(488 days)
EliA Ro52 is intended for the in vitro semi-quantitative measurement of IgG antibodies directed to Ro52 in human serum as an aid in the diagnosis of Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM) in conjunction with other laboratory and clinical findings. EliA Ro52 uses the EliA IgG method.
EliA Ro60 is intended for the in vitro semi-quantitative measurement of IgG antibodies directed to Ro60 in human serum as an aid in the diagnosis of Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA Ro60 uses the EliA IgG method.
The EliA Ro52 and EliA Ro60 Immunoassays are semi-quantitative solid-phase fluoroenzyme immunoassays, for the determination of autoantibodies against SS-A/Ro 52 kDa and 60 kDa proteins. The EliA Ro52 and EliA Ro60 test System is a fully integrated and automated system composed of assay-specific reagents, EliA method-specific reagents, and general reagents.
The provided document describes the EliA Ro52 and EliA Ro60 Immunoassays, which are intended for the semi-quantitative measurement of IgG antibodies directed to Ro52 and Ro60 in human serum, respectively. These devices aid in the diagnosis of specific autoimmune diseases. The document includes detailed analytical and clinical performance data to support the substantial equivalence claim.
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 document does not explicitly state formal "acceptance criteria" in a tabulated format. Instead, it presents various analytical and clinical performance metrics, implying that these metrics, when compared to the predicate device and established clinical utility, are deemed acceptable for the device's intended use. Based on the provided performance data, the implicit acceptance criteria would likely be related to aspects like precision, linearity, detection limits, specificity (interference), and clinical sensitivity/specificity.
Below is a table summarizing key performance indicators reported in the document:
Table 1: Key Performance Metrics for EliA Ro52 and EliA Ro60
| Performance Metric | EliA Ro52 Reported Performance | EliA Ro60 Reported Performance | Implied Acceptance Criterion (General, not prescriptive) |
|---|---|---|---|
| Precision (Total Imprecision) | On Phadia 250: %CV 4.1% - 6.9% On Phadia 2500/5000: %CV 4.2% - 6.4% | On Phadia 250: %CV 4.4% - 9.1% On Phadia 2500/5000: %CV 4.5% - 7.1% | Total imprecision (Total %CV) should be within acceptable limits for diagnostic assays, demonstrating consistency and reliability across runs, instruments, and days. |
| Linearity (R² value) | Phadia 250: 0.9899 - 0.9994 (single), 0.9928 (combined) Phadia 2500E: 0.9875 - 0.9980 (single) | Phadia 250: 0.9961 - 0.9996 (single), 0.9979 (combined) Phadia 2500E: 0.9949 - 0.9992 (single) | The assay should demonstrate linearity across its entire measuring range, indicated by a high R² value (close to 1) for regression analysis of serially diluted samples. |
| Detection Limit (LoD) | 0.3 EliA U/mL | DfU states 0.4 EliA U/mL (harmonized) | The Limit of Detection (LoD) should be sufficiently low to detect clinically relevant concentrations of the analyte. |
| Analytical Specificity | No interference observed from listed endogenous/exogenous substances. | No interference observed from listed endogenous/exogenous substances. | The assay should not be significantly affected by common interfering substances (e.g., bilirubin, hemoglobin, rheumatoid factor, common medications) at clinically relevant concentrations. |
| Method Comparison (vs. Predicate) | EliA Ro52 vs. QUANTA Flash Ro52: PPA 80.8% - 92.3%, NPA 90.7% - 98.4%, TPA 91.2% - 93.4% | EliA Ro60 vs. QUANTA Flash Ro60: PPA 93.9% - 97.0%, NPA 81.6% - 92.1%, TPA 91.3% - 93.3% | Agreement with the legally marketed predicate device (expressed as Positive Percent Agreement (PPA), Negative Percent Agreement (NPA), and Total Percent Agreement (TPA)) should be high, demonstrating comparable performance. |
| Clinical Sensitivity (EliA Ro52) | SLE: 47.5% - 50.8% SS: 50.0% - 55.0% IIM: 36.2% - 37.2% SSc: 20.9% - 26.4% | N/A (Ro52 specific) | Clinical sensitivity for the specified autoimmune diseases (Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies) should be clinically acceptable and comparable to established diagnostic benchmarks for similar assays. Specific numerical cut-offs are implied by the data presented. |
| Clinical Specificity (EliA Ro52) | SLE control: 95.6% - 96.9% SS control: 95.6% - 96.9% IIM control: 95.6% - 96.9% SSc control: 95.6% - 96.9% | N/A (Ro52 specific) | Clinical specificity against control groups (other autoimmune diseases, infectious diseases) should be high to minimize false positives. |
| Clinical Sensitivity (EliA Ro60) | N/A (Ro60 specific) | SLE: 48.3% - 50.8% SS: 68.3% - 71.7% | Clinical sensitivity for the specified autoimmune diseases (Sjögren's syndrome, systemic lupus erythematosus) should be clinically acceptable and comparable to established diagnostic benchmarks for similar assays. Specific numerical cut-offs are implied by the data presented. |
| Clinical Specificity (EliA Ro60) | N/A (Ro60 specific) | SLE control: 98.4% - 98.6% SS control: 98.4% - 98.6% | Clinical specificity against control groups (other autoimmune diseases, infectious diseases) should be high to minimize false positives. |
The acceptance of these performance metrics is implicitly based on comparison with the predicate devices (QUANTA Flash Ro52 and QUANTA Flash Ro60) and the established clinical utility in diagnosing the mentioned autoimmune diseases. The FDA's substantial equivalence determination (K210902) confirms that the submitted data supports the claim that the new devices perform comparably to the predicate devices.
