(207 days)
The ACE Alera Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative measurement of general chemistry assays, such as glucose, sodium, potassium, and chloride, for clinical use in physician office laboratories or clinical laboratories. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.
ACE Glucose Reagent is intended for the quantitative determination of glucose in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.
The ACE Ion Selective Electrode (ISE) module on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems is used to measure concentrations of sodium, potassium, and chloride in undiluted serum and lithium heparin plasma. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.
The ACE Alera Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative determination of general chemistry assays for clinical use in physician office laboratories or clinical laboratories. The ACE Alera Clinical Chemistry System consists of a bench-top analyzer and an internal computer. The bench-top analyzer includes a single pipettor (syringe module/fluid arm/probe), a temperature-controlled reagent compartment, a reaction wheel and a holographic diffraction grating spectrophotometer.
In the ACE Glucose Reagent assay, glucose in serum or heparin plasma reacts with adenosine triphosphate in the presence of hexokinase and magnesium with the formation of glucose-6-phosphate and adenosine diphosphate. Glucose-6-phosphate dehydrogenase catalyzes the oxidation of glucose-6-phosphate with NAD+ to form 6-phosphogluconate and NADH. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The total amount of NADH formed is proportional to the concentration of glucose in the sample. The increase in absorbance is measured bichromatically at 340 nm/378 nm.
The ACE Ion Selective Electrode (ISE) Module, as part of the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems, uses a potentiometric method via ion-specific electrodes to simultaneously measure sodium, potassium and chloride in undiluted serum. Ion-specific membranes measure the difference in ionic concentrations between an inner electrolyte solution and the sample. The connection of the amplifier and ground (reference electrode) to the ion selective electrode forms the measuring system. A two-point calibration utilizes ACE CAL A and CAL B undiluted ISE Calibration Solutions with precisely known ion concentrations. The measured voltage difference of the sample and the CAL A and CAL B solutions determines the ion concentration in the sample on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems.
The device is the ACE Alera Clinical Chemistry System, ACE Glucose Reagent, and ACE Ion Selective Electrode (ISE) Module. The study assesses the performance of these components, focusing on the quantitative measurement of glucose, sodium, potassium, and chloride.
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 not explicitly stated as numerical targets that the device must meet in a formal, quantifiable way (e.g., "Accuracy must be > 95%"). Instead, the study aims to demonstrate substantial equivalence to predicate devices, showing that the performance of the ACE Alera system is comparable to established systems. The performance data presented focuses on precision (reproducibility) and method comparison with existing devices.
Since specific numerical acceptance criteria were not listed, one reasonable interpretation for implied acceptance criteria for laboratory diagnostic devices typically includes:
- Acceptable Precision: Coefficients of Variation (CV) or Standard Deviations (SD) for within-run and total precision across different concentration levels should be within generally accepted laboratory limits for each analyte. For clinical chemistry, these are often defined considering medical usefulness.
- Acceptable Method Agreement: Linear regression analysis (slope, intercept, correlation coefficient) and standard error between the new device and a reference method (or predicate device) should indicate good agreement. Slopes close to 1, intercepts close to 0, and high correlation coefficients (e.g., >0.975) are generally desired.
- No Significant Interference: The device should not be significantly affected by common interfering substances (icterus, hemolysis, lipemia, ascorbic acid) at clinically relevant levels.
