LIAISON® XL MUREX HBc IgM, LIAISON® XL MUREX Control HBc IgM

P180045 · DiaSorin, Inc. · SEI · Aug 29, 2020 · Microbiology

Device Facts

• Record ID: P180045
• Device Name: LIAISON® XL MUREX HBc IgM, LIAISON® XL MUREX Control HBc IgM
• Applicant: DiaSorin, Inc.
• Product Code: SEI · Microbiology
• Decision Date: Aug 29, 2020
• Decision: APRL
• Regulation: 21 CFR 866.3173
• Device Class: Class 2
• Attributes: Pediatric

Intended Use

The LIAISON® XL MUREX HBc IgM assay is an in vitro chemiluminescent immunoassay (CLIA) for the qualitative detection of IgM anti-bodies to hepatitis B virus core antigen (HBc IgM) in human adult and pediatric (2 to 21 years) serum and plasma (lithium and sodium heparin, sodium citrate and K2 EDTA), including separator tubes, on the LIAISON® XL Analyzer. Assay results, in conjunction with other hepatitis B virus (HBV) serological markers and clinical information may be used as an aid in the diagnosis of HBV infection in patients with symptoms of hepatitis or who may be at risk for HBV infection. The presence of anti-HBc IgM is indicative of acute or recent HBV infection. This assay is not approved for use in screening blood, plasma or tissue donors.

Device Story

LIAISON® XL MUREX HBc IgM is a qualitative chemiluminescent immunoassay (CLIA) performed on the LIAISON® XL Analyzer. Input: human serum or plasma samples. Principle: magnetic particles coated with anti-human IgM capture patient IgM; recombinant HBcAg conjugated to isoluminol reacts with captured IgM; flash chemiluminescence induced by starter reagents; light signal (RLU) measured by photomultiplier proportional to IgM anti-HBc concentration. Used in clinical laboratories by technicians. Output: qualitative result (reactive/non-reactive) based on RLU thresholds. Clinicians use results alongside other HBV serological markers to diagnose acute or recent HBV infection. Benefits: aids in timely diagnosis, monitoring, and treatment initiation for hepatitis B, potentially reducing disease sequelae and transmission.

Clinical Evidence

Clinical agreement study tested 3,082 samples (prospective and retrospective) from 6 countries. Compared LIAISON® XL MUREX HBc IgM against 6 FDA-approved reference HBV assays. Overall PPA 96.6% (95% CI: 92.2%-98.5%) and NPA 98.8% (95% CI: 98.4%-99.2%). Subgroup analysis included acute, chronic, and recovery states. Pediatric performance (2-21 years) demonstrated equivalence to adult samples.

Technological Characteristics

Qualitative CLIA; magnetic particles coated with mouse monoclonal IgG to human IgM; recombinant HBcAg-isoluminol conjugate; flash chemiluminescence detection. Dimensions/form factor: Reagent Integral for LIAISON® XL Analyzer. Connectivity: Automated analyzer. Sterilization: N/A (reagents). Software: Embedded firmware on LIAISON® XL Analyzer.

Indications for Use

Indicated for qualitative detection of IgM antibodies to hepatitis B virus core antigen (HBc IgM) in human adult and pediatric (2-21 years) serum and plasma. Used as an aid in diagnosis of HBV infection in patients with symptoms of hepatitis or at risk for HBV infection. Not for blood, plasma, or tissue donor screening.

Regulatory Classification

Identification

A hepatitis B virus (HBV) antibody assay is identified as an in vitro diagnostic device intended for prescription use in the detection of antibodies to HBV in human serum, plasma, or other matrices, and as a device that aids in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Results from assays may be qualitative or quantitative, such as quantitative anti-HBs. In addition, results from an anti-HBc IgM (IgM antibodies to core antigen) assay indicating the presence of anti-HBc IgM are indicative of recent HBV infection. Anti-HBs (antibodies to surface antigen) assay results may be used as an aid in the determination of susceptibility to HBV infection in individuals prior to or following HBV vaccination or when vaccination status is unknown. The assay is not intended for screening of blood, plasma, cells, or tissue donors. The assay is intended as an aid in diagnosis in conjunction with clinical findings and other diagnostic procedures.

Special Controls

*Classification.* Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10(b) of this chapter must include: (i) A prominent statement that the assay is not intended for the screening of blood, plasma, cells, or tissue donors. (ii) A detailed explanation of the principles of operation and procedures for performing the assay. (iii) A detailed explanation of the interpretation of results. (iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include statements that indicate: (A) When appropriate, performance characteristics of the assay have not been established in populations of immunocompromised or immunosuppressed patients or other special populations where assay performance may be affected. (B) Detection of HBV antibodies to a single viral antigen indicates a present or past infection with hepatitis B virus, but does not differentiate between acute, chronic, or resolved infection. (C) The specimen types for which the device has been cleared, and that use of the assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results. (D) Diagnosis of hepatitis B infection should not be established on the basis of a single assay result but should be determined by a licensed healthcare professional in conjunction with the clinical presentation, history, and other diagnostic procedures. (E) A non-reactive assay result may occur early during acute infection, prior to development of a host antibody response to infection, or when analyte levels are below the limit of detection of the assay. (F) Results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay. (v) For devices intended for the quantitative detection of HBV antibodies (anti-HBs), in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, labeling required under § 809.10(b) of this chapter must include: (A) The assay calibrators' traceability to a standardized reference material that FDA has determined is appropriate ( *e.g.,* a recognized consensus standard) and the limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ), linearity, and precision to define the analytical measuring interval.(B) Performance results of the analytical sensitivity study testing a standardized reference material that FDA has determined is appropriate ( *e.g.,* a recognized consensus standard).(2) Design verification and validation must include the following: (i) Detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, and design of the antigen(s) and capture antibody(ies) sequences, rationale for the selected epitope(s), degree of amino acid sequence conservation of the target, and the design and composition of all primary, secondary and subsequent standards used for calibration. (ii) Documentation and characterization ( *e.g.,* supplier, determination of identity, and stability) of all critical reagents (including description of the antigen(s) and capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.(iii) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on assay performance. (iv) Final release criteria to be used for manufactured assay lots with appropriate evidence that lots released at the extremes of the specifications will meet the identified analytical and clinical performance characteristics as well as stability. (v) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range. (vi) All stability protocols, including acceptance criteria. (vii) When applicable, analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays. (viii) Analytical performance studies and results for determining the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility), including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, specimen stability, reagent stability, and cross-genotype antibody detection sensitivity, when appropriate. (ix) For devices intended for the detection of antibodies for which a standardized reference material (that FDA has determined is appropriate) is available, the analytical sensitivity study and results testing the standardized reference material. Detailed documentation of that study and its results must be provided, including the study protocol, study report, testing results, and all statistical analyses. (x) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review. (xi) Detailed documentation of clinical performance testing from a clinical study with an appropriate number of HBV reactive and non-reactive samples in applicable risk categories and conducted in the appropriate settings by the intended users. Performance must be analyzed relative to an FDA cleared or approved HBV antibody assay or a comparator that FDA has determined is appropriate. Additional relevant patient groups must be validated as appropriate. The samples must include prospective (sequential) samples for each identified specimen type and, as appropriate, additional characterized clinical samples. Samples must be sourced from geographically diverse areas. (3) For any HBV antibody assay intended for quantitative detection of anti-HBV antibodies, the following special controls, in addition to those special controls listed in paragraphs (b)(1) and (2) of this section, also apply: (i) Detailed documentation of the metrological calibration traceability hierarchy to a standardized reference material that FDA has determined is appropriate. (ii) Detailed documentation of the following analytical performance studies conducted, as appropriate to the technology, specimen types tested, and intended use of the device, including upper and lower limits of quantitation (UloQ and LloQ, respectively), linearity using clinical samples, and an accuracy study using the recognized international standard material.

