LIAISON® XL MUREX HBsAg Qual, LIAISON® MUREX Control HBsAg, and LIAISON® XL MUREX HBsAg Confirmatory Test

P190017 · DiaSorin, Inc. · LOM · Aug 29, 2020 · Microbiology

Device Facts

• Record ID: P190017
• Device Name: LIAISON® XL MUREX HBsAg Qual, LIAISON® MUREX Control HBsAg, and LIAISON® XL MUREX HBsAg Confirmatory Test
• Applicant: DiaSorin, Inc.
• Product Code: LOM · Microbiology
• Decision Date: Aug 29, 2020
• Decision: APRL
• Regulation: 21 CFR 866.3172
• Device Class: Class 2
• Attributes: Pediatric

Intended Use

The LIAISON® XL MUREX HBsAg Qual assay is an in vitro chemiluminescent immunoassay (CLIA) for the qualitative detection of hepatitis B surface antigen (HBsAg) in human adult and pediatric (2 to 21 years) serum and plasma (lithium and sodium heparin, sodium citrate and potassium EDTA), including separator tubes, on the LIAISON® XL Analyzer. Assay results, in conjunction with other hepatitis B virus (HBV) serological 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 assay may also be used to screen for HBV infection in pregnant women to identify neonates who are at risk for acquiring hepatitis B during the perinatal period. This assay is not approved for use in screening blood, plasma or tissue donors.

Device Story

LIAISON XL MUREX HBsAg Qual is a qualitative direct sandwich chemiluminescent immunoassay (CLIA) performed on the LIAISON XL Analyzer. Input: human serum or plasma samples. Process: HBsAg in sample binds to magnetic particles coated with mouse monoclonal antibodies; a second incubation adds isoluminol-conjugated mouse monoclonal antibodies; unbound material is washed away; starter reagents induce flash chemiluminescence. Output: relative light units (RLU) proportional to HBsAg concentration. Used in clinical laboratories by technicians. Results are interpreted by clinicians alongside other HBV serological markers to diagnose acute or chronic HBV infection or screen pregnant women. Benefits include accurate identification of HBV infection, enabling timely treatment to reduce morbidity, mortality, and perinatal transmission.

Clinical Evidence

Clinical study evaluated 3,082 samples (prospective and retrospective) from 6 countries. Performance compared to 6 FDA-approved reference assays. Overall PPA was 98.3% (95% CI: 96.0%-99.3%) and NPA was 99.8% (95% CI: 99.5%-99.9%). Subgroup analysis included pregnant women (PPA 100%, NPA 100%) and pediatric patients (PPA 100%, NPA 100%). Bench testing confirmed analytical sensitivity (0.05 IU/mL), specificity, and lack of interference from endogenous substances (e.g., bilirubin, biotin, hemoglobin).

Technological Characteristics

Direct sandwich CLIA. Solid phase: magnetic particles coated with mouse monoclonal anti-HBsAg antibodies. Conjugate: isoluminol-labeled mouse monoclonal antibodies. Energy source: chemiluminescent reaction measured by photomultiplier. Form factor: ready-to-use reagent integral for LIAISON XL Analyzer. Connectivity: automated analyzer platform. Software: embedded firmware for instrument control and signal processing. Sterilization: not applicable (in vitro diagnostic).

Indications for Use

Indicated for qualitative detection of HBsAg in human adult and pediatric (2-21 years) serum/plasma. Used as an aid in diagnosis of HBV infection in symptomatic patients or those at risk, and for screening pregnant women to identify neonates at risk for perinatal HBV acquisition. Not for blood/tissue donor screening.

Regulatory Classification

Identification

A qualitative hepatitis B virus (HBV) antigen assay is identified as an in vitro diagnostic device intended for prescription use for qualitative use with human serum, plasma, or other matrices that aids in the diagnosis of chronic or acute HBV infection. HBV surface antigen (HbsAg) is also used for screening of HBV infection in pregnant women to identify neonates who are at risk of acquiring hepatitis B during perinatal period. The assay is not intended for screening of blood, plasma, cells, or tissue donors.

