(40 days)
The S TEST Reagent Cartridge Carbon Dioxide (CO2) is intended for the quantitative determination of carbon dioxide concentration in serum or lithium heparin plasma using the HITACHI Clinical Analyzer E40. Carbon dioxide measurements are used in the diagnosis and treament of numerous potentially serious disorders associated with changes in body acid-base balance. The S TEST Reagent Cartridge Carbon Dioxide (CO2) is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.
The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available. The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H). System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridge Carbon Dioxide.
The provided text describes the 510(k) summary for the Hitachi S TEST Reagent Cartridge Carbon Dioxide (CO2), a device for quantitative determination of carbon dioxide concentration in serum or lithium heparin plasma. The document focuses on demonstrating the substantial equivalence of this device to a legally marketed predicate device (Carbon Dioxide L.3K Assay, Sekisui Diagnostics, PEI, Inc., Canada- K042362) through nonclinical and clinical performance studies.
Here's an analysis of the acceptance criteria and the studies conducted:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly present a table of "acceptance criteria" but rather describes the performance characteristics tested and their results, often comparing them to the predicate device or established standards. I will infer acceptance criteria based on standard clinical chemistry performance requirements and the described study outcomes.
| Performance Characteristic | Acceptance Criteria (Inferred/Standard) | Reported Device Performance (Hitachi S TEST CO2) |
|---|---|---|
| Analytical Sensitivity (Limit of Detection - LoD) | Typically, LoD should be low enough to detect clinically relevant low concentrations. LoQ (Limit of Quantitation) should have acceptable precision (e.g., %CV 0.99, slope near 1, y-intercept near 0, within specified reportable range. | y = 0.918x + 0.091; r² = 0.9988 |
| Range: 1.4 to 44.0 mmol/L (Reportable range: 5 to 40 mmol/L) | ||
| Precision (In-house) | %CVs should be within acceptable clinical limits for different concentration levels (typically lower %CV for higher concentrations). | Within-Run %CV (Total %CV) |
- Low (10.11 mmol/L): 1.3% (4.4%)
- Middle (19.41 mmol/L): 1.3% (3.7%)
- High (33.06 mmol/L): 1.2% (3.7%) |
| Precision (External POL Study) | Similar to in-house, %CVs within acceptable clinical limits. | Total %CV (n=30 for each level at each site) - Site 1: 4.1% (Low), 4.8% (Mid), 3.2% (High)
- Site 2: 6.0% (Low), 4.4% (Mid), 3.7% (High)
- Site 3: 3.1% (Low), 1.9% (Mid), 3.7% (High) |
| Interference | Recoveries between 90% and 110% of the neat value in the presence of interferents. | No interference from Lipemia (up to 1,000 mg/dL Intralipid), Ascorbic acid (up to 50 mg/dL), Hemoglobin (up to 1,000 mg/dL), Unconjugated bilirubin (up to 19.1 mg/dL) |
| Method Comparison (Accuracy) | Strong correlation (r > 0.95), slope close to 1, y-intercept close to 0, and agreement with predicate/reference method. | In-house (vs. standard lab system): n=96, r=0.981, Slope=1.03 (0.97-1.08), y-intercept=0.98 (-0.17-2.12)
External POL Study (vs. comparative method): - Site 1: n=47, r=0.984, y=0.91x+1.49 (Slope CI: 0.87-0.95, Intercept CI: 0.67-2.32)
- Site 2: n=45, r=0.970, y=0.92x+0.56 (Slope CI: 0.80-1.04, Intercept CI: -2.31-3.43)
- Site 3: n=47, r=0.982, y=0.92x+0.79 (Slope CI: 0.87-0.97, Intercept CI: -0.43-2.01) |
| Matrix Comparison (Serum vs. Plasma) | Strong correlation between serum and plasma results (r > 0.95), slope close to 1, y-intercept close to 0. | n=50, r=0.980, Slope=1.00 (0.94-1.05), y-intercept=-0.34 (-1.97-1.30) |
| Stability (Shelf Life) | Claimed shelf life supported by real-time stability data. | Supported shelf life of 6 months at 2-8°C (real-time testing ongoing). |
| Reportable Range | Match clinical requirements; within demonstrated linearity. | 5.0 to 40.0 mmol/L (Predicate: 2.9 to 50.0 mmol/L) |
| Detection Wavelength | Not an acceptance criterion for performance, but a technical specification. | 405/508 nm (Predicate: 405/415 nm) |
2. Sample Size Used for the Test Set and Data Provenance
- Analytical Sensitivity (LoD/LoQ): 60 replicates of reagent blank and three low samples. Three low-level specimens in six runs with three instruments over three days for LoQ.
- Linearity: 10 serial dilutions plus zero standard (n=11), assayed in duplicate.
- Precision (In-house): Three levels of serum-based commercial controls, each tested in two runs, twice a day, for 20 days.
- Interference Testing: Two serum pools with approximately 17 and 30 mmol/L carbon dioxide.
- Method Comparison (In-house): 96 clinical specimens (including 3 spiked and 3 diluted samples).
- Matrix Comparison: 50 matched serum/plasma samples (including 2 spiked and 4 diluted samples).