2. Sample Size Used for the Test Set and Data Provenance
The document describes several test sets for different performance characteristics:
- Precision/Reproducibility:
- Phadia 250: 5 samples, each with 252 replicate determinations (across 3 instruments, 7 days, 21 runs).
- Within-lab Imprecision: Samples in 80 replicates on 1 instrument over 20 days (40 runs).
- Phadia 2500 and Phadia 5000 series (E-module): 5 samples, each with 84 replicates (across 3 instruments, 7 days, 21 runs).
- Linearity/Assay Reportable Range: 3 patient serum samples serially diluted in at least 9 dilution steps, tested in quadruplicates.
- Detection Limit: 4 blank and 4 low-level samples, tested in 5-fold determination, across 2 different reagent sets (totaling 120 combined observations for blank and low-level per instrument type).
- Analytical Specificity (Interference): 3 serum samples (negative, equivocal, high positive), spiked with interfering substances, tested in triplicates.
- Method Comparison with Predicate Device:
- EliA Ro52: 208 patient serum samples (only 181 used in agreement calculations due to samples outside measuring range).
- EliA Ro60: 208 patient serum samples (only 104 used in agreement calculations due to samples outside measuring range).
- Clinical Sensitivity and Specificity:
- EliA Ro52: 755 clinically and ethnically defined serum samples. These include:
- Diagnostic group: SLE (n=120), Sjögren's syndrome (n=60), IIM (n=94), SSc (n=91) - total 365.
- Disease control group: 390 samples (various autoimmune and infectious diseases).
- EliA Ro60: 713 clinically and ethnically defined serum samples. These include:
- Diagnostic group: SLE (n=120), Sjögren's syndrome (n=60) - total 180.
- Disease control group: 533 samples (various autoimmune and infectious diseases, excluding SSc).
- EliA Ro52: 755 clinically and ethnically defined serum samples. These include:
Data Provenance:
The document states that the clinical samples used for sensitivity and specificity determination were from "clinically and ethnically defined serum samples, including those of US origin." This indicates a mix of retrospective (clinically defined, likely banked samples) and potentially prospective (if US origin implies some form of fresh collection for the study) data. It is not explicitly stated whether it was purely retrospective or involved prospective collections, but the description "clinically and ethnically defined serum samples" strongly suggests retrospective use of samples with established diagnoses.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not provide information on the number of experts used to establish the ground truth for the test sets (e.g., for diagnoses of SLE, SS, IIM, SSc). It only states that samples were "clinically and ethnically defined." This typically implies that patient diagnoses were established through standard clinical practice by medical professionals, but the specifics of these experts' qualifications or the consensus process are not detailed in this submission summary.
4. Adjudication Method for the Test Set
The document does not specify an adjudication method for establishing the ground truth for the test set. It refers to diagnoses as "clinically defined," which generally suggests diagnosis was made by treating physicians following clinical guidelines, but no adjudication process like 2+1 or 3+1 by independent experts is mentioned for the study.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This document describes an in vitro diagnostic (IVD) device, specifically an immunoassay for measuring antibody levels. MRMC studies are typically performed for imaging devices or other diagnostic tools where human interpretation is involved and needs to be compared with and/or augmented by AI. This device is an automated laboratory test, and its performance is evaluated directly through analytical measurements and comparison to a predicate device, as well as clinical sensitivity and specificity against established clinical diagnoses.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, this is a standalone device. The EliA Ro52 and EliA Ro60 Immunoassays are "automated semi-quantitative solid phase fluoroenzymeimmunoassays" run on "Phadia 250 instrument and the Phadia 5000 instrument series (E-modules)." The results are automatically converted to EliA U/mL. The performance characteristics described (precision, linearity, detection limit, analytical specificity, clinical sensitivity, specificity) are all based on the output of the automated instrument and reagents, independent of human interpretation during the actual test process itself. The interpretation of results (negative, equivocal, positive) is based on defined cut-off values.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
For the clinical sensitivity and specificity studies, the ground truth was clinical diagnosis. The samples were "clinically and ethnically defined serum samples" with established diagnoses of various autoimmune diseases (SLE, SS, IIM, SSc) and control conditions. This implies that the diagnosis was based on the standard clinical criteria and medical records established by healthcare professionals, rather than a separate expert consensus panel or specific pathology results for the study.
8. The Sample Size for the Training Set
The document does not describe a "training set" in the context of machine learning or AI models, as this is an immunoassay and not an AI/ML-based device.
However, if "training set" is generally interpreted as samples used for assay development, optimization, or establishing parameters like cut-offs, the relevant information is:
- Cut-off definition: A cohort of 69 healthy blood donors, 19 SLE patients, and 9 Sjögren's syndrome (SS) patients for EliA Ro52, and 70 healthy blood donors, 22 SLE patients, and 6 Sjögren's syndrome patients for EliA Ro60, were used to define the cut-off values. This can be considered the 'development' or 'calibration' set for determining the interpretive thresholds.
9. How the Ground Truth for the Training Set Was Established
As noted above, this device does not utilize a machine learning "training set" in the conventional sense. For the samples used to establish the cut-off values (which could be considered analogous to determining a 'decision boundary' in an ML context), the ground truth was established based on the clinical diagnoses of the patient samples (healthy blood donors, SLE patients, Sjögren's syndrome patients). The document states that the initial cut-off for EliA Ro52, set using SLE and SS patients, was later verified with additional IIM and SSc patient sera. This indicates clinical diagnosis as the gold standard.
§ 866.5100 Antinuclear antibody immunological test system.
(a)
Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).(b)
Classification. Class II (performance standards).