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) The specimen types for which the device has been cleared, and that use of this assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results. (B) When appropriate, performance characteristics of the assay have not been established in populations of immunocompromised or immunosuppressed patients or other populations where assay performance may be affected. (C) 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. (D) Detection of HBV antigens indicates a current infection with hepatitis B virus but does not differentiate between acute or chronic infection. False reactive HbsAg result may occur for up to 2 weeks after vaccination with HbsAg containing vaccine. (E) Current methods for the detection of hepatitis B antigens may not detect all potentially infected individuals. A non-reactive assay result does not exclude the possibility of exposure to or infection with hepatitis B virus. A non-reactive assay result in individuals with prior exposure to hepatitis B may be due to but not limited to antigen levels below the detection limit of this assay or lack of antigen reactivity to the antibodies in this assay. HBV mutants lacking the ability to produce antigens have been reported. These may occur as “escape” mutants in the presence of anti-HBV antibodies and such patients may be infectious. (F) Results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay. (2) Design verification and validation must include the following: (i) A detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, design of the capture antibody(ies), external controls, and computational path from collected raw data to reported result ( *e.g.,* how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design.(ii) For devices with assay calibrators, the design and composition of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate ( *e.g.,* a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.(iii) Documentation and characterization ( *e.g.,* supplier, determination of identity, purity, and stability) of all critical reagents (including description of the capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.(iv) 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. (v) 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. (vi) 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. (vii) All stability protocols, including acceptance criteria. (viii) Final release assay results for each lot used in clinical studies. (ix) Reproducibility study data that includes the testing of three independent production lots. (x) Detailed documentation of analytical performance studies conducted, as appropriate to the technology, specimen types tested, and intended use of the device, including, 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, prominent mutants/variants detection ( *e.g.,* for HbsAg), specimen stability, reagent stability, and cross-genotype antigen detection sensitivity, when appropriate.(xi) Analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays. (xii) 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. (xiii) Detailed documentation and results from a clinical study. Performance must be analyzed relative to an FDA cleared or approved HBV antigen assay or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with an appropriate number of HBV reactive and non-reactive samples in applicable risk and disease categories, and any applicable confirmatory testing. 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. This study must be conducted in the appropriate settings by the intended users to demonstrate clinical performance.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Detection of Hepatitis B surface antigen (HBsAg)

Device Trade Name: LIAISON® XL MUREX HBsAg Qual
LIAISON® XL MUREX Control HBsAg Qual
LIAISON XL MUREX HBsAg Confirmatory Test

Device Procode: LOM

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

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190017

Date of FDA Notice of Approval: August 29, 2020

II. INDICATIONS FOR USE

LIAISON XL MUREX HBsAg Qual

The LIAISON® XL MUREX HBsAg Qual assay is an in vitro chemiluminescent immunoassay (CLIA) for the qualitative detection of hepatitis B surface antigen (HBsAg) in human adult and pediatric (2 to 21 years) serum and plasma (lithium and sodium heparin, sodium citrate and potassium EDTA), including separator tubes, on the LIAISON® XL Analyzer. Assay results, in conjunction with other hepatitis B virus (HBV) serological 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 assay may also be used to screen for HBV infection in pregnant women to identify neonates who are at risk for acquiring hepatitis B during the perinatal period.

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

LIAISON XL MUREX Control HBsAg Qual

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

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 HBsAg Qual labeling.

# V. DEVICE DESCRIPTION

LIAISON XL MUREX HBsAg Qual is a qualitative direct sandwich chemiluminescent immunoassay (CLIA). A mixture of mouse monoclonal antibodies is used for coating magnetic particles (solid phase) and a different mixture of mouse monoclonal antibodies directed to different epitopes is linked to an isoluminol derivative. During the first incubation, HBsAg present in calibrators, samples or controls binds to the solid phase. During the second incubation, the antibody conjugate reacts with HBsAg already bound to the solid phase. After second 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 conjugate, is measured by a photomultiplier as relative light units (RLU) and is directly proportional to HBsAg concentration present in calibrators, samples or controls.

# Components of the LIAISON XL MUREX HBsAg Qual assay

All reagents are supplied ready to use

The table below describes the components of the LIAISON XL MUREX HBsAg Qual kit.

Table 1: Components of the LIAISON XL MUREX HBsAg Qual

| Magnetic Particles
1 vial – 2.3 mL | Magnetic particles coated with antibodies to HBsAg (mouse monoclonal), biotinylated BSA, streptavidin, BSA, PBS buffer, < 0.1% sodium azide. |
| --- | --- |
| Calibrator 1
1 vial – 3.0 mL | Low levels of recombinant HBsAg (obtained in mammalian cells), BSA, phosphate buffer, EDTA, 0.2% ProClin® 300, an inert yellow dye. |
| Buffer L
1 vial – 28 mL | Non-specific IgG (mouse polyclonal), casein, TRIS buffer, EDTA, 0.1% ProClin® 300. |
| Conjugate
2 vial – 23.0 mL | Mouse monoclonal antibodies to HBsAg having balanced reactivity for ad and ay subtypes, conjugated to an isoluminol derivative, human and animal sera, BSA, phosphate buffer, preservatives. |
| Number of tests | 200 |

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

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

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| NEGATIVE CONTROL
2 vials – 4.0 mL each | Human plasma non-reactive for hepatitis B surface antigen and antibody 0.2% ProClin® 300 and preservatives. |
| --- | --- |
| POSITIVE CONTROL
2 vials – 4.0 mL each | Human serum containing HBsAg (obtained in E. coli by the recombinant DNA technology), 0.2% ProClin® 300, preservatives |

## Interpretation of the Results (HBsAg):

The interpretation of results for the LIAISON XL MUREX HBsAg Qual is as follows:

Cutoff of 1.00 index value determines whether a sample has detectable levels of HbsAg:

- Reactive: Samples with HBsAg levels equal to or above an index value of 1.00 are considered Reactive and presumed positive for HBsAg.
- Non-Reactive: Samples with HBsAg levels below an index value of 1.00 are considered Non-reactive and presumed negative for HBsAg
- Initially reactive samples must be retested in duplicate. Samples with HBsAg levels below a S/CO value of 1.00 in both replicates at the retest are considered Non-Reactive and presumed negative for HBsAg. Samples that are repeatedly equal to or above a S/CO of 1.00 (i.e. at least 2 out of 3 results) are considered repeatedly Reactive and presumed positive for HBsAg. Samples that are repeatedly Reactive for HBsAg must be evaluated with the LIAISON XL MUREX HBsAg Confirmatory Test.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the detection of HBsAg. 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

The LIAISON® XL MUREX HBsAg Qual assay (318250) and LIAISON® XL MUREX Control HBsAg Qual (318251) are new kits for the United States and have not been marketed in the U.S. or any foreign country. LIAISON® XL MUREX HBsAg Confirmatory assay (318110) has not been marketed in the U.S. or any foreign country

LIAISON® XL MUREX HBsAg Confirmatory assay (318110) is essentially the same as the CE-marked LIAISON® HBsAg Confirmatory Test assay (310110) except for the replacement in the neutralizing solution composition of the Human serum/plasma

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positive for Anti-HBs with the Goat plasma positive for Anti-HBs and some minor modifications to raw material manufacturing processes.

The LIAISON® HBsAg Confirmatory Test (310110) has been marketed in multiple countries and has not been withdrawn from the market in any country for reasons relating to safety and effectiveness.

Table 2: Countries Where CE-Marked Versions Have Been Marketed

| Austria | Algeria |
| --- | --- |
| Australia | Belgium |
| Belarus | Bahrain |
| Brazil | Brunei |
| Croatia | Czech Republic |
| Denmark | Dominican Republic |
| Egypt | Finland |
| France | Germany |
| Hongkong | Hungary |
| Iran | Iraq |
| Ireland | Italy |
| Kuwait | Jordan |
| Lithuania | Luxembourg |
| Mexico | Morocco |
| Netherlands | Norway |
| Poland | Qatar |
| Russia | Saudi Arabia |
| Slovak republic | Spain |
| Thailand | The Philippines |
| Trinidad, Tobago | Tunisia |
| Turkey | United Kingdom |
| Uruguay | |

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

The LIAISON XL MUREX HBsAg Qual is intended for *in vitro* diagnostic use, and as a result, there is no direct adverse effect on the patient. Standard good laboratory practices are considered sufficient to minimize risks to the end user.

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.

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

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Risks of a false positive test include improper patient management, including further investigation of hepatitis B infection with other laboratory tests to determine if a patient is acutely or chronically infected. It is possible that a clinician would decide to treat hepatitis B infection with antiviral medications in a patient without hepatitis B infection. Antiviral medication 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. These risks are mitigated by the fact that this test would then be part of a panel, and incongruous test results in a hepatitis panel would lead a clinician to retest the patient before starting treatment.

Risks of a false negative test include improper patient management, including missing the opportunity to treat chronic Hepatitis B infection. A clinician may falsely believe that a patient is not acutely or chronically infected, but rather is currently susceptible or immune to the infection. False negative results may lead a clinician to vaccinate an infected patient. This risk is likely mitigated by the fact that this test is usually ordered as part of a panel of hepatitis B tests, and incongruous test results in a hepatitis panel would lead a clinician to retest the patient. A false negative result may alternatively result in a clinician missing the opportunity to further investigate and initiate treatment in a patient in whom treatment is otherwise be recommended, as HBsAg is often the first test sent as part of the evaluation of hepatitis B infection.

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 100 samples (50 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 1.00 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 HBsAg Qual assay has been demonstrated by testing 30 commercial seroconversion panels in comparison to a reference HBsAg 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 HBsAg Qual yielded a positive result sooner by one or more blood draws than the comparator assay in 1 of the 30 panels and later than the reference HBsAg assay in 2 panels.

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3. Analytical Sensitivity/Dilution Study with Standard

The sensitivity of the LIAISON XL MUREX HBsAg Qual was evaluated by preparing serial dilutions of the WHO 3rd International Standard for HBsAg, (HBV genotype B4, HBsAg subtypes ayw1/adw2) – NIBSC standard code 12/226.

Dilutions were tested in five replicates on three reagent lots, using one lot of kit controls, across four LIAISON XL Analyzers.

The cutoff concentration corresponds to 0.05 IU/mL.

4. Analytical Specificity (Cross-Reactivity)

A study was conducted to evaluate the LIAISON XL MUREX HBsAg Qual for cross-reactivity with specimens from individuals with medical conditions unrelated to HBV infection. A total of 385 samples from 28 unrelated medical conditions were tested in singlicate on one kit lot of LIAISON XL MUREX HBsAg Qual and on a reference HBsAg assay.

Of the 385 samples, 1 sample was found to be non-reactive with the reference assay and reactive with the LIAISON XL MUREX HBsAg Qual assay. The results of each potential cross reactant are shown in table below.