- Precision (External POL Study): Three blinded serum samples (low, middle, high CO2 concentrations). Each sample assayed six times per day for five days, reporting 30 results per level per site.
- Method Comparison (External POL Study): 47 serum specimens (including three spiked and four diluted samples) per site (Site 2 used 45 samples due to 2 below dynamic range).
Data Provenance:
- The studies were performed by Hitachi Chemical Diagnostics, Inc. ("in-house") and at three external Physician Office Laboratory (POL)-type sites.
- Specific countries of origin for the clinical specimens are not explicitly stated, but the company address is Mountain View, CA, USA, and POL studies suggest U.S. clinical settings.
- The studies appear to be prospective for the purpose of validating the device's performance characteristics.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number or qualifications of experts used to establish "ground truth" for the test set in the traditional sense of expert consensus for diagnostic interpretation. Instead, the ground truth is established through:
- Reference Methods/Comparative Methods: In the method comparison studies, a "standard laboratory system" or "comparative method as the reference method" was used. The qualifications of the operators of these reference methods are not provided.
- Known Concentrations: For studies like linearity, precision, and interference, known concentrations (e.g., commercial controls, spiked samples, diluted samples) are used.
- Industry Standards: Adherence to CLSI (Clinical and Laboratory Standards Institute) guidelines (e.g., CLSI EP17-A2, CLSI EP-6A, CLSI EP5-A2, CLSI EP7-A2) implies reliance on established laboratory best practices for determining analytical performance.
4. Adjudication Method for the Test Set
This type of in vitro diagnostic device (IVD) performance study (analytical and clinical chemistry accuracy/precision) typically does not involve adjudication by multiple human readers in the same way an imaging or pathology study might. Instead, the device's results are compared against:
- Reference measurements: From the predicate device or a "standard laboratory system."
- Known values: For controls, linearity standards, and spiked/diluted samples.
The document states that method comparison samples were assayed "in singleton and in a blinded fashion" (in-house) and "assayed on the Hitachi E40 Clinical Analyzer... and a comparative method as the reference method" (external POL study), implying direct comparison without a formal adjudication panel.
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 design is typically used for diagnostic imaging or pathology devices where multiple human readers interpret cases, and the AI's impact on their performance is assessed. For an in vitro diagnostic (IVD) device like a CO2 reagent cartridge, the evaluation focuses on analytical performance characteristics (accuracy, precision, linearity, etc.) rather than human reader improvement with AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop) Performance Was Done
Yes, the studies conducted are standalone performance studies. The Hitachi S TEST Reagent Cartridge Carbon Dioxide operates as an in vitro diagnostic device on an automated analyzer (Hitachi Clinical Analyzer E40). The performance results (accuracy, precision, linearity, etc.) described are the performance of the device and its associated system without direct "human-in-the-loop" interpretive input influencing the result generation. Human operators load samples and reagents and review results, but the device itself generates the quantitative CO2 concentration.
7. The Type of Ground Truth Used
The ground truth for the performance studies was established using a combination of:
- Reference Measurement/Comparative Method: For method comparison, results from a "standard laboratory system" or "comparative method" served as the reference.
- Known Values: For analytical studies like linearity, precision, LoD, and interference, commercial controls, calibrators, and spiked/diluted samples with known or traceable concentrations were used.
- Industry Standards: Adherence to CLSI guidelines ensures that the methods for establishing ground truth for these analytical parameters align with recognized best practices in laboratory medicine.
8. The Sample Size for the Training Set
The document does not describe a "training set" in the context of machine learning or AI development. This is an IVD device providing a quantitative measurement based on a chemical reaction and photometric detection. Its underlying "algorithm" is the chemistry reaction and calculation based on Beer-Lambert Law, not a learned AI model that requires a training set. Manufacturers establish internal specifications and calibration parameters based on extensive R&D and analytical validation, but this typically does not involve an external "training set" as understood in AI/ML.
9. How the Ground Truth for the Training Set Was Established
As explained above, there is no "training set" for this type of IVD device in the AI sense. The "ground truth" for manufacturing and calibration would be established through:
- Primary Reference Materials: Traceability to primary reference standards (e.g., American Chemical Society (ACS) reagent grade sodium carbonate alkalimetric standard for CO2).
- Internal Validation: Rigorous internal testing and validation during the device's development to ensure the chemical reaction and photometric measurements yield accurate and precise results across the dynamic range.
- Quality Control: Ongoing use of quality control materials with known values to monitor performance.
The document states, "Each lot of S TEST Reagent Cartridge Carbon Dioxide (CO2) is calibrated by the manufacturer prior to shipment using material referenced to a standard which is traceable to American Chemical Society (ACS) reagent grade sodium carbonate alkalimetric standard." This describes the process for establishing and maintaining calibration, which is akin to "ground truth" for the device's quantitative output.
§ 862.1160 Bicarbonate/carbon dioxide test system.
(a)
Identification. A bicarbonate/carbon dioxide test system is a device intended to measure bicarbonate/carbon dioxide in plasma, serum, and whole blood. Bicarbonate/carbon dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance.(b)
Classification. Class II.