Reference Devices

• ETI-CORE-IgMK PLUS

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: IgM antibody to Hepatitis B core antigen (Anti-HBc IgM)

Device Trade Name: LIAISON® XL MUREX HBc IgM
LIAISON® XL MUREX Control HBc IgM

Device Procode: LOM

Applicant’s Name and Address: DiaSorin Inc.
1951 Northwestern Avenue
Stillwater, Minnesota 55082-0285

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P180045

Date of FDA Notice of Approval: August 29, 2020

II. INDICATIONS FOR USE

LIAISON® XL MUREX Anti-HBc IgM

The LIAISON® XL MUREX HBc IgM assay is an in vitro chemiluminescent immunoassay (CLIA) for the qualitative detection of IgM anti-bodies to hepatitis B virus core antigen (HBc IgM) in human adult and pediatric (2 to 21 years) serum and plasma (lithium and sodium heparin, sodium citrate and K2 EDTA), including separator tubes, on the LIAISON® XL Analyzer. Assay results, in conjunction with other hepatitis B virus (HBV) serological markers and clinical information may be used as an aid in the diagnosis of HBV infection in patients with symptoms of hepatitis or who may be at risk for HBV infection. The presence of anti-HBc IgM is indicative of acute or recent HBV infection.

This assay is not approved for use in screening blood, plasma or tissue donors.

LIAISON® XL MUREX Control Anti-HBc IgM

The LIAISON® XL MUREX Control HBc IgM (negative and positive) is intended for use as assayed quality control samples to monitor the performance of the LIAISON® XL MUREX HBc IgM assay. The performance characteristics of LIAISON® XL MUREX Control HBc IgM have not been established for any other assays or instrument platforms.

III. CONTRAINDICATIONS

There are no known contraindications.

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the LIAISON XL MUREX HBc IgM labeling.

# V. DEVICE DESCRIPTION

LIAISON® XL MUREX HBc IgM is a qualitative chemiluminescent immunoassay (CLIA). IgG to human IgM (mouse monoclonal) is used for coating magnetic particles (solid phase) and recombinant HBcAg is linked to an isoluminol derivative (isoluminol-HBcAg conjugate). During the first incubation, IgM antibodies present in calibrators, samples, or controls bind to the solid phase. During the second incubation, the HBcAg conjugate reacts with IgM anti-HBc 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-HBcAg conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of the general IgM anti-HBc concentration present in calibrators, samples, or controls.

# Components of the LIAISON XL MUREX HBc IgM assay

All reagents are supplied ready to use.

The table below describes the components of the LIAISON XL MUREX HBc IgM kit.

Table 1: Components of the LIAISON XL MUREX HBc

| Magnetic Particles
1 vial – 1.3 mL | Magnetic particles coated with IgG to human IgM (mouse monoclonal), BSA, phosphate buffer, < 0.1% sodium azide. |
| --- | --- |
| Calibrator 1
1 vial – 3.6 mL | Low levels of chimeric IgM anti-HBc antibodies (human and mouse monoclonal), animal proteins, buffer, 0.2% ProClin® 300, preservatives, an inert red dye. |
| Calibrator 2
1 vial – 3.6 mL | High levels of chimeric IgM anti-HBc antibodies (human and mouse monoclonal), animal proteins, buffer, 0.2% ProClin® 300, preservatives, an inert blue dye. |
| Conjugate
1 vial – 1.3 mL | HBcAg (obtained in E. coli by the recombinant DNA technology) conjugated to an isoluminol derivative, BSA, phosphate buffer, 0.2% ProClin® 300, and preservatives. |
| Specimen diluent 1
vial - 15.5 mL | Non-specific human IgG (polyclonal), BSA, phosphate buffer, EDTA, 0.2% ProClin® 300, preservatives, an inert blue dye. |
| Buffer E
1 vial - 12 mL | Human serum/plasma, BSA, phosphate buffer, 0.2% ProClin® 300, preservatives. |

LIAISON® XL MUREX Control HBc IgM set consists of two (2) controls (positive and negative) that are ready to use. Each control set contains enough solution to allow for at

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least 20 tests. The control set is an additional material required to perform the test. The controls are used for monitoring the performance of the LIAISON XL MUREX HBc IgM assay.

The control set is additional material required to perform the test.

| NEGATIVE CONTROL 2 vials - 0.9 mL each | Human serum without anti-HBc antibodies with 0.2% ProClin® 300 and preservatives. |
| --- | --- |
| POSITIVE CONTROL 2 vials - 0.9mL each | Chimeric IgM anti-HBc antibodies (human and mouse monoclonal), 0.2% ProClin® 300, preservatives and an inert yellow dye. |

## Interpretation of the Results (anti-HBc IgM):

The interpretation of results for the LIAISON XL MUREX HBc IgM is as follow:

Table 2: Results Interpretation

| Initial Result (mIU/ml) | Repeat Result (mIU/ml) | Interpretation |
| --- | --- | --- |
| x ≥ 9.00 | N/A | Reactive |
| 7.00 ≤ x < 9.00 (Equivocal) | 2 out of 3 are ≥8.00 | Reactive |
| | 2 out of 3 are <8.00 | Non-reactive |
| x < 7.00 | N/A | Non-Reactive |

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the detection of IgM antibodies to hepatitis B core antigen (Anti-HBc IgM). There are currently several FDA approved in vitro diagnostic tests commercially available for serological markers of hepatitis B virus (HBV) infection which, when used in conjunction with a patient's medical history, clinical examination, and other laboratory finding, may be used as an aid in the diagnosis of HBV infection in patients with symptoms of hepatitis or who may be at risk for HBV infection. The assay may be used as an aid in determining acute infection. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

LIAISON® XL MUREX HBc IgM (318140) is essentially the same as the CE-marked LIAISON® HBc IgM (310140) with improvements to some of the raw material manufacturing processes. LIAISON® XL MUREX Control HBc IgM (Catalog Number 318141) is a different composition (serum based) compared to the CE marked LIAISON® Control HBc IgM (Catalog Number 310141).

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The LIAISON® XL MUREX HBc IgM assay (318140) and LIAISON® XL MUREX Control HBc IgM (318141) have not been marketed in the U.S. or any foreign country.

The LIAISON® HBc IgM (310140) and the LIAISON® Control HBc IgM (310141) have been marketed in multiple countries. These devices have not been withdrawn from the market in any country for reasons relating to safety and effectiveness.

The following table includes a list all countries where the CE-marked versions have been marketed in the past year.

Table 3: Countries Where CE-Marked Versions Have Been Marketed
| Austria | Argentina | Australia |
| --- | --- | --- |
| Bangladesh | Belgium | Bulgaria |
| Brunei | Brazil | Bahamas |
| Switzerland | Chile | Colombia |
| Cyprus | Czech Republic | Germany |
| Denmark | Dominican Republic | Ecuador |
| Egypt | Spain | Finland |
| France | United Kingdom | Greece |
| Croatia | Hungary | Israel |
| Iraq | Iran | Italy |
| Lebanon | Luxembourg | Morocco |
| Mexico | Netherlands | Norway |
| Peru | Poland | Portugal |
| Paraguay | Qatar | Romania |
| Serbia | Saudi Arabia | Slovenia |
| Sweden | Thailand | Tunisia |
| Turkey | Venezuela | Vietnam |
| South Africa | China | |

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. The LIAISON® XL MUREX HBc IgM is intended for in vitro diagnostic use, and as a result, there is no direct adverse effect on the patient. A blood draw is unlikely to cause adverse effects on the patient. In performing the test, standard good laboratory practices are considered sufficient to minimize risks to the end user of obtaining an incorrect result.