Table 3: Summary of Cross-Reactivity Study

| Organism/Condition | N | Comparator HBsAg assay | LIAISON® XL MUREX HBsAg Qual | |
| --- | --- | --- | --- | --- |
| | | | Nonreactive | Reactive |
| Anti-nuclear antibodies (ANA) | 14 | Negative | 14 | 0 |
| Non-viral liver diseases (i.e. Auto-immune hepatitis) | 15 | Negative | 15 | 0 |
| C. trachomatis (anti-chlamydia positive) | 15 | Negative | 14 | 1 |
| CMV (anti-CMV positive) | 13 | Negative | 13 | 0 |
| EBV (anti-EBV positive) | 13 | Negative | 13 | 0 |
| HSV (anti-HSV positive) | 15 | Negative | 15 | 0 |
| Fatty liver disease | 14 | Negative | 10 | 0 |
| HAMA | 10 | Negative | 15 | 0 |
| Hemodialysis patient | 15 | Negative | 11 | 0 |
| Hepatitis A Virus (anti-HAV positive) | 11 | Negative | 15 | 0 |
| Hepatitis C Virus (anti-HCV positive) | 15 | Negative | 12 | 0 |
| Hepatocellular carcinoma | 12 | Negative | 2 | 0 |
| HIV-1 (anti-HIV-1 positive) | 2 | Negative | 13 | 0 |
| HIV-2 (anti-HIV-2 positive) | 12 | Negative | 12 | 0 |
| HIV (anti-HIV positive) | 15 | Negative | 15 | 0 |
| HTLV-1/2 (anti-HTLV positive) | 15 | Negative | 15 | 0 |
| IgG monoclonal gammopathy | 16 | Negative | 16 | 0 |

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| Organism/Condition | N | Comparator HBsAg assay | LIAISON® XL MUREX HBsAg Qual | |
| --- | --- | --- | --- | --- |
| | | | Nonreactive | Reactive |
| IgM monoclonal gammopathy | 4 | Negative | 4 | 0 |
| Influenza vaccine recipients | 15 | Negative | 15 | 0 |
| Multiparous pregnancies | 15 | Negative | 15 | 0 |
| Multiple myeloma | 14 | Negative | 14 | 0 |
| Multiple transfusion recipients | 15 | Negative | 15 | 0 |
| N. gonorrhoeae
(anti-Neisseria positive) | 12 | Negative | 12 | 0 |
| Pregnancy 1st trimester | 15 | Negative | 15 | 0 |
| Pregnancy 2nd trimester | 15 | Negative | 15 | 0 |
| Pregnancy 3rd trimester | 15 | Negative | 15 | 0 |
| Rheumatoid Factor | 15 | Negative | 15 | 0 |
| T. pallidum
(anti-treponema positive) | 12 | Negative | 12 | 0 |
| T. cruzi (anti-T. cruzi positive) | 14 | Negative | 14 | 0 |
| Syphilis (T. pallidum) | 10 | Negative | 10 | 0 |
| Toxoplasmosis (Toxoplasma gondii) | 10 | Negative | 10 | 0 |
| CMV (Cytomegalovirus) | 13 | Negative | 13 | 0 |
| EBV (Epstein-Barr virus) | 10 | Negative | 10 | 0 |
| HAV (Hepatitis A virus) | 10 | Negative | 10 | 0 |
| HIV (human immunodeficiency virus) | 27 | Negative | 26 | 1 |
| HSV (herpes simplex virus) | 10 | Negative | 10 | 0 |
| HTLV (Human T-Lymphotropic virus)-1/2 | 7 | Negative | 7 | 0 |
| Parvovirus B19 | 10 | Negative | 10 | 0 |
| Rubella virus | 10 | Negative | 9 | 1 |
| Varicella-zoster virus | 12 | Negative | 10 | 2 |
| N. gonorrhoeae | 12 | Negative | 12 | 0 |
| T. Cruzi | 10 | Negative | 10 | 0 |
| Staphylococcus aureus | 10 | Negative | 10 | 0 |
| Pseudomonas aeruginosa | 10 | Negative | 10 | 0 |
| E. coli | 10 | Negative | 10 | 0 |
| Hepatitis C (HCV) | 10 | Negative | 10 | 0 |
| Chlamydia (C. trachomatis) | 15 | Negative | 14 | 1 |

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# 5. Endogenous Interference

A study was conducted to evaluate the LIAISON XL MUREX HBsAg Qual for endogenous interference. Ten negative samples or negative pools were spiked with an HBsAg high positive sample in order to achieve two levels of samples: high negative and low positive. The spiked sets were divided into two 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 twenty-six replicates each, on one lot of kit reagents and with one lot of kit controls.

