(108 days)
The LIAISON® HAV IgM assay is an in vitro chemiluminescent immunoassay intended for the qualitative detection of IgM antibodies to hepatitis A virus (IgM anti-HAV) in human serum and sodium heparin plasma using the LIAISON® Analyzer. Assay results, in conjunction with other serological and clinical information, may be used for testing specimens from individuals who have signs and symptoms consistent with acute hepatitis as an aid in the laboratory diagnosis of acute or recent HAV infection. This assay is not intended for screening blood or solid or soft tissue donors. Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients. The user is responsible for establishing their own assay performance characteristics in these populations. The LIAISON® Control HAV IgM (negative and reactive) is intended for use as assayed quality control samples to monitor the performance of the LIAISON® HAV IgM assay.
The method for qualitative determination of HAV IgM is an antibody capture chemiluminescence immunoassay (CLIA). IgG to human IgM (mouse monoclonal) is used for coating magnetic particles (solid phase) and a mouse monoclonal antibody to HAV is linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, IgM antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with HAV antigen just added and the immune complex thus formed reacts with IgM already bound to the solid phase. After each incubation, the unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of anti-HAV IgM present in calibrators, samples or controls.
Here's a summary of the acceptance criteria and study details for the LIAISON® HAV IgM device based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a separate section. However, the "Conclusion" section summarizes the achieved performance which implies these were the target performance metrics for demonstrating equivalence. The "Comparative Clinical Trials" section details the studies that generated these performance metrics.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance | Study Type |
|---|---|---|---|
| Overall Agreement (Prospective: "At Risk" and "HAV Testing" populations) | High agreement with predicate ELISA | 99.9% (95% CI = 99.1 - 100%) | Comparative Clinical Trial (Prospective) |
| Overall Agreement (Pediatric Population) | High agreement with predicate ELISA | 100.0% (95% CI = 97.3 - 100%) | Comparative Clinical Trial (Prospective) |
| Reactive Percent Agreement (Retrospective: Acute HAV Infection) | High agreement with predicate ELISA | 96.7% (95% CI = 92.7 - 98.9%) | Comparative Clinical Trial (Retrospective) |
| Analytical Sensitivity (Seroconversion Panels) | Equivalent to or more sensitive than predicate assay | Equivalent to or more sensitive than comparator assay | Analytical Sensitivity (Seroconversion Panels) |
| Reproducibility (Overall %CV) | Low coefficient of variation (typical for diagnostic assays) | Ranged from 10.7% to 54.2% across various samples (lower for reactive, higher for negative/equivocal) | Reproducibility/Precision Study |
| Cross-Reactivity | No false positives for tested interfering substances | 0 reactive results out of 195 samples for various organisms/conditions | Cross-Reactivity Study |
| Interference from other substances (Hemoglobin, Lipemia, Bilirubin, Albumin, Gamma Globulin) | No impact on results at specified concentrations | No impact at: Hemoglobin (1000 mg/dL), Lipemia (3000 mg/dL), Icterus (20 mg/dL), Albumin (5 g/dL), y-Globulin (4 g/dL) | Potentially Interfering Substances Study |
2. Sample Size Used for the Test Set and Data Provenance:
- Prospective Studies:
- Individuals sent to the lab for HAV testing: 500 samples (from Northeastern US).
- Individuals At Risk for Viral Hepatitis: 239 individuals (from various locations based on at-risk groups like homosexual males, healthcare workers, commercial sex workers, drug users, prison inmates, dialysis patients, hemophiliacs).
- Pediatric Population: 108 prospectively collected samples (from children in the United States).
- Retrospective Study:
- Acute HAV Infection: 123 samples (including 42 acute pediatric samples from Egypt).
- Seroconversion Panels: 5 commercially available panels.
- Reproducibility Study: A coded panel of 12 frozen "engineered" serum samples.
- Cross-Reactivity Study: 195 samples from individuals with various organisms/conditions.
- Potentially Interfering Substances Study: Not explicitly stated, implied to be laboratory-prepared samples.
- Data Provenance: Mixed.
- Prospective: Northeastern US (for general HAV testing population), United States (for pediatric), and various unspecified locations (for at-risk groups).
- Retrospective: Egypt (for some pediatric acute HAV cases), and generally from individuals with acute HAV infection (locations not fully specified beyond that).
- Seroconversion panels: Commercially available.
- Reproducibility: Samples prepared by DiaSorin S.p.A.
- Cross-Reactivity: No specific country of origin mentioned for these diverse samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
The document doesn't mention the use of experts to establish ground truth for the test set. Instead, the LIAISON® HAV IgM assay performance was compared against a "Comparator ELISA," which is an FDA-approved method (DiaSorin Inc. ETI-HA-IGMK Plus Kit). This indicates that the ground truth was established by the results of this predicate device, implying its established validity.
4. Adjudication Method for the Test Set:
No adjudication method is described. The comparison is directly between the LIAISON® HAV IgM assay and the Comparator ELISA.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size:
No MRMC study was mentioned. This device is an in vitro diagnostic (IVD) assay, not typically subject to MRMC studies designed for imaging or clinical interpretation where human readers are involved. It's an automated assay reporting a result without human interpretation of raw data.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:
Yes, the studies described are standalone performance studies for the LIAISON® HAV IgM assay. The device measures IgM antibodies in a sample and provides a qualitative result (Reactive, Equivocal, Negative) without a human interpreting the raw chemiluminescence signal to assign the final diagnosis. The intended use clearly states it's for in vitro diagnostic use, producing results in conjunction with other serological and clinical information.
7. The Type of Ground Truth Used:
The primary ground truth used for the comparative clinical trials was the result from an FDA-approved comparator ELISA assay (DiaSorin Inc. ETI-HA-IGMK Plus Kit). For the acute HAV infection cases, the samples were from individuals "who had an (Acute) HAV infection," implying a clinical diagnosis potentially confirmed by other means, but the direct comparison was still against the predicate ELISA. For seroconversion panels, these are well-characterized commercial panels with known seroconversion profiles.
8. The Sample Size for the Training Set:
The document does not explicitly mention a "training set" or "validation set" in the context of machine learning model development. This is a traditional IVD assay, not an AI/ML diagnostic. The clinical trials described are for performance evaluation against a predicate.
9. How the Ground Truth for the Training Set Was Established:
As this is not an AI/ML diagnostic, there is no explicit "training set" or associated ground truth establishment process for machine learning. The device's performance was evaluated against an established FDA-approved method (predicate ELISA) and known seroconversion panels.
§ 866.3310 Hepatitis A virus (HAV) serological assays.
(a)
Identification. HAV serological assays are devices that consist of antigens and antisera for the detection of hepatitis A virus-specific IgM, IgG, or total antibodies (IgM and IgG), in human serum or plasma. These devices are used for testing specimens from individuals who have signs and symptoms consistent with acute hepatitis to determine if an individual has been previously infected with HAV, or as an aid to identify HAV-susceptible individuals. The detection of these antibodies aids in the clinical laboratory diagnosis of an acute or past infection by HAV in conjunction with other clinical laboratory findings. These devices are not intended for screening blood or solid or soft tissue donors.(b)
Classification. Class II (special controls). The special control is “Guidance for Industry and FDA Staff: Class II Special Controls Guidance Document: Hepatitis A Virus Serological Assays.” See § 866.1(e) for the availability of this guidance document.