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510(k) Data Aggregation
(21 days)
The Copalis® Multiplex EBV Antibody Assay uses Coupled Particle Light Scattering technology in a microparticle agglutination-based assay for the qualitative or semiquantitative detection of antibodies to EBV VCA (total antibodies), EBNA (IgG), and EA (IgG and IgM) antigens. The assay is designed for human serum using the Copalis® I Immunoassay System. The presence of VCA, EBNA and EA antibodies is used as an aid in the diagnosis of EBV associated mononucleosis when used in conjunction with other EBV serologies in pediatric, adult, transplant donor and transplant recipient populations. The disease state distinction is made based on the antibody pattern of reactivity. When evaluating properly paired sera, the results of these assays are used to demonstrate seroconversion or significant change in antibody titer as evidence of recent infection. Both specimens should be tested simultaneously.
Coupled Particle Light Scattering (Copalis®) technology provides a rapid method for the measurement of antibodies to specific pathogens. The Copalis® Multiplex EBV Antibody Assay is a microparticle agglutination test using the Copalis® light scattering technology. Polystyrene microparticles of 3 sizes are coated with VCA synthetic peptide, EBNA recombinant antigen or EA recombinant antigen and are contained within a special covered reaction well in the test cup. The dried reagent is reconstituted with a reaction buffer on the instrument at the start of the assay. Patient sample is added to the reaction mixture and incubated for 10 minutes. The presence of antibodies specific to EBV antigens in the patient sample results in agglutination of the monomer microparticles to form aggregates. The reaction mixture is passed through a flow cell and the instrument uses light scattering technology to measure the monomer concentration. The decrease in the monomer population resulting from agglutination is related to the amount of antibody in the sample. The residual monomer concentration in each reaction mixture is compared to a cutoff value to determine sample reactivity and nonreactivity.
The provided document does not explicitly state acceptance criteria in the typical format of pre-defined thresholds that the device must meet. Instead, the study aims to demonstrate substantial equivalence to existing predicate devices (Gull Laboratories EBV IgG IFA, Gull Laboratories EBV-NA IFA, Gull Laboratories EBV-EA IFA) by comparing the Copalis® Multiplex EBV Antibody Assay's performance to expected marker patterns and agreement with IFA results.
Here's an interpretation of the "acceptance criteria" based on the presented data, which appear to be the results obtained to support the claim of substantial equivalence, and the study details:
1. Table of Acceptance Criteria and Reported Device Performance
Since no explicit quantitative acceptance criteria are given, the "acceptance criteria" are inferred from the goal of demonstrating comparable performance to IFA and expected serological patterns. The reported device performance is taken directly from the provided tables. The values in the "Acceptance Criteria" column reflect the general ranges or levels that would likely be considered acceptable for demonstrating substantial equivalence based on the comparison to IFA and expected patterns.
| Test Parameter / Population | Antigen Detected | Inferred Acceptance Criteria (Based on demonstrating comparability with IFA and expected patterns) | Reported Device Performance (Copalis® Multiplex EBV Antibody Assay) |
|---|---|---|---|
| Primary Disease State - Adult | VCA | Relative Sensitivity: High (e.g., >90%) | 100.0% (94.1 - 100%) |
| EBNA | Relative Specificity: High (e.g., >90%) | 94.9% (85.8 - 98.9%) | |
| EA vs Heterophile/IFA | Relative Sensitivity: High (e.g., >90%) | 94.9% (85.8 - 98.9%) | |
| Primary Disease State - Pediatric | VCA | Relative Sensitivity: High (e.g., >90%) | 100.0% (73.5 - 100.0%) |
| EBNA | Relative Specificity: Good (e.g., >50-70%) | 50.0% (21.1 - 78.9%) | |
| EA vs Heterophile/IFA | Relative Sensitivity: High (e.g., >90%) | 100.0% (73.5 - 100.0%) | |
| Reactivated Disease State | VCA | Relative Sensitivity: High (e.g., >90%) | 100.0% (91.8 - 100%) |
| EBNA | Relative Sensitivity: High (e.g., >85%) | 89.7% (75.8 - 97.1%) | |
| EA | Relative Sensitivity: High (e.g., >90%) | 100.0% (91.0 - 100%) | |
| EBV Screening Population - Adult | VCA | Relative Sensitivity: Good (e.g., >90%) | 96.8% (83.3 - 99.9%) |
| Relative Specificity: Good (e.g., >70%) | 100.0% (15.8 - 100.0%) | ||
| EBNA | Relative Sensitivity: Good (e.g., >90%) | 92.0% (74.0 - 99.0%) | |
| Relative Specificity: Good (e.g., >70%) | 75.0% (19.4 - 99.4%) | ||
| EA | Relative Sensitivity: Moderate (e.g., >70%) | 83.3% (58.6 - 96.4%) | |
| Relative Specificity: Moderate (e.g., >70%) | 77.8% (40.0 - 97.2%) | ||
| Seronegative Population - Adult | VCA | Relative Specificity: Moderate (e.g., >60%) | 62.5% (24.5 - 91.5%) |
| EBNA | Relative Specificity: High (e.g., >90%) | 100.0% (63.1 - 100.0%) | |
| EA | Relative Specificity: High (e.g., >90%) | 100% (59.0 - 100.0%) | |