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

Table 4: Interfering Substances

| Substances | Tested Concentrations |
| --- | --- |
| Triglycerides | 3000 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Unconjugated bilirubin | 40 mg/dL |
| Conjugated bilirubin | 40 mg/dL |
| Albumin | 6000 mg/dL |
| Cholesterol | 350 mg/dL |
| Vitamin H (Biotin) | 3500 ng/mL |

# 6. Sample Equivalence/Matrix Effect

Twenty-five paired sets of matched serum (with and without gel SST) and plasma (lithium heparin, sodium heparin, sodium citrate, and potassium EDTA) samples were tested to determine if these sample types provided equivalent results on the LIAISON XL MUREX HBsAg Qual. Each sample was divided into three aliquots. Two sets of aliquots were spiked with an HBsAg high positive sample to achieve two 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), lithium heparin, sodium heparin, sodium citrate, and potassium EDTA.

# 7. 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 one HBsAg 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.

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8. High Dose Hook Effect

Testing was performed to assess the saturation effect that may appear when testing samples containing extremely high levels of analyte resulting in a reported result that is lower than the actual analyte concentration. Four samples with analyte level above the upper end of the assay were tested neat and after serial dilution in Specimen Diluent of the LIAISON XL MUREX HBsAg Confirmatory. A high dose hook effect (decrease in signal) was observed at HBsAg S/CO values &gt;2990 S/CO (high positive); however, the samples were still high positive.

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 HBsAg 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 4, 14, 24, 28, 43, 48, and 52 hours of storage at RT.
- -20 °C study – samples were tested unstressed (T=0) and stored at -20 °C or lower for 1, 3, 4, and 5 months.
- Freeze/Thaw (F/T) study – samples were tested unstressed (T=0) and after 1, 2, 3, 4, 5, 6, 7, 8, and 9 F/T cycles. Samples were frozen for 12-24 hours at -20°C or lower and thawed at room temperature.

Table 5: 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 | 7 | 7 days | 3 months | 3 days |

Reagent Stability-Real-Time (Shelf-Life)

Studies were performed to establish the shelf-life for the LIAISON XL MUREX HBsAg Qual. Three lots of LIAISON XL MUREX HBsAg Qual 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 HBsAg Qual (positive and negative) and an internal stability panel consisting of eleven samples. Study demonstrated that reagents are stable and continue to meet acceptance criteria for the following number of months when stored at 2-8°C: LIAISON XL MUREX HBsAg Qual 15 months after date of manufacture, LIAISON MUREX CONTROL HBsAg 14 months after date of manufacture, and LIAISON XL MUREX HBsAg Confirmatory Test 12 months after date of manufacture.

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## Reagent Stability- Reagent On-Board

Stability studies were conducted to determine the length of time the LIAISON XL MUREX HBsAg Qual Reagent Integral can be stored on-board the LIAISON XL Analyzer in the refrigerated area once open. One lot of LIAISON XL MUREX HBsAg Qual and LIAISON XL MUREX Control HBsAg Qual (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 HBsAg Qual 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 HBsAg Qual 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 HBsAg Qual and one lot of LIAISON XL MUREX Control HBsAg Qual 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 HBsAg Qual calibrators are included on the Reagent Integral. All studies for the Reagent Integral are applicable to the calibrators provided.

## Control Stability-Real Time Shelf-Life

Studies were performed to establish the shelf-life for the LIAISON XL MUREX Control HBsAg Qual. Three lots of LIAISON XL MUREX Control HBsAg Qual 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 14 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 HBsAg Qual. LIAISON XL MUREX Control HBsAg Qual was within the established range. The LIAISON XL MUREX Control HBsAg Qual 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 1 lot of kit reagents and 1 lot of kit controls. All testing performed met acceptance criteria under various simulated transport conditions.

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# 10. Precision

# Internal 20 Day

A precision/reproducibility study was carried out over a period of 20 days on the LIAISON XL MUREX HBsAg Qual 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 11 serum-based samples and controls were tested in 2 replicates per run, in 2 runs per day, by multiple operators, using 3 reagent kit lots and 3 Controls lots, over a period of 20 days. The testing days were spanned 2 calibration cycles.

The results are shown in the following table.