Failure of the product to perform as intended or human error in the use of the test may lead to a false result. Appropriate Warnings and Precautions for identified risks are contained in the labeling and assay Instructions for Use.

A false positive result in a diagnostic setting includes improper patient management, including treatment for hepatitis B with antiviral medication. Antiviral medical has risks

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including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are co-infected but undiagnosed with other viruses using the same antiviral medication, such as HIV, can lead to viral resistance; however, the chance of an undiagnosed co-infection in a patient tested for hepatitis B is exceedingly unlikely.

Because hepatitis B core IgM antibody is ordered as part of a panel in clinical practice, the risk of a false positive result will likely be mitigated as incongruous test results would lead a clinician to either retest the patient or further investigate the etiology of hepatitis. Hepatitis B core antigen IgM is only used as the sole diagnostic for acute hepatitis B in a patient with clinical findings suspicious for acute hepatitis who is in the "window period" between HBsAg seroconversion to HBsAg antibodies; however, the number of patients that will be tested who are in this specific category is extremely small, mitigating the risk of a false positive.

A false negative result includes missing the opportunity to treat a patient who has hepatitis B infection and whose clinical picture warrants antiviral treatment. Again, because hepatitis B core IgM antibody is ordered as part of a panel in clinical practice, this risk will likely be mitigated as incongruous test results would lead a clinician to either retest the patient and further investigate the etiology of clinical hepatitis.

## IX. SUMMARY OF NONCLINICAL STUDIES

### A. Laboratory Studies

#### 1. Cut-Off Determination

The cut-off was established internally at DiaSorin and verified by testing a total of 105 samples (55 known negative and 50 known positive). A receiver Operating Characteristics (ROC) analysis was performed on the results of the specimens tested. The assay's cutoff was evaluated with the observed results to demonstrate that its selection represents the best level of specificity, without compromising the sensitivity.

The cut-off value of 0.8 is within the optimal range determined by the ROC curve to discriminate between negative and positive results.

#### 2. Sensitivity/Seroconversion Panels

The seroconversion sensitivity of the LIAISON® XL MUREX HBc IgM assay has been demonstrated by testing eight (8) commercial seroconversion panels in comparison to a reference HBc IgM immunoassay in terms of number of days from initial draw to first positive sample, as well as the difference between the last negative results and the first positive results.

The LIAISON® XL MUREX HBc IgM yielded a positive result sooner by one or more blood draws or more than the comparator assay in six (6) of the eight (8) panels.

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3. Analytical Sensitivity/Dilution Study with Standard

The sensitivity of the LIAISON® XL MUREX HBc IgM was evaluated by preparing serial dilutions of the HBc Reference material IgM 84 (IgM anti-HBc, Paul-Ehrlich-Institute Germany).

Dilutions were tested in triplicate on three (3) reagent lots, using one lot of kit controls, across four (4) LIAISON XL Analyzers.

The cutoff concentration corresponds to 15.9 PEI U/mL.

4. Analytical Specificity (Cross-Reactivity)

A study was conducted to evaluate the LIAISON XL MUREX HBc IgM for cross-reactivity with specimens from individuals with medical conditions unrelated to HBV infection. A total of 301 samples from 28 unrelated medical conditions were tested in singlicate on one kit lot of LIAISON XL MUREX HBc IgM and on a reference HBC IgM assay.

Of the 301 samples, no evidence of cross-reactivity was observed. The results of each potential cross reactant are shown in table below.

Table 4: Summary of Cross-Reactivity Study

| | | No. of observed negative results | |
| --- | --- | --- | --- |
| Potential cross reactant | No. of expected negative samples | LIAISON® XL MUREX HBc IgM | ETI-CORE-IgMK PLUS |
| Anti-nuclear antibodies (ANA) | 10 | 10 | 10 |
| Auto-immune hepatitis | 10 | 10 | 10 |
| C. trachomatis | 11 | 11 | 11 |
| CMV (anti-CMV IgG and/or IgM positive) | 11 | 11 | 11 |
| EBV (anti-VCA IgG and/or IgM positive) | 11 | 11 | 11 |
| Fatty liver disease | 11 | 11 | 11 |
| HAMA | 11 | 11 | 11 |
| Hemodialysis patient | 11 | 11 | 11 |
| Hepatitis A Virus (anti-HAV IgG and/or IgM positive) | 11 | 11 | 11 |
| Hepatitis C Virus (anti-HCV IgG and/or IgM positive) | 11 | 11 | 11 |
| Hepatocellular carcinoma | 11 | 11 | 11 |
| HIV-1 (anti-HIV-1 positive) | 11 | 11 | 11 |
| HIV-2 (anti-HIV-2 positive) | 11 | 11 | 11 |
| HSV (anti-HSV IgG and/or IgM positive) | 11 | 11 | 11 |
| HTLV-1/2 (anti-HTLV positive) | 11 | 11 | 11 |

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| | | No. of observed negative results | |
| --- | --- | --- | --- |
| Potential cross reactant | No. of expected negative samples | LIAISON® XL MUREX HBc IgM | ETI-CORE-IgMK PLUS |
| IgG monoclonal gammopathy | 11 | 11 | 11 |
| IgM monoclonal gammopathy | 10 | 10 | 10 |
| Influenza vaccine recipients | 11 | 11 | 11 |
| Multiparous pregnancies | 11 | 11 | 11 |
| Multiple myeloma | 11 | 11 | 11 |
| Multiple transfusion recipients | 11 | 11 | 11 |
| N. gonorrhoeae | 11 | 11 | 11 |
| Pregnancy 1st trimester | 11 | 11 | 11 |
| Pregnancy 2nd trimester | 11 | 11 | 11 |
| Pregnancy 3rd trimester | 11 | 11 | 11 |
| Rheumatoid Factor | 11 | 11 | 11 |
| T. pallidum (anti-T. pallidum IgG and/or IgM positive) | 11 | 11 | 11 |
| T. cruzi (anti-T. cruzi positive) | 11 | 11 | 11 |

5. Endogenous Interference

A study was conducted to evaluate the LIAISON® XL MUREX HBc IgM for endogenous interference. Ten (10) negative samples or negative pools were spiked with an HBc IgM high positive sample in order to achieve two (2) levels of samples: high negative and low positive. The spiked sets were divided into two (2) aliquots. The first aliquot was spiked with high concentration of potentially interfering substance. The second set of high negative and low positive aliquots (samples without any potentially interfering substances) were used as control samples for the study. Both samples with and without potentially interfering substance were tested in the same run, in 26 replicates each, on one lot of kit reagents and with one lot of kit controls. Biotin was not evaluated in this study because the assay does not employ biotin-streptavidin technology.

No interference was observed at the concentration for each substance listed below.

Table 5: Interfering Substances

| Substances | Tested Concentrations |
| --- | --- |
| Triglycerides | 3000 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Unconjugated bilirubin | 20 mg/dL |
| Conjugated bilirubin | 20 mg/dL |
| Albumin | 6000 mg/dL |
| Cholesterol | 350 mg/dL |

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6. Antibody Class Specificity

Antibody class specificity for IgM has been demonstrated by testing 10 specific IgM positive samples (including samples around the cut-off value) treated with dithiotreitol (DTT) in order to denature IgM and very the assay specificity in the detection of specific antibodies bellowing to IgM class. The results show that the assay specifically detects HBc IgM.

7. Sample Equivalence/Matrix Effect

Twenty-five (25) paired sets of matched serum (with and without gel SST) and plasma (lithium heparin, sodium heparin, sodium citrate, and dipotassium EDTA) were tested to determine if these sample types provide equivalent results on the LIAISON XL MUREX HBc IgM. Each sample was divided into three (3) aliquots. Two (2) sets of aliquots were spiked with an HBc IgM high positive sample to achieve two (2) levels of samples: high negative and low positive samples. The third aliquot served as un-spiked control. The results of the negative and low positive samples did not change the classification of the expected result. The results obtained on the serum-plasma paired samples indicate that there is equivalence among serum (with and without Gel SST), plasma (lithium heparin, sodium heparin, sodium citrate, and dipotassium EDTA).

