(30 days)
EliA M2 is intended for the in vitro semi-quantitative measurement of IgG antibodies directed to M2 in human serum and plasma (Li-heparin, EDTA) to aid in the clinical diagnosis of primary biliary cirrhosis in conjunction with other laboratory and clinical findings. EliA M2 uses the EliA IgG method on the instrument Phadia 2500/5000.
The method-specific reagents are identical with K141375 (EliA M2 on Phadia 250), but are filled in containers specific for the Phadia 2500/5000 instrument. Each device consists of:
- Test Wells: -EliA M2 Wells are coated with native pyruvate dehydrogenase complex from mitochondria and recombinant M2-antigen - 4 carriers (12 wells each), ready to use:
- EliA Sample Diluent: PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 6 bottles, 48 mL each, ready to use; or 6 bottles, 400 mL each, ready to use;
- EliA IgG Conjugate 50 or 200: ß-Galactosidase labeled anti-IgG (mouse monoclonal antibodies) in PBS containing BSA and 0.06% (w/v) sodium azide – 6 wedge shaped bottles, 5 mL each, ready to use; or 6 wedge shaped bottles, 19 mL each, ready to use
- EliA IgG Calibrator Strips: Human IgG (0, 4, 10, 20, 100, 600 µg/L) in PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 5 strips, 6 singleuse vials per strip, 0.3 mL each, ready to use;
- -EliA IgG Curve Control Strips: Human IgG (20 ug/L) in PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
- EliA IgG Calibrator Well: Coated with mouse monoclonal antibodies 4 carriers (12 wells each), ready to use.
The Phadia EliA Immunodiagnostic System is an automated system for immunodiagnostic testing. The EliA reagents are available as modular packages, each purchased separately. All packages are required to carry out EliA M2 tests.
The provided text describes the 510(k) premarket notification for the EliA™ M2 Immunoassay, specifically focusing on its performance on new instrument platforms (Phadia® 2500/5000) compared to a previously cleared device (EliA M2 on Phadia 250 instrument, K141375).
This document is for an in vitro diagnostic (IVD) device, which measures IgG antibodies to M2 to aid in the clinical diagnosis of primary biliary cirrhosis. The "device" in this context is the immunoassay system, which includes the reagents and the instrument platforms.
Therefore, the acceptance criteria and study details discussed pertain to the analytical performance of this IVD device. The concepts of "human readers," "expert consensus for image interpretation," "MRMC," and "standalone algorithm performance" are not applicable here, as this is not an AI/ML imaging device or a device requiring human interpretation of complex visual data. The "ground truth" for an IVD diagnostic test is typically established through reference methods, established clinical diagnoses, or highly characterized samples.
Here's a breakdown of the acceptance criteria and study proof based on the provided text, focusing on the analytical performance of the immunoassay system.
Acceptance Criteria and Reported Device Performance
The core of the "acceptance criteria" for this 510(k) submission is demonstrating substantial equivalence to the predicate device. This is achieved by showing that the analytical performance characteristics of the EliA M2 immunoassay on the Phadia 2500/5000 instruments are comparable and acceptable. The document highlights various analytical performance parameters with their respective results.
1. Table of Acceptance Criteria and Reported Device Performance
Since this is an IVD device, the "acceptance criteria" aren't explicitly stated as pass/fail thresholds in a table, but rather implied by the data presented for substantial equivalence. The document presents the study results for various analytical performance metrics.
| Performance Characteristic | Implicit Acceptance Criteria (Comparative) | Reported Device Performance (EliA M2 on Phadia 2500/5000) |
|---|---|---|
| Precision/Reproducibility | Low variability across runs, instruments, and within-run. CVs should be acceptable for diagnostic assays. | Total Imprecision %CV: |
| 1.7 U/mL: 15.8% | ||
| 4.0 U/mL: 8.4% | ||
| 5.9 U/mL: 6.2% | ||
| 74.8 U/mL: 6.5% | ||
| 175.9 U/mL: 9.1% | ||
| Linearity/Reportable Range | Observed/Expected ratios for linearity close to 1, strong correlation (R² close to 1). Linear range and measuring range should be clearly defined. | Dilution Range (U/mL) / Slope / Intercept / R²: |
| 0.7 - 48.3 / 0.99 / -0.32 / 1.00 | ||
| 2.1 - 211.3 / 1.02 / 1.90 / 1.00 | ||
| 5.7 - 253.2 / 1.03 / 2.36 / 1.00 | ||
| 0.5 - 16.6 / 1.02 / 0.13 / 1.00 | ||
| Measuring Range: 0.8 U/mL (LoQ) to 220 U/mL | ||
| Detection Limit (LoD) | LoD should be adequately determined and clinically acceptable. | LoD: 0.5 U/mL (determined based on CLSI EP17-A guidelines) |
| Limit of Quantitation (LoQ) | LoQ should be adequately determined for quantitative measurements. | LoQ: 0.8 U/mL (determined based on CLSI EP17-A guidelines, target uncertainty 20%) |
| Analytical Specificity (Interference) | Should be free from significant interference from common substances. | "Previously reviewed in K141375" (implies no new interference studies needed if the chemistry is the same). |
| Analytical Specificity (Carry-over) | Should be no significant carry-over between samples/reagents. | No carry-over from samples to conjugate due to disposable tips and separate pipettes. |
| Method Comparison (vs. Predicate) | Strong correlation (slope close to 1, intercept close to 0) between new and predicate instruments. | Slope: 1.04 (95% CI: 1.02 to 1.06) |
| Intercept: -0.14 (95% CI: -0.46 to 0.03) | ||
| PPA, NPA, TPA (Equivocal Positive) | High agreement (e.g., >90%) with predicate based on clinical classification. | PPA: 100.0% (96.0% – 100%) |
| NPA: 93.3% (68.1% – 99.8%) | ||
| TPA: 99.1% (94.9% – 100%) | ||
| PPA, NPA, TPA (Equivocal Negative) | High agreement (e.g., >90%) with predicate based on clinical classification. | PPA: 100.0% (95.7% - 100%) |
| NPA: 95.5% (77.2% - 99.9%) | ||
| TPA: 99.1% (94.9% - 100%) |
2. Sample Size Used for the Test Set and Data Provenance
- Precision/Reproducibility:
- Sample Size: Each sample was tested in four replicates/run, over 7 days, on 3 instruments. This totals 84 replicates per sample (
4 replicates * 7 days * 3 instruments = 84 replicates). The document doesn't specify the number of distinct "samples" (control materials or patient samples) used to establish precision at different concentration levels, but it shows results for 5 different mean concentration levels (1.7, 4.0, 5.9, 74.8, 175.9 U/mL). Typically, these would be control materials or pooled patient samples. - Data Provenance: Not explicitly stated, but clinical studies for cut-off determination (K141375) and reference ranges mentioned a "Caucasian population obtained from a blood bank." For analytical studies like precision, standard reference materials or well-characterized internal controls are commonly used. The study was performed over 7 days.