Table 6: Summary of 20-Day Precision Study

| | | | LIAISON® XL MUREX HBsAg Qual Assay - All 3 Lots Combined | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample ID | N | Mean (S/CO) | Repeatability | | Between Run | | Between-Day | | Between-Lots | | Within Laboratory | |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Kit Ctrl Neg lot 1 | 240 | 0.41 | 0.023 | 5.8% | 0.023 | 5.6% | 0.026 | 6.5% | 0.035 | 8.6% | 0.055 | 13.5% |
| Kit Ctrl Neg lot 2 | 240 | 0.41 | 0.026 | 6.4% | 0.016 | 4.0% | 0.029 | 7.2% | 0.031 | 7.5% | 0.053 | 12.8% |
| Kit Ctrl Neg lot 3 | 240 | 0.41 | 0.026 | 6.2% | 0.014 | 3.4% | 0.031 | 7.5% | 0.035 | 8.4% | 0.055 | 13.3% |
| Kit Ctrl Pos lot 1 | 240 | 1.96 | 0.070 | 3.6% | 0.041 | 2.1% | 0.085 | 4.4% | 0.096 | 4.9% | 0.152 | 7.8% |
| Kit Ctrl Pos lot 2 | 240 | 1.83 | 0.062 | 3.4% | 0.036 | 2.0% | 0.082 | 4.5% | 0.065 | 3.5% | 0.127 | 7.0% |
| Kit Ctrl Pos lot 3 | 240 | 1.79 | 0.059 | 3.3% | 0.034 | 1.9% | 0.081 | 4.5% | 0.060 | 3.4% | 0.122 | 6.8% |
| HBS1U10 | 240 | 0.39 | 0.030 | 7.9% | 0.034 | 8.9% | 0.022 | 5.8% | 0.017 | 4.3% | 0.054 | 13.9% |
| HBS1U11 | 240 | 0.73 | 0.035 | 4.8% | 0.021 | 2.9% | 0.039 | 5.3% | 0.025 | 3.4% | 0.062 | 8.4% |
| HBS1U12 | 240 | 0.72 | 0.030 | 4.1% | 0.019 | 2.6% | 0.046 | 6.3% | 0.027 | 3.7% | 0.064 | 8.8% |
| HBS1U13 | 240 | 0.72 | 0.028 | 3.9% | 0.021 | 2.9% | 0.039 | 5.5% | 0.028 | 3.9% | 0.060 | 8.3% |
| HBS1U14 | 240 | 1.12 | 0.037 | 3.3% | 0.024 | 2.1% | 0.082 | 7.3% | 0.045 | 4.0% | 0.103 | 9.2% |
| HBS1U15 | 240 | 1.12 | 0.039 | 3.5% | 0.034 | 3.1% | 0.082 | 7.3% | 0.044 | 3.9% | 0.106 | 9.5% |
| HBS1U16 | 240 | 1.13 | 0.039 | 3.4% | 0.034 | 3.0% | 0.074 | 6.5% | 0.041 | 3.7% | 0.099 | 8.8% |
| HBS1U17 | 240 | 3.02 | 0.079 | 2.6% | 0.078 | 2.6% | 0.114 | 3.8% | 0.129 | 4.3% | 0.205 | 6.8% |
| HBS1U18 | 240 | 3.06 | 0.057 | 1.8% | 0.057 | 1.9% | 0.135 | 4.4% | 0.128 | 4.2% | 0.202 | 6.6% |
| HBS1U19 | 240 | 3.04 | 0.055 | 1.8% | 0.063 | 2.1% | 0.122 | 4.0% | 0.108 | 3.5% | 0.183 | 6.0% |
| HBS1U20 | 240 | 1.06 | 0.035 | 3.3% | 0.020 | 1.8% | 0.042 | 4.0% | 0.037 | 3.5% | 0.069 | 6.5% |

# External Precision 5-day Study

A 5 day precision/reproducibility study was conducted at 2 external laboratories and at DiaSorin Inc. to verify the precision of the LIAISON XL MUREX HBsAg Qual. The CLSI document EP15-A3 was consulted in the preparation of the testing protocol. The coded panel comprised 11 serum-based samples was the same panel used in the 20-day precision study.

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

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The following table shows the results.

Table 7: Summary of 5-Day Precision Study

| Sample ID | N | LIAISON® XL MUREX HBsAg Qual Assay - 5 Day Multi-Site/Multi-Lot | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Mean | Repeatability | | Between-Day/Runs | | Within Laboratory | | Between Sites/Lots | | Reproducibility | |
| | | (S/CO) | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Ctrl Neg (all 3 lots) | 90 | 0.38 | 0.033 | 8.6% | 0.029 | 7.7% | 0.044 | 11.5% | 0.044 | 11.6% | 0.062 | 16.3% |
| Ctrl Pos (all 3 lots) | 90 | 1.859 | 0.041 | 2.2% | 0.04 | 2.2% | 0.058 | 3.1% | 0.052 | 2.8% | 0.077 | 4.2% |
| HBS1U10 | 90 | 0.342 | 0.022 | 6.5% | 0.023 | 6.8% | 0.032 | 9.4% | 0.023 | 6.8% | 0.04 | 11.6% |
| HBS1U11 | 90 | 0.734 | 0.026 | 3.5% | 0.031 | 4.2% | 0.04 | 5.4% | 0.042 | 5.8% | 0.058 | 7.9% |
| HBS1U12 | 90 | 0.726 | 0.029 | 4.0% | 0.03 | 4.1% | 0.042 | 5.8% | 0.043 | 5.9% | 0.06 | 8.2% |
| HBS1U13 | 90 | 0.721 | 0.031 | 4.3% | 0.033 | 4.6% | 0.045 | 6.3% | 0.03 | 4.1% | 0.054 | 7.5% |
| HBS1U14 | 90 | 1.138 | 0.033 | 2.9% | 0.03 | 2.7% | 0.045 | 3.9% | 0.038 | 3.4% | 0.059 | 5.2% |
| HBS1U15 | 90 | 1.135 | 0.031 | 2.7% | 0.041 | 3.6% | 0.051 | 4.5% | 0.036 | 3.2% | 0.062 | 5.5% |
| HBS1U16 | 90 | 1.146 | 0.035 | 3.0% | 0.037 | 3.2% | 0.051 | 4.4% | 0.026 | 2.3% | 0.057 | 5.0% |
| HBS1U17 | 90 | 3.213 | 0.065 | 2.0% | 0.051 | 1.6% | 0.083 | 2.6% | 0.116 | 3.6% | 0.143 | 4.4% |
| HBS1U18 | 90 | 3.196 | 0.057 | 1.8% | 0.04 | 1.2% | 0.069 | 2.2% | 0.104 | 3.2% | 0.125 | 3.9% |
| HBS1U19 | 90 | 3.211 | 0.066 | 2.1% | 0.052 | 1.6% | 0.084 | 2.6% | 0.107 | 3.3% | 0.136 | 4.2% |
| HBS1U20 | 90 | 1.099 | 0.034 | 3.1% | 0.034 | 3.1% | 0.048 | 4.3% | 0.05 | 4.5% | 0.069 | 6.3% |

