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.

Device Description

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.

AI/ML Overview

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).

Summary

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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is a stylized image of three human profiles facing to the right, stacked on top of each other.

August 25, 2016

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

Public Health Service

DiaSorin, Inc. Carol A. DePouw Regulatory Affairs Specialist 1951 Northwestern Avenue Stillwater, MN 55082-0285

Re: K160650

Trade/Device Name: LIAISON® HAV IgM and LIAISON® Control HAV IgM Regulation Number: 21 CFR 866.3310 Regulation Name: Hepatitis A virus (HAV) serological assays Regulatory Class: II Product Code: LOL, JJX Dated: July 27, 2016 Received: July 28, 2016

Dear Ms. DePouw:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21. Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Steven R. Gitterman -S

for Uwe Scherf M. Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K160650

Device Name LIAISON® HAV IgM Assay LIAISON® Control HAV IgM

Indications for Use (Describe)

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.

Type of Use (Select one or both, as applicable)

Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)

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5.0 510(k) SUMMARY

SUBMITTED BY:	Carol A. DePouwRegulatory Affairs SpecialistDiaSorin Inc.1951 Northwestern AvenueStillwater, MN 55082-0285Phone (651) 351-5850Fax (651) 351-5669Email: carol.depouw@diasorin.com
NAME OF DEVICE:
Trade Name:	LIAISON® HAV IgM,LIAISON® Control HAV IgM
Common Names/Descriptions:	Hepatitis A Test (Antibody and IgM Antibody)and Controls
Classification Names:	Hepatitis A Virus (HAV) Serological assays21 CFR 866.3310 Class II Special ControlsMicrobiologySingle (Specified) analyte controls (assayedand unassayed); Class I reserved;21 CFR 862.1660: Clinical Chemistry
Product Code:	LOL, JJX
PREDICATE DEVICES	DiaSorin Inc. ETI-HA-IGMK Plus Kit(PMA #P890014)

DEVICE DESCRIPTION:

INTENDED USE:

The LIAISON® HAV IqM 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 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.

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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 laM assav.

The method for qualitative determination of HAV IgM is an KIT DESCRIPTION: antibody capture chemiluminescence immunoassay (CLIA).

lgG 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.

REASON FOR SUBMISSION:

The purpose of this 510(k) Submission is to present the proposed modifications to the DiaSorin LIAISON® HAV IgM and the LIAISON® Control HAV IgM (K082050).

Description of modifications to the LIAISON® HAV IgM and the LIAISON® Control HAV IgM:

Proprietary changes to the monoclonal antibodies and conjuqate.
Extension of stability claims for the calibration curve, on-board and open use storage.

1. Addition of sample types and sample stabilities.
1. Change from buffer based controls to serum based controls.

PERFORMANCE DATA:

The following studies were conducted to demonstrate that the modifications to the LIAISON® HAV IgM assay confirm the substantial equivalence to the predicate device and raise no new questions of safety and effectiveness. Studies not pertaining to the modifications may be found in the original 510(k) K082050.

COMPARATIVE STUDIES:

Five commercially available HAV seroconversion panels were tested using the LIAISON® HAV IgM and the FDA-approved comparator assay to determine sensitivity of the assay. The results are summarized in Table 1.

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Panel ID	LIAISON® HAV IgM		Comparator Assay		Differencein daysfrom lastreactiveresult
	Post-bleedday ofearliestreactiveresult	Post-bleedday of lastreactiveresult	Post-bleedday ofearliestreactiveresult	Post-bleedday of lastreactiveresult
0615-0026 seroconversion	14	27	14	27	0
PHT902 seroconversion	16	21	16	21	0
PHT903 seroconversion	38	108	38	108	0
RP004 seroconversion	6	62	6	62	0
RP013 seroconversion	8	189	8	189	0

Table 1

The sensitivity of the LIAISON® HAV IgM was equivalent to the comparator assay in the five seroconversion panels tested.

REPRODUCIBILITY:

A 5 day reproducibility/precision study was conducted at three external laboratories. The CLSI document EP15-A3 was consulted in the preparation of the testing protocol. A coded panel comprised of 6 frozen serum samples was prepared by DiaSorin S.p.A. The coded panel was prepared by either spiking or diluting samples as necessary to contain negative, low positive and mid positive samples.