8. Carry-Over Study

A carry-over study was performed to evaluate the extent of carryover and the associated residual risk for signal carryover in the instrument's measuring cell as a result of a high signal-generating sample. The study included on HBc IgM negative serum sample, one low positive serum sample and one high positive sample. The samples were tested in singlicate in five (5) runs in the following sequence: High Pos, Neg, High Pos, Neg, High Pos, Neg, High Pos, Neg, High Pos, Neg.

All acceptance criteria were met demonstrating that no significance amount of analyte is carried over from one sample reaction into the subsequent sample reactions.

9. Stability Studies

**Sample Stability**

Studies were performed to determine the storage stability of patient serum and plasma samples at storage temperatures of 2-8°C, room temperature (RT), -20 °C. A multiple freeze/thaw (F/T) study was also performed.

Serum and plasma samples tested contained HBc IgM analyte levels of negative, high negative, and low positive.

- 2-8 °C study – samples were tested unstressed (T=0), and again after 1, 2, 3, 4, 5, 7, and 8 days of storage at 2-8°C for 24 hours per day.
- room temperature study (RT) - samples were tested immediately after preparation and again after 1, 2, 3, 4, and 5 days of storage at RT for 24 hours each day.

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- -20 °C study – samples were tested unstressed (T=0) and stored at -20 °C or lower for 1, 3, and 4 months.
- Freeze/Thaw (F/T) study – samples were tested unstressed (T=0) and after 1, 2, 3, 4, 5, 6, and 7 F/T cycles. Samples were frozen for 12-24 hours at -20°C or lower and thawed at room temperature.

Table 6: Sample Stability Claims in Serum and Plasma

| | Sample Stability Claims | | | |
| --- | --- | --- | --- | --- |
| Sample Matrix | Number of Freeze and Thaw Cycles | Storage at 2-8°C | Storage at -20°C | Storage at Room Temperature |
| Serum and plasma | 6 | 7 days | 3 months | 4 days |

## Reagent Stability-Real-Time (Shelf-Life)

Studies were performed to establish the shelf-life for the LIAISON® XL MUREX HBc IgM. Three lots of LIAISON® XL MUREX HBc IgM were stored at the recommended storage temperature of 2-8°C throughout the study. Performance was assessed against clinically relevant acceptance criteria using three lots of LIAISON XL MUREX Control HBc IgM (positive and negative) and an internal stability panel consisting of eleven samples. Study demonstrated that reagents are stable and continue to meet acceptance criteria 9 months after date of manufacture.

## Reagent Stability- Reagent On-Board

Stability studies were conducted to determine the length of time the LIAISON® XL MUREX HBc IgM Reagent Integral can be stored on-board the LIAISON® XL Analyzer in the refrigerated area once open. One lot of LIAISON® XL MUREX HBc IgM and LIAISON® XL MUREX Control HBc IgM (negative and positive) along with the internal stability panel were tested in duplicate at one week intervals up to 13 weeks. The LIAISON® XL MUREX HBc IgM is stable on-board the LIAISON XL Analyzer for 12 weeks.

## Reagent Stability- Open Use

The aim of this study was to assess the open use stability of the LIAISON XL MUREX HBc IgM kit reagents by stimulating normal conditions of use as specified in the instructions for use. Testing of samples was performed in duplicate, on one lot of LIAISON® XL MUREX HBc IgM and one lot of LIAISON® XL MUREX Control HBc IgM. Results were calculated using the initial (time zero) assay calibration. The opened Reagent Integral was then removed from the XL Analyzer and stored at 2-8°C. Kit performance using the opened Reagent Integral was evaluated weekly up to 13 weeks. The Reagent Integral is stable after opening for 12 weeks when stored at 2-8°C.

## Reagent Stability-Calibrator stability

The LIAISON® XL MUREX HBc IgM calibrators are included on the Reagent Integral. All studies for the Reagent Integral are applicable to the calibrators provided.

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## Control Stability-Real Time Shelf-Life

Studies were performed to establish the shelf-life for the LIAISON® XL MUREX Control HBc IgM. Three (3) lots of LIAISON® XL MUREX Control HBc IgM were stored at the recommended storage temperature of 2-8°C throughout the study. Results demonstrate that the positive and negative controls are stable and continue to meet acceptance criteria at 19 months when stored at 2-8°C.

## Control Stability-Open Use

The aim of this study was to assess stability of opened Control vials by simulating normal conditions of use, as specified in the instructions for use. Testing was performed in duplicate on one lot of LIAISON® XL MUREX Control HBc IgM. LIAISON® XL MUREX Control HBc was within the established range. The LIAISON® XL MUREX Control HBc IgM is stable for 12 weeks after opening when stored at 2-8°C between uses.

## Temperature Stress/Reagent Transport Study

The transport simulation tests were performed in order to ensure that kit reagents maintain their properties during the shipment and delivery conditions to the customer. After being subjected to simulates stress conditions, testing was performed on three (3) lots of kit reagents and three (3) lots of kit controls, with a fresh calibration at each test time point. All testing performed met acceptance criteria under various simulated transport conditions.

## 10. Precision

### Internal 20 Days

A precision/reproducibility study was carried out over a period of 20 days on the LIAISON® XL MUREX HBc IgM using the LIAISON XL Analyzer. The CLSI document EP05-A3 was consulted in the preparation of the testing protocol. The testing was performed internally at DiaSorin S.p.A.

A coded panel of 10 serum-based samples and controls were tested in two (2) replicates per run, in two (2) runs per day, by multiple operators, using three (3) reagent kit lots and three (3) Controls lots, over a period of 20 days. The testing days were within one calibration cycle.

The results are shown in the following table.

| | LIAISON® XL MUREX HBc IgM Assay All 3 Lots Combined |
| --- | --- |
| Sample ID | N | Mean | Repeatability | Between Run | Between Day | Between Lot | Within Laboratory |
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Ctrl Neg #RS-707 | 240 | 570.03* | 24.423 | 4.3% | 17.557 | 3.1% | 15.698 | 2.8% | 29.190 | 5.1% | 44.757 |
| Ctrl Neg | 240 | 571.97* | 22.276 | 3.9% | 16.431 | 2.9% | 17.512 | 3.1% | 29.218 | 5.1% | 43.892 |