| Reproducibility (VCA, EBNA, EA) | Control Samples | Total %CV: Low (e.g., <25%) | Neg Control: 3.9% (VCA), 2.8% (EBNA), 5.4% (EA); Low Pos Control: 12.3% (VCA), 7.3% (EBNA), 8.7% (EA); High Pos Control: 21.8% (VCA), 14.5% (EBNA), 19.5% (EA) |
| RP Samples | Within Run %CV: Low (e.g., <10%); Total %CV: Low (e.g., <25%) | Generally <10% for Within Run %CV, and <25% for Total %CV across all RPs and antigens. |
2. Sample Size Used for the Test Set and Data Provenance
- Total Sample Size: 423 samples (50 fresh (12%) and 373 frozen (88%))
- Disease State Sample Sizes:
- Primary Disease State - Adult: 61 samples (for VCA, EBNA, Heterophile/IFA comparison, but EA had 59 samples for some comparisons)
- Primary Disease State - Pediatric: 12 samples
- Reactivated Disease State: 43 samples (for VCA, EBNA, EA comparison, with slight variations for specific antigen comparisons)
- EBV Screening Population - Adult: 29 samples
- EBV Screening Population - Pediatric: 13 samples
- Seronegative Population - Adult: 8 samples (for VCA, EBNA, EA comparison, with slight variations per antigen)
- Seronegative Population - Pediatric: 34-42 samples (depending on antigen)
- Apparently Healthy Population: 98-102 samples (depending on antigen)
- Transplant Recipients: 48 samples
- Transplant Donors: 50-53 samples (depending on antigen)
- Data Provenance: The samples were collected from patients representing the eastern, midwestern, and western United States. The study was conducted at "two clinical laboratories and at DiaSorin," indicating a multi-site clinical study. The samples were retrospective (frozen) and prospective (fresh).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts
The document does not explicitly state the "number of experts" or their specific "qualifications" (e.g., "radiologist with 10 years of experience") used to establish the ground truth.
However, the ground truth was established by:
- "expected patterns of serological testing results for the 4 EBV markers (EBV VCA IgG and IgM, EBNA, and EA), and for primary infection, heterophile test."
- This implies a reliance on established diagnostic algorithms and interpretation of results from multiple serological tests, including IFA and heterophile tests. This process would typically involve clinical laboratory professionals or infectious disease specialists, but their number and specific qualifications are not detailed.
4. Adjudication Method for the Test Set
The document does not describe a formal "adjudication method" in the sense of a panel reviewing conflicting results from multiple readers. Instead, the ground truth was "based on comparison to expected patterns of serological testing results" and "IFA results for VCA IgM, VCA IgG and EBNA" and heterophile test results. Discrepancies (e.g., "Equivocal results by Copalis or IFA or non-specific staining by IFA") were "not included in the calculations." This indicates a methodical approach to classifying samples based on a pre-defined diagnostic algorithm using a combination of established tests, rather than an adjudication among human readers.
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. The study compares the performance of the Copalis® device to predicate devices (IFA) and established serological patterns, not to human readers with or without AI assistance.
6. If a Standalone Study (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, this was a standalone study. The Copalis® Multiplex EBV Antibody Assay is an automated immunoassay system. The reported performance metrics (sensitivity, specificity, agreement) directly reflect the algorithm's performance in detecting antibodies based on its light scattering technology, without human intervention in the result generation or interpretation process for the purpose of the device's output. The comparison to IFA serves as validation against a recognized lab test, not as a human-in-the-loop comparison.
7. The Type of Ground Truth Used
The ground truth used was a composite reference standard based on:
- Expert Consensus/Established Serological Patterns: "Expected patterns of serological testing results for the 4 EBV markers" and for primary infection, heterophile test.
- Reference Laboratory Testing (Predicate Devices): Specifically, IFA results for VCA IgM, VCA IgG, EBNA, and EA, as well as heterophile test results. The inclusion/exclusion criteria for different disease states were defined by these reference test results.
8. The Sample Size for the Training Set
The document does not describe a separate "training set" for the Copalis® device in the context of a machine learning algorithm. The device is an immunoassay, the "training" would refer to its development and calibration, which is not detailed here. The clinical samples discussed are the "test set" used for performance evaluation.
9. How the Ground Truth for the Training Set Was Established
As there is no explicitly mentioned "training set" for a machine learning algorithm, this question is not directly applicable. For the immunoassay's development and calibration, general laboratory practices for standard curves, controls, and characterization would have been used, but specific details on how ground truth was established for that phase are not provided in this regulatory submission.
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