(170 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 plasma (sodium citrate, potassium EDTA, lithium and sodium heparin, and citrate dextrose (ACD)) 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 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 positive) are 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.
The provided text describes the LIAISON® HAV IgM assay, an in vitro chemiluminescent immunoassay for the qualitative detection of IgM antibodies to hepatitis A virus (IgM anti-HAV). The submission is a 510(k) for proposed modifications to the original device (K082050), not for a new device requiring extensive de novo studies. Therefore, the information provided focuses on demonstrating that the modifications do not raise new questions of safety and effectiveness and maintain substantial equivalence to the predicate device.
Here's an analysis based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" in a quantitative table for accuracy or clinical performance metrics (like sensitivity and specificity) of the modified device. Instead, it demonstrates equivalence to a comparator assay for sensitivity and elaborates on reproducibility and stability. The primary "acceptance criteria" for the modifications appear to be about maintaining the performance established by the original device and ensuring that the changes do not negatively impact its intended use, which is demonstrated through comparative studies and reproducibility.
However, based on the comparative studies, the implicit acceptance criterion for sensitivity was equivalence to the comparator assay in seroconversion panels.
| Performance Metric | Acceptance Criteria (Implicit) | Reported Device Performance (LIAISON® HAV IgM) |
|---|---|---|
| Sensitivity (Seroconversion Panels) | Equivalent to comparator assay | Equally identified the earliest and latest reactive results in all five seroconversion panels compared to the comparator assay. |
| Reproducibility (Total %CV) | Not explicitly stated, but typical for diagnostic assays, demonstrating acceptable precision. | *Negative Control (HAVM Negative)**: 6.5% |
| Positive Control: 11.8% | ||
| HAVM-P00: 4.9% | ||
| HAVM-P01*: 8.6% | ||
| HAVM-P04: 11.2% | ||
| HAVM-P14: 6.7% | ||
| HAVM-P15: 8.8% | ||
| HAVM-P16: 10.1% | ||
| Sample Equivalency (Plasma vs. Serum) | Slopes between 0.90-1.10 and bias within ± 10% compared to serum. | All slopes were between 0.90-1.10, and the bias was within ± 10%. |
| Sample Stability (Room Temperature) | 2 days | 2 days |
| Sample Stability (Refrigerated) | 7 days | 7 days |
| Sample Stability (Freeze/Thaw Cycles) | 5 cycles | 5 cycles |
| Calibration Curve Stability | 4 weeks | 4 weeks |
| Open Use Storage On-board Analyzer Stability | 8 weeks | 8 weeks |
| Open Use Storage at 2-8°C Stability (Reagent) | 8 weeks | 8 weeks |
| Open Use Storage at 2-8°C Stability (Control) | 4 weeks | 4 weeks |
| Cut-off Verification | Original cut-off values remain appropriate. | Confirmed original cut-off values are appropriate. |
Note: For HAVM Negative and HAVM-P01, RLU (Relative Light Units) were used for calculations as they were below the detectable limit of the curve.
2. Sample Size Used for the Test Set and Data Provenance
- Seroconversion Panels (Sensitivity): 5 commercially available HAV seroconversion panels. The provenance (country of origin, retrospective/prospective) is not specified for these panels, but they are commercial and commonly used for such evaluations.
- Reproducibility/Precision Study: A coded panel comprised of 6 frozen serum samples (negative, low positive, mid positive) and 2 controls (negative and positive). The provenance is not specified other than being prepared by DiaSorin S.p.A.
- Sample Equivalency and Stability Studies: 40 matched sets of samples (serum, serum in SST, and plasma in Sodium Citrate, Potassium EDTA, Lithium and Sodium heparin, and Citrate Dextrose (ACD)). The provenance is not specified.
- Overall: The studies appear to be retrospective as they use pre-existing seroconversion panels, frozen serum samples, and matched sample sets to evaluate the modifications.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not mention the use of experts to establish ground truth for the test set beyond the inherent nature of the seroconversion panels and the classification of samples (negative, low positive, mid positive) in the reproducibility study.
- For the seroconversion panels, the "ground truth" for the timing of seroconversion is established by the commercial panel provider, typically based on comprehensive characterization.
- For other studies, the "ground truth" for the samples is based on their preparation (e.g., spiking or diluting) or their known status prior to testing.
4. Adjudication Method for the Test Set
No explicit adjudication method (e.g., 2+1, 3+1) is mentioned for establishing the ground truth or resolving discrepancies for the test set performance. Results are compared directly to the comparator assay or the expected values based on sample preparation.
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
This device is an in vitro diagnostic (IVD) immunoassay, not an AI-powered imaging or interpretation device that would involve human "readers" in the sense of a MRMC study. Therefore, this section is not applicable. The device provides a quantitative result (RLU) that is converted into an Index value and then interpreted qualitatively (Negative, Equivocal, Reactive) by the healthcare professional using the provided cut-off values.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies presented evaluate the standalone performance of the LIAISON® HAV IgM assay. The assay itself provides a quantitative result and then an interpreted qualitative result based on predefined cut-off values. There is no "human-in-the-loop" interaction with the algorithm itself for interpretation; the human uses the algorithm's output (qualitative result) in conjunction with other clinical information.
7. The Type of Ground Truth Used
The ground truth used depends on the study:
- Seroconversion Panels: The ground truth for seroconversion timing is established by the commercial panel manufacturer, likely based on multiple reference assays and characterization of the samples.
- Reproducibility/Precision: The "expected" result for each sample (negative, low positive, mid positive) is based on how the panel was prepared (spiking or diluting) by DiaSorin S.p.A.
- Sample Equivalency and Stability: The ground truth for comparison is largely the serum specimen from the matched set, assumed as the reference for other matrix types. The stability ground truth is based on the initial characterization of the samples.
- Cut-off Verification: This implicitly relies on the original clinical validity studies for the un-modified device to ensure the continued appropriateness of the existing cut-offs.
8. The Sample Size for the Training Set
This document describes studies for modifications to an already approved device (K082050). IVD assays typically do not have "training sets" in the machine learning sense. The assay parameters (like detection antibodies, conjugate, and cut-offs) are established during the original device development. The studies here are for verification and validation of the modifications, not for training a new algorithm. Therefore, the concept of a "training set" as it applies to AI/ML is not applicable here. The original device development would have involved extensive sample testing to establish initial assay parameters and cut-offs.
9. How the Ground Truth for the Training Set Was Established
As explained above, the concept of a "training set" in the AI/ML sense is not applicable for this IVD immunoassay. The ground truth for establishing the original assay's performance and cut-offs (which these modification studies confirm are still valid) would have been established through extensive testing of clinical samples with known HAV infection status (confirmed by reference methods, clinical diagnosis, and potentially follow-up outcomes).
§ 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.