# 11. Pediatric and Adult Sample equivalency

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

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

The samples were tested in duplicate, with the LIAISON XL MUREX HBsAg Qual. 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 HBsAg Qual.

PMA P190017: FDA Summary of Safety and Effectiveness Data

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PMA P190017: FDA Summary of Safety and Effectiveness Data
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## 12. HBsAg Genotypes Detection

Thirty (30) specimens from commercially available HBsAg performance panels containing the most common hepatitis B surface antigen genotypes (A through H) were tested to assess the performance of the assay. All 30 specimens were HBsAg reactive with both the LIAISON XL MUREX HBsAg Qual and an FDA-approved reference assay.

## 13. HBsAg mutant detection

A panel of 10 recombinant mutants were tested with the LIAISON XL MUREX HBsAg Qual and an FDA-approved reference assay to determine correct antigenic detection of the HBsAg structure. The mutants contained important epitope clusters within amino acids 100-160 that include the “a determinant region” (amino acids 124-147), the most important target for serological diagnosis. The recombinant mutants were diluted in HBsAg negative human serum to yield a low positive sample. All 10 recombinant mutants were recognized with LIAISON XL MUREX HBsAg Qual and are shown in the following table.

Table 8: HBsAg Recombinant Mutants Tested

| Sample ID | Mutation | Comparator HBsAg assay | LIAISON® XL MUREX HBsAg Qual assay |
| --- | --- | --- | --- |
| Mutant-01 | T123N | Reactive | Reactive |
| Mutant-02 | T123N-T124S | Reactive | Reactive |
| Mutant-03 | P142L-F/Y143H-D144E-G145-R | Reactive | Reactive |
| Mutant-04 | I110R-SS117I-G119R-T123N | Reactive | Reactive |
| Mutant-05 | 122+DT | Reactive | Reactive |
| Mutant-06 | 122+DT-G145R | Reactive | Reactive |
| Mutant-07 | G145R | Reactive | Reactive |
| Mutant-08 | D114A | Reactive | Reactive |
| Mutant-09 | P142L-G145R | Reactive | Reactive |
| Mutant-10 | P142S-G145R | Reactive | Reactive |

## 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 hepatitis-B antigen with the LIAISON XL MUREX HBsAg Qual using samples that would routinely be tested for hepatitis in the US. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

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PMA P190017: FDA Summary of Safety and Effectiveness Data
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# A. Study Design

A multi-site clinical agreement study was conducted to evaluate the clinical performance of the LIAISON XL MUREX HBsAg Qual 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 3082 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 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.

Prospective (unselected) subjects were 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.
- 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 retrospective (selected/archived) samples were from male (69.5%), female (21.9%), and unknown gender (8.6%) subjects diagnosed with acute and/or chronic Hepatitis having an age range of 17 - 67 years of age from the following ethnicities: Asian (1.6%), Black/African American (23.8%), Caucasian (73%), other (1.2%) and 0.4% Unknown.

A total of 800 pregnant women were all from the United States including Puerto Rico. Of the 800 total, 797 (99.6%) were between the ages of 15 and 47, with 3 (0.4%) of unknown age. Of the 800 pregnant women, 383 (48%) were in their 1st trimester of pregnancy, 193 (24%) in the 2nd trimester, 190 (24%) in the 3rd trimester, and 35 (4%) trimester was unknown. The pregnant women included the following ethnicities: Asian (4.6%), Black/African American (12.4%), Native Hawaiian/Pacific Islander (0.1%), White (81.4%), Other (1.3%), and Unknown (0.3%).