The LIAISON® Control HAV IgM (negative and positive) were also included in the 5 day study. The LIAISON® HAV IgM Negative Control as well as negative panel sample (HAVM-P00) read below the detectable limit of the curve <<0.10; therefore, standard deviation (SD) and %CVs were calculated using the Relative Light Units (RLU's) for each respective sample

Results

The 5 day results are summarized in Table 2 (combined sites). The mean Index value, standard deviation, and coefficient of variation (%CV) of the results were computed for each of the tested specimens for intra- run, run to run, between site, and Total across sites.

		Intra-Run		Run to Run		Between Site		Total
Sample ID	mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV
HAVM Negative*	334	18.70	5.6	7.45	2.2%	8.28	2.5	21.80	6.5%
HAVM Positive	2.22	0.26	11.7%	0.05	2.2%	0.05	2.3%	0.26	11.8%
HAVM-P00	535	20.50	3.8%	16.10	3.0%	0.00	0.0%	26.00	4.9%
HAVM-P01*	1.48	0.12	8.4%	0.01	0.7%	0.03	2.1%	0.13	8.6%
HAVM-P04	0.60	0.07	11.0%	0.01	1.7%	0.01	1.2%	0.07	11.2%
HAVM-P14	1.18	0.08	6.6%	0.02	1.9%	0.02	1.3%	0.08	6.7%
HAVM-P15	2.42	0.21	8.6%	0.03	1.3%	0.03	1.2%	0.21	8.8%
HAVM-P16	5.62	0.48	8.5%	0.00	0.0%	0.31	5.5%	0.57	10.1%

Table 2: Combined Sites

*RLU used in calculations

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STABILITY STUDIES: REAGENTS

LIAISON® HAV IgM
Study	Stability
Calibration Curve	4 weeks
Open Use storage On-board Analyzer	8 weeks
Open Use storage at 2-8°C	8 weeks

LIAISON® Control HAV IgM
Study	Stability
Open Use storage at 2-8°C	4 weeks

SAMPLE EQUIVALENCY AND STABILITY STUDIES:

Sample sets of matched serum/multiple plasma were used in the study to evaluate the risk of potential unspecific reaction related to the use of different sample matrix.

Forty (40) matched sets of samples were assayed. The samples were collected as serum, serum in serum separator tubes, and plasma in anticoagulants Sodium Citrate, Potassium EDTA, Lithium and Sodium heparin and Citrate Dextrose (ACD). The serum specimen in the set was assumed as the reference. Samples belonging to each set were tested in triplicate with one LIAISON® HAV IgM reagent lot on one instrument in a single run.

Results of the SST tube and all plasma samples were compared to serum by Passing and Bablok regression and Bland Altman agreement.

All slopes were between 0.90-1.10, and the bias was within ± 10%.

Human serum, SST serum, Sodium Citrate Plasma, Potassium EDTA Plasma, Lithium Heparin Plasma, Sodium Heparin Plasma, or ACD Plasma are acceptable sample types for use in the LIAISON® HAV IgM assay.

SAMPLE STABILITY:

Studies were performed to evaluate the stability of samples at different sample storage conditions. The results are provided in the table below.

Specimen
Study	Stability
Room Temperature (15-30°C)	2 days
Refrigerated (2-8°C)	7 days
Freeze/Thaw Cycles	5 cycles

CUT-OFF VERIFICATION:

A verification study was performed to ensure that the original cut-off values were appropriate for the modified LIAISON® HAV IgM.

The user may continue to use the following cut-off values for interpretation of patient results.

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Index	Results	Interpretation
< 0.90	Negative(No further testing)	No detectable IgM antibodies to HAV were found.A negative result generally indicates that the patient has notbeen infected. If clinical exposure to HAV is suspecteddespite a negative finding, a second sample should becollected and tested no less than one to two weeks later.
≥ 0.90 and < 1.10	Equivocal(Retest in duplicate)	Equivocal samples should be retested in duplicate by theLIAISON® HAV IgM assay to confirm the initial result.Samples which are reactive (≥ 1.10) on both repeat testsshould be considered reactive. Samples which are negative(< 0.90) on both repeat tests should be considered negative.A second sample should be collected and tested no lessthan one to two weeks later when at least one of the repeatresults is equivocal or if the duplicates of the repeat resultsare reactive and negative.*
≥ 1.10	Reactive(No further testing)	Indicates the presence of detectable IgM antibodies to HAV.A reactive result generally indicates that the patient has anacute HAV infection. A reactive anti-HAV IgM result does notrule out other hepatitis infections.

CONCLUSION:

The material submitted in this premarket notification is complete and supports a substantial equivalence decision. The labeling is sufficient and it satisfies the requirements of 21CFR 809.10.

Regulation Number and Section

§ 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.