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| | LIAISON® XL MUREX HBc IgM Assay All 3 Lots Combined | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample ID | N | Mean | Repeatability | | Between Run | | Between Day | | Between Lot | | Within Laboratory | |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| #RS-708 | | | | | | | | | | | | |
| Ctrl Neg #RS-709 | 240 | 572.29* | 24.086 | 4.2% | 18.344 | 3.2% | 15.987 | 2.8% | 28.939 | 5.1% | 44.830 | 7.8% |
| Ctrl Pos #RS-710 | 240 | 2.27 | 0.037 | 1.6% | 0.038 | 1.7% | 0.068 | 3.0% | 0.085 | 3.8% | 0.121 | 5.3% |
| Ctrl Pos #RS-711 | 240 | 2.95 | 0.052 | 1.8% | 0.083 | 2.8% | 0.077 | 2.6% | 0.092 | 3.1% | 0.155 | 5.2% |
| Ctrl Pos #RS-712 | 240 | 2.60 | 0.045 | 1.7% | 0.067 | 2.6% | 0.060 | 2.3% | 0.090 | 3.5% | 0.134 | 5.2% |
| HBCM-1-U1 | 240 | 0.43 | 0.008 | 1.8% | 0.009 | 2.0% | 0.016 | 3.7% | 0.032 | 7.5% | 0.038 | 8.8% |
| HBCM-1-U2 | 240 | 0.60 | 0.011 | 1.8% | 0.010 | 1.7% | 0.025 | 4.1% | 0.032 | 5.3% | 0.043 | 7.2% |
| HBCM-1-U3 | 240 | 0.63 | 0.011 | 1.7% | 0.013 | 2.0% | 0.023 | 3.7% | 0.036 | 5.7% | 0.046 | 7.3% |
| HBCM-1-U4 | 240 | 0.63 | 0.011 | 1.7% | 0.011 | 1.7% | 0.026 | 4.1% | 0.017 | 2.7% | 0.034 | 5.5% |
| HBCM-2-U5 | 240 | 3.76 | 0.048 | 1.3% | 0.078 | 2.1% | 0.107 | 2.9% | 0.083 | 2.2% | 0.164 | 4.4% |
| HBCM-2-U6 | 240 | 1.75 | 0.022 | 1.2% | 0.023 | 1.3% | 0.038 | 2.2% | 0.056 | 3.2% | 0.075 | 4.3% |
| HBCM-2-U7 | 240 | 4.43 | 0.062 | 1.4% | 0.083 | 1.9% | 0.126 | 2.8% | 0.080 | 1.8% | 0.181 | 4.1% |
| HBCM-2-U8 | 240 | 1.74 | 0.018 | 1.0% | 0.026 | 1.5% | 0.050 | 2.9% | 0.086 | 5.0% | 0.105 | 6.0% |
| HBCM-1-U9 | 240 | 2.00 | 0.027 | 1.3% | 0.030 | 1.5% | 0.052 | 2.6% | 0.057 | 2.8% | 0.087 | 4.3% |
| HBCM-1-U10 | 240 | 3.22 | 0.045 | 1.4% | 0.058 | 1.8% | 0.090 | 2.8% | 0.089 | 2.7% | 0.146 | 4.5% |

*Samples below the reading range of the assay, precision calculations are based on signal (RLU)

## External Precision 5-day Study

A five (5) day precision/reproducibility study was conducted at two (2) external laboratories and at DiaSorin Inc. to verify the precision of the LIAISON® XL MUREX HBc IgM. The CLSI document EP15-A3 was consulted in the preparation of the testing protocol. The coded panel comprised 10 serum-based samples was the same panel used in the 20-day precision study.

The precision panel was tested at all three (3) sites on the LIAISON XL Analyzer using six (6) replicates per run in 1 run per day for five (5) days with multiple technicians performing the testing.

The following table shows the results.

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Table 8: Summary of 5-Day Precision Study

| Sample ID | N | Mean | Repeatability | | Between-Day/Run | | Within Laboratory Precision | | Between-Site/Lots | | Total Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Ctrl Neg (all 3 lots) | 90 | *482.28 | 19.71 | 4.1% | 15.44 | 3.2% | 25.04 | 5.2% | 24.33 | 5.0% | 34.03 | 7.1% |
| Ctrl Pos (all 3 lots) | 90 | 2.386 | 0.046 | 1.9% | 0.118 | 5.0% | 0.127 | 5.3% | 0.492 | 20.6% | 0.505 | 21.2% |
| HBCM-1-U1 | 90 | 0.469 | 0.011 | 2.4% | 0.028 | 5.9% | 0.030 | 6.3% | 0.052 | 11.1% | 0.059 | 12.5% |
| HBCM-1-U2 | 90 | 0.662 | 0.015 | 2.3% | 0.033 | 4.9% | 0.036 | 5.4% | 0.093 | 14.0% | 0.098 | 14.9% |
| HBCM-1-U3 | 90 | 0.679 | 0.015 | 2.2% | 0.031 | 4.6% | 0.035 | 5.1% | 0.100 | 14.8% | 0.105 | 15.5% |
| HBCM-1-U4 | 90 | 0.682 | 0.015 | 2.1% | 0.028 | 4.1% | 0.032 | 4.6% | 0.082 | 12.1% | 0.087 | 12.8% |
| HBCM-2-U5 | 90 | 3.845 | 0.075 | 1.9% | 0.167 | 4.3% | 0.183 | 4.7% | 0.281 | 7.3% | 0.326 | 8.5% |
| HBCM-2-U6 | 90 | 1.779 | 0.024 | 1.4% | 0.078 | 4.4% | 0.082 | 4.6% | 0.106 | 6.0% | 0.129 | 7.3% |
| HBCM-2-U7 | 90 | 4.482 | 0.078 | 1.7% | 0.182 | 4.1% | 0.198 | 4.4% | 0.241 | 5.4% | 0.301 | 6.7% |
| HBCM-2-U8 | 90 | 1.795 | 0.027 | 1.5% | 0.058 | 3.2% | 0.063 | 3.5% | 0.175 | 9.7% | 0.184 | 10.3% |
| HBCM-1-U9 | 90 | 2.056 | 0.032 | 1.6% | 0.089 | 4.3% | 0.095 | 4.6% | 0.120 | 5.8% | 0.147 | 7.2% |
| HBCM-1-U10 | 90 | 3.297 | 0.057 | 1.7% | 0.138 | 4.2% | 0.149 | 4.5% | 0.203 | 6.2% | 0.244 | 7.4% |

*Precision calculations are based on signal (RLU) for the negative cohort

# 11. Pediatric and Adult Sample equivalency

Pediatric samples were tested to determine if these types of samples provide equivalent results to adult human serum.

A total of 30 negative pediatric patient samples were used for this study. The pediatric samples encompassed the age range of two (2) months to 21 years. Ten (10) pediatric samples were spiked with an HBc IgM high positive sample to obtain high negative samples. Ten (10) pediatric samples were spiked with an HBc IgM high positive sample to obtain low positive samples. Ten (10) pediatric samples were spiked with an HBc IgM high positive sample to obtain moderate positive samples. Adult negative pool samples were used as controls and were spiked with an HBc IgM high positive sample to achieve the same three (3) levels of samples: high negative, low positive, and moderate positive samples.

The samples were tested in duplicate, with the LIAISON® XL MUREX HBc IgM. Percent (\%) recovery of the analyte from the pediatric and adult blood was calculated for each sample.

All acceptance criteria were met demonstrating acceptable performance of pediatric samples. It can be concluded that pediatric samples react in the same way as the adult samples and are acceptable for use in the LIAISON® XL MUREX HBc IgM.

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B. Animal Studies

Not Applicable

C. Additional Studies

Not Applicable

X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness for the detection of antibodies to hepatitis-B core antigen with the LIAISON® XL MUREX HBc IgM using samples that would routinely be tested for hepatitis in the United States. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

A. Study Design

A multi-site clinical agreement study was conducted to evaluate the clinical performance of the LIAISON® XL MUREX HBc IgM on samples that would routinely be tested for hepatitis and samples that were selected from individuals that were diagnosed with acute or chronic Hepatitis B infection.

The clinical agreement study involved the testing of 3,082 samples on six (6) FDA approved reference assays, each detecting a unique serological marker (HBsAg, HBeAg, Anti-HBs, Anti-HBc, Anti-HBc IgM, and Anti-HBe) in order to determine the HBV classification for each of the samples tested.

The samples were collected from six (6) different countries: Russia, Colombia, Cameroon, Ghana, Nigeria, and the United States. The U.S. samples were from multiple locations including Ohio, Pennsylvania, Indiana, Florida, California, Texas, New Jersey, Tennessee, Massachusetts, and Puerto Rico.