Here's the performance data as reported, which serves as the evidence that these implicit acceptance criteria are met:
| Analyte | Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (ACE Alera) |
|---|---|---|---|
| Glucose | Precision (SD, %CV) | Low CVs and SDs across different concentrations. | Serum Low (62 mg/dL): Within-Run SD 0.6, CV 0.9%; Total SD 0.8, CV 1.3% |
| Serum Mid (121 mg/dL): Within-Run SD 1.2, CV 1.0%; Total SD 1.5, CV 1.3% | |||
| Serum High (366 mg/dL): Within-Run SD 6.4, CV 1.8%; Total SD 6.9, CV 1.9% | |||
| POL Precision | Similar precision across different lab settings. | In-House Sample 1 (63.5 mg/dL): Within-Run SD 1.2, CV 1.9%; Total SD 1.3, CV 2.1% | |
| POL 1 Sample 1 (64.3 mg/dL): Within-Run SD 1.1, CV 1.7%; Total SD 1.5, CV 2.3% | |||
| (Similar data for other POLs and samples) | |||
| Method Comparison | Slope close to 1, Intercept close to 0, R > 0.975. | POL 1: Slope 1.015, Intercept 0.1, R 0.9993 | |
| POL 2: Slope 1.005, Intercept 3.1, R 0.9995 | |||
| POL 3: Slope 0.988, Intercept 3.2, R 0.9993 | |||
| Sodium | Precision (SD, %CV) | Low CVs and SDs across different concentrations. | Serum Low (111.2 mmol/L): Within-Run SD 0.59, CV 0.5%; Total SD 0.93, CV 0.8% |
| Serum Mid (139.0 mmol/L): Within-Run SD 0.80, CV 0.6%; Total SD 0.87, CV 0.6% | |||
| Serum High (159.9 mmol/L): Within-Run SD 0.38, CV 0.2%; Total SD 0.90, CV 0.6% | |||
| POL Precision | Similar precision across different lab settings. | In-House Sample 1 (107.5 mmol/L): Within-Run SD 0.80 CV 0.7%; Total SD 1.50 CV 1.4% | |
| POL 1 Sample 1 (108.4 mmol/L): Within-Run SD 0.93 CV 0.9%; Total SD 1.44 CV 1.3% | |||
| (Similar data for other POLs and samples) | |||
| Method Comparison | Slope close to 1, Intercept close to 0, R > 0.975. | POL 1: Slope 1.025, Intercept -1.74, R 0.9974 | |
| POL 2: Slope 1.021, Intercept -2.92, R 0.9958 | |||
| POL 3: Slope 1.044, Intercept -6.27, R 0.9979 | |||
| Potassium | Precision (SD, %CV) | Low CVs and SDs across different concentrations. | Serum Low (2.2 mmol/L): Within-Run SD 0.04, CV 1.6%; Total SD 0.05, CV 2.4% |
| Serum Mid (4.0 mmol/L): Within-Run SD 0.07, CV 1.8%; Total SD 0.07, CV 1.8% | |||
| Serum High (7.9 mmol/L): Within-Run SD 0.07, CV 0.9%; Total SD 0.11, CV 1.4% | |||
| POL Precision | Similar precision across different lab settings. | In-House Sample 1 (3.70 mmol/L): Within-Run SD 0.06 CV 1.6%; Total SD 0.06 CV 1.7% | |
| POL 1 Sample 1 (3.73 mmol/L): Within-Run SD 0.07 CV 1.8%; Total SD 0.08 CV 2.2% | |||
| (Similar data for other POLs and samples) | |||
| Method Comparison | Slope close to 1, Intercept close to 0, R > 0.975. | POL 1: Slope 1.032, Intercept -0.108, R 0.9983 | |
| POL 2: Slope 1.008, Intercept -0.054, R 0.9971 | |||
| POL 3: Slope 0.984, Intercept 0.150, R 0.9942 | |||
| Chloride | Precision (SD, %CV) | Low CVs and SDs across different concentrations. | Serum Low (75.0 mmol/L): Within-Run SD 0.80, CV 1.1%; Total SD 1.50, CV 2.0% |
| Serum Mid (99.2 mmol/L): Within-Run SD 0.80, CV 0.8%; Total SD 0.90, CV 0.9% | |||
| Serum High (119.3 mmol/L): Within-Run SD 0.50, CV 0.4%; Total SD 1.10, CV 0.9% | |||
| POL Precision | Similar precision across different lab settings. | In-House Sample 1 (77.3 mmol/L): Within-Run SD 0.50 CV 0.6%; Total SD 1.20 CV 1.6% | |
| POL 1 Sample 1 (78.1 mmol/L): Within-Run SD 0.76 CV 1.0%; Total SD 1.30 CV 1.7% | |||
| (Similar data for other POLs and samples) | |||
| Method Comparison | Slope close to 1, Intercept close to 0, R > 0.975. | POL 1: Slope 1.004, Intercept 0.96, R 0.9972 | |
| POL 2: Slope 1.000, Intercept 0.29, R 0.9956 | |||
| POL 3: Slope 1.006, Intercept 0.16, R 0.9946 | |||
| Interference | No significant interference | Thresholds for common interferents. | GLU: No significant interference at or below 26 mg/dL Icterus, 1000 mg/dL Hemolysis, 104 mg/dL Lipemia (Intralipid), 525 mg/dL Lipemia (Triglycerides), 6 mg/dL Ascorbic Acid. |
| (Similar thresholds for Na, K, Cl) |
The study essentially acts as a validation against these implied criteria, demonstrating that the ACE Alera system's performance is acceptable for its intended use, comparable to the predicate devices.