- Sample Size: Each sample was tested in four replicates/run, over 7 days, on 3 instruments. This totals 84 replicates per sample (
- Linearity/Assay Reportable Range:
- Sample Size: Four patient serum samples were diluted.
- Data Provenance: Not explicitly stated regarding country of origin or retrospective/prospective nature for these specific samples.
- Detection Limit (LoB, LoD, LoQ):
- Sample Size:
- LoB: One blank sample, measured in twelve replicates in each of six runs (72 determinations total).
- LoD: Five low-level samples, measured in twelve replicates in each of six runs (360 low level replicates total).
- LoQ: 360 determinations.
- Data Provenance: Not explicitly stated.
- Sample Size:
- Method Comparison (Instrument Comparison):
- Sample Size: More than 100 samples.
- Data Provenance: Not explicitly stated regarding country of origin or retrospective/prospective nature. Samples were run in "single replicates" on one Phadia 250 and one Phadia 2500/5000 instrument.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- Not applicable. This is an in vitro diagnostic (IVD) immunoassay system, not an AI/ML imaging device that requires human expert interpretation of visual data. The "ground truth" for IVD laboratory tests is typically established by:
- Quantitative values: Directly measured by reference methods or highly characterized (e.g., gravimetric, spectrophotometric) standards traceability.
- Qualitative results (positive/negative): Defined by cut-off values derived from clinical studies, often comparing against a gold standard diagnostic method (e.g., biopsy, established clinical diagnosis of PBC).
4. Adjudication Method for the Test Set
- Not applicable. This concept (e.g., 2+1, 3+1) relates to consensus reading in imaging studies. For an IVD assay, results are quantitative values or interpreted based on pre-defined cut-offs.
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 IVD immunoassay device, not an AI-assisted diagnostic imaging system. There are no "human readers" in the context of image interpretation improving with AI assistance. The device directly measures antibody levels.
6. If a Standalone (i.e. Algorithm Only Without Human-in-the Loop Performance) Was Done
- Partially applicable, but in a different sense. The device itself performs the measurement and provides a quantitative result. The "performance" demonstrated (precision, linearity, LoD, method comparison) is inherently "standalone" in that it's the instrument and reagents producing the values. The "human-in-the-loop" would be the clinician interpreting the numerical result in conjunction with other clinical findings for diagnosis. There isn't an "algorithm" making a diagnostic call independently like in an imaging AI; rather, it's a measurement system.
7. The Type of Ground Truth Used
- Analytical Performance:
- Reference materials and statistical methods: For precision, linearity, and detection limit, the ground truth is based on highly characterized control materials, serial dilutions, and established statistical methodologies (e.g., CLSI guidelines EP05-A3, EP06-A, EP17-A).
- Clinical Performance (Cut-off determination and comparison):
- Clinical diagnosis and predicate device comparison: The clinical cut-off values for "Negative," "Equivocal," and "Positive" were "derived from the clinical studies (s. K141375)." This implies that the cut-offs were established using patient samples with confirmed clinical diagnoses of primary biliary cirrhosis (or healthy controls) as the ground truth in the predicate device's original studies.
- For the current submission, the "ground truth" for the method comparison study (comparing Phadia 2500/5000 to Phadia 250) is the result generated by the predicate device (EliA M2 on Phadia 250 instrument). The goal is to show the new instrument produces substantially equivalent results to the established predicate.
8. The Sample Size for the Training Set
- Not applicable in the AI/ML sense. This is an immunoassay system; it does not have a "training set" in the context of machine learning model development. The development process would involve formulation optimization, reagent stability testing, and calibration studies, but not "training data" for an algorithm that learns patterns. The calibration curve is established using calibrators provided with the kit.
9. How the Ground Truth for the Training Set Was Established
- Not applicable. See point 8. For IVDs, the "ground truth" for establishing a calibration curve (which is somewhat analogous to "training" the system to interpret raw signals into quantitative units) is defined by the known concentrations of the calibrator materials provided in the kit. These calibrators are rigorously manufactured and assigned values traceable to reference standards.
§ 866.5090 Antimitochondrial antibody immunological test system.
(a)
Identification. An antimitochondrial antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the antimitochondrial antibodies in human serum. The measurements aid in the diagnosis of diseases that produce a spectrum of autoantibodies (antibodies produced against the body's own tissue), such as primary biliary cirrhosis (degeneration of liver tissue) and chronic active hepatitis (inflammation of the liver).(b)
Classification. Class II (performance standards).