The prospective (unselected) subjects were defined as follows:

- Pediatric and adult male (38.2%), female (61.8%), and unknown gender (0.1%) subjects at risk for hepatitis due to medical conditions (dialysis, transplantation), occupation, lifestyle, behavior, or a known exposure event.
- Subjects showing signs or symptoms and individuals living in an area with a higher probability of HBV infection.
- The demographic breakdown of the prospective population was as follows: American Indian/Alaskan Native (0.1%), Asian (0.8%), Black/African American (31.2%), Caucasian (62.5%), Other (5.2%), and Unknown (0.2%) with an age range of 2 - 98 years of age.

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The distribution of LIAISON® XL MUREX HBc IgM reactive and non-reactive results by age and gender of the overall prospective population are presented below.

Table 9: Demographic Summary of Prospective Population

| Age Range | Gender | LIAISON® XL MUREX | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | | + | | - | | Total |
| | | n | % | n | % | |
| 0-9 | F | 5 | 100.0% | 0 | 0.0% | 5 |
| | M | 3 | 30.0% | 7 | 70.0% | 10 |
| 10-19 | F | 21 | 52.5% | 19 | 47.5% | 40 |
| | M | 8 | 53.3% | 7 | 46.7% | 15 |
| 20-29 | F | 251 | 64.5% | 138 | 35.5% | 389 |
| | M | 130 | 55.8% | 103 | 44.2% | 233 |
| 30-39 | F | 253 | 53.4% | 221 | 46.6% | 474 |
| | M | 111 | 49.6% | 113 | 50.4% | 224 |
| 40-49 | F | 121 | 41.7% | 169 | 58.3% | 290 |
| | M | 68 | 33.8% | 133 | 66.2% | 201 |
| 50-59 | F | 106 | 45.7% | 126 | 54.3% | 232 |
| | M | 70 | 37.8% | 115 | 62.2% | 185 |
| 60-69 | F | 62 | 39.2% | 96 | 60.8% | 158 |
| | M | 50 | 46.3% | 58 | 53.7% | 108 |
| 70-79 | F | 15 | 32.6% | 31 | 67.4% | 46 |
| | M | 16 | 41.0% | 23 | 59.0% | 39 |
| 80-89 | F | 8 | 57.1% | 6 | 42.9% | 14 |
| | M | 2 | 28.6% | 5 | 71.4% | 7 |
| 90-98 | F | 4 | 100.0% | 0 | 0% | 4 |
| | M | 0 | 0% | 0 | 0% | 0 |
| Unk | F | 1 | 100.0% | 0 | 0% | 1 |
| | M | 1 | 100.0% | 0 | 0% | 1 |
| Total | | 1306 | 48.8% | 1370 | 51.2% | 2676 |

Hepatitis B Status Classification

Hepatitis B status classification was based on testing all samples with FDA approved HBV assays for HBsAg, HBeAg, Anti-HBc, Anti-HBc IgM, Anti-HBe, and Anti-HBs. HBV classification for the prospective and retrospective specimens is presented below.

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Table 10: Serological Classification by FDA-approved HBV Panel

| HBV Classification | HBsAg | HBeAg | Total Anti-HBc | Anti-HBc IgM | Anti-HBe | Anti-HBs | Prospective (n) | Retrospective (n) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Acute | R | NR | NR | NR | NR | NR | 12 | 97 |
| Acute | R | R | NR | NR | NR | NR |
| Acute | R | R | R | R | NR | NR |
| Acute | R | R | R | R | R | NR |
| Acute | R | R | R | R | EQV | NR |
| Acute | R | NR | R | EQV | R | NR |
| Acute | R | NR | R | R | EQV | NR |
| Acute | R | R | R | R | NR | NR |
| Acute | R | R | R | R | NR | R |
| Acute | R | R | R | R | R | R |
| Acute | R | R | R | R | R | R |
| Late Acute | R | NR | R | R | R | NR | 2 | 32 |
| Late Acute | R | NR | R | R | R | R |
| Chronic | R | NR | NR | NR | R | NR | 76 | 68 |
| Chronic | R | NR | R | NR | NR | R |
| Chronic | R | R | R | NR | NR | R |
| Chronic | R | R | R | NR | NR | NR |
| Chronic | R | R | R | NR | NR | NR |
| Chronic | R | R | R | R | R | R |
| Chronic | R | R | R | R | R | R |
| Chronic | R | R | R | R | R | R |
| Early Recovery | NR | NR | R | R | R | NR | 48 | 9 |
| Early Recovery | NR | NR | R | EQV | R | R |
| Early Recovery | NR | NR | R | R | NR | NR |
| Early Recovery | NR | NR | R | NR | R | NR |
| Early Recovery | NR | NR | R | NR | R | R |
| Early Recovery | NR | NR | R | R | R | R |
| Recovery | NR | NR | R | NR | R | R | 131 | 36 |
| Recovery | NR | NR | NR | NR | R | R |
| Recovery | NR | NR | R | NR | EQV | R |

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| HBV Classification | HBsAg | HBeAg | Total Anti-HBc | Anti-HBc IgM | Anti-HBe | Anti-HBs | Prospective (n) | Retrospective (n) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Immune Due to Natural Infection | NR | NR | R | NR | NR | R | 104 | 3 |
| Immune Due to Natural Infection | NR | NR | R | NR | NR | EQV | | |
| HBV Vaccine Response | NR | NR | NR | NR | NR | R | 1144 | 8 |
| HBV Vaccine Response | NR | NR | NR | NR | NR | EQV | | |
| Not Previously Infected | NR | NR | NR | NR | NR | NR | 1302 | 1 |
| Not Interpretable | NR | NR | NR | NR | R | NR | 7 | 2 |
| Not Interpretable | NR | NR | NR | R | NR | NR | | |
| Not Interpretable | NR | R | NR | NR | NR | NR | | |
| Not Interpretable | NR | R | NR | NR | NR | R | | |
| Not Interpretable | NR | R | R | R | NR | EQV | | |
| Not Interpretable | NR | R | R | R | NR | R | | |
| Not Interpretable | R | NR | NR | NR | NR | R | | |
| Total | | | | | | | 2826 | 256 |

## Clinical Agreement Study Analysis

Comparison results of the LIAISON® XL MUREX HBc IgM to the reference HBc IgM assay are presented with negative and positive percent agreement (NPA and PPA, respectively) with the 95% confidence intervals for combined prospective and retrospective specimens for each of the HBV classification categories. In addition, Pediatric Cumulative (prospective and retrospective) Clinical Agreement results are presented below.

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Table 11: Cumulative Clinical Agreement Adult and Pediatric (Combined Prospective and Retrospective) LIAISON® XL MUREX HBc IgM vs Reference Assay by Characterization

| HBV Classification | Reference HBc IgM Assay | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Reactive | | Equivocal | | Positive | | |
| | LIAISON MUREX HBc IgM | | LIAISON MUREX HBc IgM | | LIAISON MUREX HBc IgM | | |
| | Positive | Negative | Positive | Negative | Positive | Negative | |
| Acute | 97 | 1 | 2 | 0 | 0 | 9 | 109 |
| Late Acute | 32 | 2 | 0 | 0 | 0 | 0 | 34 |
| Chronic | 0 | 0 | 0 | 0 | 21 | 123 | 144 |
| Early Recovery | 10 | 0 | 0 | 1 | 1 | 45 | 57 |
| Recovery | 0 | 0 | 0 | 0 | 7 | 160 | 167 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 0 | 0 | 107 | 107 |
| HBV Vaccine Response | 0 | 0 | 0 | 0 | 2 | 1150 | 1152 |
| Not Previously Infected | 0 | 0 | 0 | 0 | 1 | 1302 | 1303 |
| Not Interpretable | 2 | 1 | 0 | 0 | 0 | 6 | 9 |
| Total | 141 | 4 | 2 | 1 | 32 | 2902 | 3082 |

