (NGSP) or HbA1c fraction mmol/mol (IFCC) in human whole blood and hemolysate on the ARCHITECT c 4000 System. The information provided primarily focuses on the device's technical specifications, performance evaluation, and substantial equivalence to a predicate device (ARCHITECT Hemoglobin A1c assay, K130255).
I will extract the requested information based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" in a definitive table format with pass/fail thresholds. However, performance studies are conducted with implied expectations for meeting certain analytical standards. I will synthesize the performance data provided across various sections to address the "reported device performance."
| Performance Metric | Acceptance Criteria (Implied/Standard) | Reported Device Performance (NGSP) | Reported Device Performance (IFCC) |
|---|---|---|---|
| Precision (20-Day) | Low %CV for varying HbA1c levels | Whole Blood: 0.02-0.04 SD; 0.3-0.4 %CV; 0.3 %CV | Not explicitly detailed in the document |
| Hemolysate: 0.01-0.02 SD; 0.2-0.5 %CV; 0.3-0.4 %CV | Not explicitly detailed in the document | ||
| Limit of Blank (LoB) | Low value | 2.51 %HbA1c | 3.89 mmol/mol |
| Limit of Detection (LoD) | Low value | 2.52 %HbA1c | 4.05 mmol/mol |
| Interferences (Endogenous Substances) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference observed for listed substances | No significant interference observed for listed substances |
| Interferences (Hemoglobin Variants) | No significant interference; Difference within ± 5% for samples ~6.0 and ~9.0 %HbA1c | HbC, HbD, HbE, HbS, HbA2: Generally within acceptable ranges. HbF: Significant interference if >5% | HbC, HbD, HbE, HbS, HbA2: Generally within acceptable ranges. HbF: Significant interference if >5% |
| Interferences (Drugs) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference observed for listed drugs | No significant interference observed for listed drugs |
| Interferences (Rheumatoid Factor) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference for RF ≤ 200 IU/mL | No significant interference for RF ≤ 200 IU/mL |
| Interferences (Hemoglobin Derivatives) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference from acetylated, carbamylated, or labile Hb | No significant interference from acetylated, carbamylated, or labile Hb |
| Linearity (Correlation Coefficient) | Close to 1 | 0.9996 (intercept -0.40, slope 0.9709) | 0.9997 (intercept -6.17, slope 0.9831) |
| Method Comparison (to Reference) | Slope ~1, r-value ~1 | Hemolysate: Slope 1.00, r 0.996. Whole Blood: Slope 1.01, r 0.995 | Hemolysate: Slope 0.98, r 0.996. Whole Blood: Slope 1.00, r 0.996 |
| Method Comparison (ATD Zone) | High percentage in ATD Zone | Hemolysate: 100.0% (95% CI 97.1%). Whole Blood: 100.0% (95% CI 97.1%) | Hemolysate: 96.9% (95% CI 92.2%). Whole Blood: 96.9% (95% CI 92.2%) |
| Total Error (TE) | Acceptable values (device-specific) | Hemolysate: 2.5 - 3.4%. Whole Blood: 1.9 - 3.6% | Not explicitly detailed in the document |
| Measuring Interval | Demonstrated range | 4.0 to 14.0 %HbA1c | 20.22 to 129.51 mmol/mol HbA1c |
| Method Comparison (to Predicate) | Slope ~1, r-value ~1 | Hemolysate: Slope 0.99, r 0.999. Whole Blood: Slope 1.00, r 0.999 | Hemolysate: Slope 0.99, r 1.000. Whole Blood: Slope 1.00, r 1.000 |
2. Sample size used for the test set and the data provenance
- Precision Study (Within-Laboratory Precision):
- Sample Size: Three levels of human whole blood controls and human whole blood panels were tested. Each level was tested a minimum of 2 replicates, twice per day, for 20 testing days.
- Data Provenance: Not specified (e.g., country of origin, retrospective/prospective).
- Limit of Blank (LoB) and Detection (LoD) Study:
- Sample Size: Zero-level samples (minimum 3 replicates), low-level samples (minimum 2 replicates).
- Data Provenance: Not specified.
- Interferences (Endogenous Substances, Hemoglobin Variants, Drugs, Rheumatoid Factor, Hemoglobin Derivatives):
- Sample Size: Test and reference samples were tested in a minimum of 12 replicates for endogenous substances, drugs, RF, and hemoglobin derivatives. For hemoglobin variants, the number of samples (n) varied per variant (e.g., HbC: 43, HbD: 40, HbE: 50, HbS: 31, HbA2: 24, HbF: 28).
- Data Provenance: Not specified.
- Matrix Comparison:
- Sample Size: Specimens from a minimum of 43 different donors. Each sample tested in a minimum of 2 replicates.
- Data Provenance: Not specified.
- Linearity:
- Sample Size: 9 samples (4 commercial linearity levels + 5 prepared samples). Each sample tested in a minimum of 2 replicates.
- Data Provenance: Not specified.
- Method Comparison and Predicted Bias (against NGSP secondary reference laboratory method):
- Sample Size: A minimum of 120 human whole blood specimens. Tested in replicates of 2.
- Data Provenance: Not specified (likely laboratory-based, not patient-derived with demographic context).
- Method Comparison to Predicate Device:
- Sample Size: A minimum of 120 human whole blood specimens. Tested in replicates of 2.
- Data Provenance: Not specified.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
The document does not mention the use of "experts" in the traditional sense (e.g., radiologists, pathologists) for establishing ground truth. Instead, the ground truth for the method comparison studies was established using NGSP secondary reference laboratory methods for HbA1c measurement. These are highly standardized analytical methods, not dependent on expert interpretation. For calibrators and controls, traceability is to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method. The qualifications of personnel performing these reference methods are typically certified laboratory technicians or scientists, but this is not detailed.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
There is no mention of an adjudication method in the context of expert review for establishing ground truth, as the ground truth is based on reference analytical measurements.
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
This is a clinical chemistry assay, not an imaging or diagnostic device that involves "human readers" or "AI assistance" in interpretation in the way a MRMC study would apply. Therefore, no MRMC comparative effectiveness study was conducted or is applicable here. The device automatically provides a quantitative measurement.
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 assay system (reagents + instrument). The device provides a quantitative measurement of Hemoglobin A1c, and its performance (precision, linearity, interference, method comparison) is assessed based on the accuracy and reliability of these measurements against reference methods or established analytical standards. There is no "human-in-the-loop" component for result generation, only for sample handling and result interpretation for clinical decision-making.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth used for performance evaluation, particularly for method comparison, is based on:
- Reference Laboratory Methods: Specifically, an NGSP secondary reference laboratory method (e.g., Tosoh HPLC analyzer) for comparison of patient samples.
- Traceability to International Standards: Calibrators and controls are "value assigned using secondary calibrators that are traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method."
8. The sample size for the training set
The document describes performance evaluation (test set data) for the device. It does not provide information about a "training set" in the context of machine learning/AI development. This device is a quantitative in vitro diagnostic assay, not an AI/ML-based diagnostic software.
9. How the ground truth for the training set was established
Not applicable, as no training set (in the AI/ML context) is described for this in vitro diagnostic device.
§ 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.