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision Studies: The document does not explicitly state the number of individual sample replicates for the core (non-POL) precision studies. However, for the POL Precision studies, for each analyte (Glucose, Sodium, Potassium, Chloride), there were 3 samples tested in each of 4 labs (In-House and 3 POLs). The tables show means, within-run, and total standard deviations/CVs, which typically imply multiple replicates per sample (e.g., 20 or more replicates are common in such studies).
- Method Comparison Studies:
- Glucose: n = 46 samples for each of the three POL comparisons.
- Sodium: n = 42 samples for each of the three POL comparisons.
- Potassium: n = 43 samples for each of the three POL comparisons.
- Chloride: n = 41 samples for each of the three POL comparisons.
- Data Provenance: The method comparison data is identified as "(2012 Data)" and collected from an "In-House" lab comparing against "ACE Alera system POL" data from three different Physician Office Laboratories (POLs 1, 2, 3), suggesting multi-center evaluation within the United States. The data is retrospective in the sense that it's reported for a 510(k) submission, but the studies themselves would have been conducted prospectively as a part of the device validation. The term "POL" indicates that these are real-world, clinical laboratory settings.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
There were no human experts establishing ground truth in the context of interpretation for these types of in vitro diagnostic devices. The "ground truth" or reference values for chemical assays like glucose, sodium, potassium, and chloride are established by:
- Reference Methods: Often, a more established or gold-standard laboratory analyzer (in this case, the predicate ACE system in the In-House lab) is used to generate the "reference" values for comparison.
- Certified Reference Materials: Calibrators and controls with precisely known concentrations are used to calibrate and verify the accuracy of the instruments.
The qualifications of personnel operating these instruments are typically trained medical technologists or clinical laboratory scientists, but they do not establish "ground truth" in the way an expert radiologist might interpret an image.
4. Adjudication Method for the Test Set
Not applicable for this type of in vitro diagnostic device study. Adjudication methods (like 2+1, 3+1 consensus) are used for subjective interpretations, such as medical image analysis, where human experts might disagree. For quantitative chemical measurements, the comparison is directly between numerical results from different instruments.
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. This is an in vitro diagnostic device for quantitative chemical analysis, not an AI-assisted diagnostic tool that involves human interpretation of "cases" or "reads" in the way an MRMC study would evaluate.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the studies presented are essentially standalone performance evaluations of the ACE Alera Clinical Chemistry System, the ACE Glucose Reagent, and the ACE Ion Selective Electrode (ISE) Module. The tables show the performance characteristics (precision, method comparison, interference) of the device itself in generating quantitative results. Human involvement is limited to operating the instrument, performing quality control, and routine maintenance, not subjective interpretation of results. The output (e.g., glucose concentration) is a direct numerical value from the instrument.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)
The ground truth for the test set (the samples used in the method comparison studies) was established by comparison against a legally marketed predicate device, the Alfa Wassermann ACE system (specifically the ACE plus ISE/Clinical Chemistry System, K930140, K933862), effectively treating the predicate device's measurements as the reference standard. This is a common approach for demonstrating substantial equivalence for new IVD devices.
8. The Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of a machine learning algorithm. For clinical chemistry analyzers, the "training" analogous to machine learning would be:
- Instrument Calibration: The device is calibrated using commercially available calibrator solutions with known concentrations. The specific number of calibration points is not detailed but is typically specified by the manufacturer.
- Reagent Development and Optimization: The reagents themselves (like ACE Glucose Reagent) undergo extensive development and optimization, which involves testing on numerous samples to establish their performance characteristics (e.g., linearity, stability, interference). The exact sample sizes used during this development are not provided in this regulatory summary.
9. How the Ground Truth for the Training Set Was Established
As above, for an IVD analyzer, the "ground truth" for calibration or reagent development typically relies on:
- Certified Reference Materials: These are materials with highly accurate and traceable analyte concentrations, used to set the instrument's measurement scale.
- Validated Reference Methods: Established laboratory methods, often more complex or time-consuming, that are known to be highly accurate and precise for measuring the analyte.
The document implies that the ground truth for comparison samples was the predicate ACE system, and it is reasonable to assume that the calibration and internal controls for the ACE Alera system would rely on industry-standard reference materials and methods to establish accurate known values.
§ 862.1345 Glucose test system.
(a)
Identification. A glucose test system is a device intended to measure glucose quantitatively in blood and other body fluids. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.(b)
Classification. Class II (special controls). The device, when it is solely intended for use as a drink to test glucose tolerance, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.