Table 12: Cumulative Clinical Agreement Adult and Pediatric (Combined Prospective and Retrospective) LIAISON® XL MUREX HBc IgM vs Reference Assay by Characterization

| HBV Classification | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| Acute | 97/98 (99.0%)
95% CI: 99.4% to 99.8% | 9/11 (81.4%)
95% CI: 52.3% to 94.9% |
| Late Acute | 32/34 (94.1%)
95% CI: 80.9% to 98.4% | N/A |
| Chronic | N/A | 123/144 (85.4%)
95% CI: 78.7% to 90.3% |
| Early Recovery | 10/11 (90.9%)
95% CI: 62.3% to 98.4% | 45/46 (97.8%)
95% CI: 88.7% to 99.6% |
| Recovery | N/A | 160/167 (95.8%)
95% CI: 91.6% to 98.0% |
| Immune Due to Natural Infection | N/A | 107/107 (100.0%)
95% CI: 96.5% to 100.0.0% |
| HBV Vaccine Response | N/A | 1150/1152 (99.8%)
95% CI: 99.4% to 100.0% |

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| HBV Classification | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| Not Previously Infected | N/A | 1302/1303 (99.9%)
95% CI: 99.6% to 100.0% |
| Not Interpretable | 2/3 (66.7%)
95% CI: 20.8% to 93.9% | 6/6 (100%)
95% CI: 61.0% to 100.0% |
| Total | 141/146 (96.6%)
95% CI: 92.2% to 98.5% | 2902/2936 (98.8%)
95% CI: 98.4% to 99.2% |

## Clinical Endpoints

With regard to safety, as an in vitro diagnostic test, the LIAISON® XL MUREX HBc IgM test involves taking a sample of plasma or serum from a patient. The test, therefore, presents no additional safety hazard to an individual being tested relative to other tests where blood samples are drawn. Safety issues regarding false positive and negative test results are discussed in section VIII.

With regards to effectiveness, the clinical performance of the LIAISON® XL MUREX HBc IgM was evaluated versus an FDA approved HBc IgM test for patients at risk of infection with hepatitis B and for patients with signs and symptoms of hepatitis.

With regard to success/failure criteria, the assay performed well with a positive percent agreement (PPA) of 96.6% and a negative percent agreement (NPA) of 98.2% among subjects in various states of HBV infection.

## B. Accountability of PMA Cohort

The clinical agreement study involved the testing of 3,082 samples on six (6) FDA approved reference assays, each detecting a unique serological marker (HBsAg, HBeAg, Anti-HBs, Anti-HBc, Anti-HBc IgM, and Anti-HBe) in order to determine the HBV classification for each of the samples tested.

The samples were collected from six (6) different countries: Russia, Colombia, Cameroon, Ghana, Nigeria, and the United States. The U.S. samples were from multiple locations including Ohio, Pennsylvania, Indiana, Florida, California, Texas, New Jersey, Tennessee, Massachusetts, and Puerto Rico.

## C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for an HBc IgM detection study performed in the U.S.

The prospective (unselected) subjects were defined as follows:

- Pediatric and adult male (38.2%), female (61.6%), and unknown gender (0.2%) subjects at risk for hepatitis due to medical conditions (dialysis, transplantation), occupation, lifestyle, behavior, or a known exposure event.

PMA P180045: FDA Summary of Safety and Effectiveness Data

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- Subjects showing signs or symptoms and individuals living in an area with a higher probability of HBV infection.
- The demographic breakdown of the prospective population was as follows: American Indian/Alaskan Native (0.1%), Asian (0.8%), Black/African American (31.2%), Caucasian (62.5%), Other (5.2%), and Unknown (0.2%) with an age range of 2 - 98 years of age.

The tables below shows the demographic distribution of the cohort.

Table 13: Prospective and Retrospective Demographic Summary by Gender

| | Adult | | | | Pediatric (2-21) | | | | Unknown Age | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Prospective | | Retrospective | | Prospective | | Retrospective | | Prospective | | Retrospective | |
| Gender | n | % | N | % | n | % | n | % | n | % | n | % |
| Female | 1643 | 61.7% | 54 | 26.2% | 98 | 60.9% | 2 | 6.5% | 1 | 50.0% | 0 | 0.0% |
| Male | 1017 | 38.2% | 151 | 73.3% | 61 | 37.9% | 29 | 93.5% | 1 | 50.0% | 0 | 0.0% |
| Unknown | 3 | 0.1% | 1 | 0.5% | 2 | 1.2% | 0 | 0.0% | 0 | 0.0% | 21 | 100.0% |
| Total | 2663 | 100.0% | 206 | 100.0% | 161 | 100.0% | 31 | 100.0% | 2 | 100.0% | 21 | 100.0% |

Table 14: Prospective and Retrospective Demographic Summary by Race

| | Adult | | | | Pediatric (2-21) | | | | Unknown Age | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Prospective | | Retrospective | | Prospective | | Retrospective | | Prospective | | Retrospective | |
| Race | n | % | n | % | n | % | n | % | n | % | n | % |
| American Indian/Alaskan Native | 2 | 0.1% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| Asian | 21 | 0.8% | 4 | 1.9% | 3 | 1.9% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| Black/African American | 832 | 31.2% | 57 | 27.7% | 64 | 39.8% | 4 | 13.8% | 0 | 0.0% | 0 | 0.0% |
| Native Hawaiian or Other Pacific Islander | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| White | 1664 | 62.5% | 141 | 68.4% | 89 | 55.3% | 27 | 87.1% | 2 | 100.0% | 21 | 100.0% |
| Unknown | 6 | 0.2% | 1 | 0.5% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| Other | 138 | 5.2% | 3 | 1.5% | 5 | 3.1% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| Total | 2663 | 100.0% | 206 | 100.0% | 161 | 100.0% | 31 | 100.0% | 2 | 100.0% | 21 | 100.0% |

The following table shows the combined prospective and retrospective pediatric clinical agreement.

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Table 15: Cumulative Pediatric Clinical Agreement (Combined Prospective and Retrospective)
LIAISON® XL MUREX HBc IgM vs Reference Assay by Characterization

| HBV Classification | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| Acute | 20/20 (100%)
95% CI: 83.9% to 100.0% | N/A |
| Late Acute | 7/7 (100%)
95% CI: 64.6% to 100.0% | N/A |
| Chronic | N/A | 6/7 (85.7%)
95% CI: 48.7% to 97.4% |
| Early Recovery | 1/1 (100%)
95% CI: 20.7% to 100.0% | N/A |
| Recovery | N/A | 5/5 (100%)
95% CI: 56.6% to 100.0% |
| Immune Due to Natural Infection | N/A | 3/3 (100%)
95% CI: 43.9% to 100.0% |
| HBV Vaccine Response | N/A | 63/63 (100%)
95% CI: 94.3% to 100.0% |
| Not Previously Infected | N/A | 84/84 (100%)
95% CI: 95.6% to 100.0% |
| Not Interpretable | 0/1 (0.0%)
95% CI: 0.0% to 79.4% | 1/1 (100%)
95% CI: 20.7% to 100.0% |
| Total | 28/29 (96.6%)
95% CI: 82.8% to 99.4% | 162/163 (99.4%)
95% CI: 96.6% to 99.9% |

D. Safety and Effectiveness Results

1. Safety Results

With regard to safety, as an in vitro diagnostic test, the LIAISON® XL MUREX HBc IgM test involves taking a sample of plasma or serum for a patient. The test, therefore, presents no more safety hazard to an individual being tested than other tests where blood samples are drawn.

There were no adverse effects that occurred in the PMA clinical study.

2. Effectiveness Results

The analysis of effectiveness was based on the 3082 evaluable patients. Key effectiveness outcomes are presented in Tables below.

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Table 16: Cumulative Clinical Agreement (Combined Prospective and Retrospective)

| HBV Classification | Reference HBc IgM Assay | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Reactive | | Equivocal | | Positive | | |
| | LIAISON MUREX HBc IgM | | LIAISON MUREX HBc IgM | | LIAISON MUREX HBc IgM | | |
| | Positive | Negative | Positive | Negative | Positive | Negative | |
| Acute | 97 | 1 | 2 | 0 | 0 | 9 | 109 |
| Late Acute | 32 | 2 | 0 | 0 | 0 | 0 | 34 |
| Chronic | 0 | 0 | 0 | 0 | 21 | 123 | 144 |
| Early Recovery | 10 | 0 | 0 | 1 | 1 | 45 | 57 |
| Recovery | 0 | 0 | 0 | 0 | 7 | 160 | 167 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 0 | 0 | 107 | 107 |
| HBV Vaccine Response | 0 | 0 | 0 | 0 | 2 | 1150 | 1152 |
| Not Previously Infected | 0 | 0 | 0 | 0 | 1 | 1302 | 1303 |
| Not Interpretable | 2 | 1 | 0 | 0 | 0 | 6 | 9 |
| Total | 141 | 4 | 2 | 1 | 32 | 2902 | 3082 |

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Table 17: Cumulative Clinical Agreement (Combined Prospective and Retrospective)

| HBV Classification | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| Acute | 97/98 (99.0%)
95% CI: 99.4% to 99.8% | 9/11 (81.4%)
95% CI: 52.3% to 94.9% |
| Late Acute | 32/34 (94.1%)
95% CI: 80.9% to 98.4% | N/A |
| Chronic | N/A | 123/144 (85.4%)
95% CI: 78.7% to 90.3% |
| Early Recovery | 10/11 (90.9%)
95% CI: 62.3% to 98.4% | 45/46 (97.8%)
95% CI: 88.7% to 99.6% |
| Recovery | N/A | 160/167 (95.8%)
95% CI: 91.6% to 98.0% |
| One Due to Natural Infection | N/A | 107/107 (100.0%)
95% CI: 96.5% to 100.0% |
| HBV Vaccine Response | N/A | 1150/1152 (99.8%)
95% CI: 99.4% to 100.0% |
| Not Previously Infected | N/A | 1302/1303 (99.9%)
95% CI: 99.6% to 100.0% |
| Not Interpretable | 2/3 (66.7%)
95% CI: 20.8% to 93.9% | 6/6 (100%)
95% CI: 61.0% to 100.0% |
| Total | 141/146 (96.6%)
95% CI: 92.2% to 98.5% | 2902/2936 (98.8%)
95% CI: 98.4% to 99.2% |

3. **Subgroup Analyses**
The study design enabled an assessment of assay performance by subgroup as depicted in table above which show subjects stratified by state of HBV infection.

4. **Pediatric Extrapolation**
In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

E. **Financial Disclosure**
The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included three (3) investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data.

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XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Microbiology Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

A. Effectiveness Conclusions

The effectiveness of the LIAISON® XL MUREX HBc IgM test for the qualitative detection of IgM antibodies to hepatitis-B core antigen in human serum and plasma (lithium heparin, sodium heparin, sodium citrate, and K₂EDTA) samples including separator tubes, on the LIAISON XL Analyzer has been demonstrated in the following patient populations: adults and pediatric patients (2-21 years). The results of this test may be used as an aid in the diagnosis of hepatitis B virus (HBV) infection in patients with symptoms of hepatitis. The PPA of the assay is 96.6% with a two-sided 95% confidence interval (CI) of 92.2%-98.5%, and the NPA of 98.8% with a two-sided 95% CI of 98.4%-99.2%.

B. Safety Conclusions

The risks of the device are based on nonclinical laboratory studies as well as data collected in a clinical study conducted to support PMA approval as described above. Based on the results of these studies, the LIAISON® XL MUREX HBc IgM when used according to the manufacturer's instructions can aid the physician in the diagnosis of HBV infection. The PPA of the assay is 96.6% with a two-sided 95% confidence interval (CI) of 92.2%-98.5%, and the NPA of 98.8% with a two-sided 95% CI of 98.4%-99.2%.

C. Benefit-Risk Determination

The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The benefits of the assay are the determination, as part of a hepatitis B panel, the appropriate diagnosis and treatment of acute or chronic hepatitis B infection including initiation of appropriate monitoring, antiviral medications, and improved patient knowledge regarding the condition. Treatment for appropriate patients can mitigate the sequelae of hepatitis B infection and may result in improved morbidity and mortality in these patients. Known sequelae of hepatitis B infection include continued symptoms, increases in all-cause mortality, liver disease-related complications and death, hepato-cellular carcinoma rates, and need for liver transplantation. Additionally, diagnosis and appropriate treatment can potentially decrease transmission and disease burden in the general population as well as in populations at high risk for hepatitis B infection. While the clinical performance of the LIAISON® XL MUREX HBc IgM suggests

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that patients will benefit from the assay, low prevalence of certain HBV classifications (namely acute infection, chronic infection, and early recovery) is a source of expected and acceptable uncertainty when analyzing the prospective and retrospective samples, contributing to wide confidence intervals for those subgroups.

The risks associated with the device, when used as intended, are those related to the risk of incorrect test results, failure to correctly interpret the test results, and failure to correctly operate the instrument.

Risks of false positive tests includes improper patient management, including treatment for hepatitis B with antiviral medication. Antiviral medical has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are co-infected but undiagnosed with other viruses using the same antiviral medication, such as HIV, can lead to viral resistance, however the chance of an undiagnosed co-infection in a patient tested for hepatitis B is exceedingly unlikely. Additionally, and likely more importantly, because hepatitis B core IgM antibody is ordered as part of a panel in clinical practice, this risk will likely be mitigated as incongruous test results would lead a clinician to either retest the patient or further investigate the etiology of hepatitis. Hepatitis B c IgM is only used as the sole diagnostic for acute hepatitis B in a patient with clinical findings suspicious for acute hepatitis who is in the "window period" between disappearance of HBsAg and appearance if HBsAb; however, the number of patients that will be tested who are in this specific category is extremely small, mitigating the risk of a false positive.

Risks of false negative tests include missing the opportunity to treat a patient who has hepatitis B infection and whose clinical picture warrants antiviral treatment. As noted previously, because hepatitis B core IgM antibody is ordered as part of a panel in clinical practice, this risk will likely be mitigated as incongruous test results would lead a clinician to either retest the patient or further investigate the etiology of hepatitis.

The clinical benefits outweigh the risks for the proposed assay, considering the mitigations of the risks provided in the premarket approval as well as general controls. The required premarket approval helps to ensure that errors will be uncommon and will facilitate accurate assay implementation and interpretation of results. The device's performance observed in the clinical study suggests that errors will be uncommon and that the assay will provide substantial benefits to patients as an aid in the diagnosis of HBV infection when used in conjunction with other laboratory results and clinical information.

1. Patient Perspective
This submission either did not include specific information on patient perspectives or the information did not serve as part of the basis of the decision to approve or deny the PMA for this device.

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In conclusion, given the available information above, the data support the claimed intended use and that the probable benefits outweigh the probable risks.

## D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. The probable clinical benefits outweigh the probable risks for the proposed assay considering the performance of the device in the clinical study and the low risk and associated risk mitigations in clinical practice. The proposed assay labeling will facilitate accurate assay implement and interpretation of results. The clinical performance observed in the prospective and retrospective clinical trial suggests that errors will be uncommon and that the assay may provide substantial benefits to patients as an accurate and sensitive aid in the diagnosis of HBV infection when used in conjunction with other laboratory results and clinical information.

## XIII. CDRH DECISION

CDRH issued an approval order on August 29, 2020.

The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

## XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

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