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

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Table 9: Demographic Summary of Prospective Population

| Age Range | Gender | LIAISON® XL MUREX HBsAg Qual | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | | + | | - | | Total |
| | | n | % | n | % | |
| 0-9 | F | 0 | 0.0% | 5 | 100.0% | 5 |
| | M | 0 | 0.0% | 10 | 100.0% | 10 |
| 10-19 | F | 0 | 0.0% | 40 | 100.0% | 40 |
| | M | 0 | 0.0% | 15 | 100.0% | 15 |
| 20-29 | F | 13 | 3.3% | 376 | 96.7% | 389 |
| | M | 15 | 6.4% | 218 | 93.6% | 233 |
| 30-39 | F | 9 | 1.9% | 465 | 98.1% | 474 |
| | M | 16 | 7.1% | 208 | 92.9% | 224 |
| 40-49 | F | 4 | 1.4% | 286 | 98.6% | 290 |
| | M | 8 | 4.0% | 193 | 96.0% | 201 |
| 50-59 | F | 4 | 1.7% | 228 | 98.3% | 232 |
| | M | 3 | 1.6% | 182 | 98.4% | 185 |
| 60-69 | F | 2 | 1.3% | 156 | 98.7% | 158 |
| | M | 0 | 0.0% | 108 | 100.0% | 108 |
| 70-79 | F | 0 | 0.0% | 46 | 100.0% | 46 |
| | M | 0 | 0.0% | 39 | 100.0% | 39 |
| 80-89 | F | 0 | 0.0% | 14 | 100.0% | 14 |
| | M | 0 | 0.0% | 7 | 100.0% | 7 |
| 90-98 | F | 0 | 0.0% | 4 | 100.0% | 4 |
| | M | 0 | NA | 0 | NA | 0 |
| Unk | F | 0 | 0.0% | 1 | 100.0% | 1 |
| | M | 0 | 0.0% | 1 | 100.0% | 1 |
| Total | | 74 | 2.8% | 2602 | 97.2% | 2676 |

Table 10: Pregnant Women Results Stratified by Age

| Age Range | LIAISON® XL MUREX HBsAg Qual | | | | |
| --- | --- | --- | --- | --- | --- |
| | + | | - | | Total |
| | n | % | n | % | |
| 10-19 | 0 | 0.0% | 62 | 100.0% | 62 |
| 20-29 | 0 | 0.0% | 464 | 100.0% | 464 |
| 30-39 | 3 | 1.2% | 246 | 98.8% | 249 |
| 40-49 | 1 | 4.5% | 21 | 95.5% | 22 |
| 50-59 | 0 | NA | 0 | NA | 0 |
| Unk | 0 | 0.0% | 3 | 100.0% | 3 |
| Total | 4 | 0.5% | 796 | 99.5% | 800 |

PMA P190017: FDA Summary of Safety and Effectiveness Data

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# 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.

Table 11: Hepatitis B Infection Status Classification

| HBV Classification | HBsAg | HBeAg | 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 | R | R | NR |
| Acute | R | NR | R | R | R | 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 | NR | R | NR |
| Chronic | R | R | R | R | R | R |
| Chronic | R | R | R | R | R | R |
| Chronic | R | EQV | R | NR | NR | NR |
| Early Recovery | NR | NR | R | R | R | NR | 48 | 9 |
| Early Recovery | NR | NR | R | R | R | R |
| Early Recovery | NR | NR | R | R | R | R |
| Early Recovery | NR | NR | R | NR | R | NR |
| Early Recovery | NR | NR | R | NR | R | NR |
| Early Recovery | NR | NR | R | R | 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 | R | R |
| Immune Due to Natural Infection | NR | NR | R | NR | NR | R | 104 | 3 |
| Immune Due to Natural Infection | NR | NR | R | NR | NR | R |

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| HBV Classification | HBsAg | HBeAg | Anti-HBc | Anti-HBc IgM | Anti-HBe | Anti-HBs | Prospective (n) | Retrospective (n) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 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 | R | NR | NR | 7 | 2 |
| 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 | | |
| Not Interpretable | R | NR | NR | NR | NR | R | | |
| Total | | | | | | 2826 | 256 | |

## Clinical Agreement Study Analysis

Comparison results of the LIAISON XL MUREX HBsAg Qual to the reference HBsAg 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. Additional performance tables for the pregnancy and pediatric cohorts are presented.

Table 12: Cumulative Adult and Pediatric Clinical Agreement (Combined Prospective and Retrospective) HBV Classification

| | Reference HBsAg assay | | | | Total |
| --- | --- | --- | --- | --- | --- |
| | Reactive | | Nonreactive | | |
| | LIAISON® XL MUREX HBsAg Qual | | LIAISON® XL MUREX HBsAg Qual | | |
| | Reactive | Non reactive | Reactive | Non reactive | |
| Acute | 106 | 3 | 0 | 0 | 109 |
| Late Acute | 33 | 1 | 0 | 0 | 34 |
| Chronic | 144 | 0 | 0 | 0 | 144 |
| Early Recovery | 0 | 0 | 0 | 57 | 57 |
| Recovery | 0 | 0 | 4 | 163 | 167 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 107 | 107 |
| HBV Vaccine Response | 0 | 0 | 0 | 1152 | 1152 |
| Not Previously Infected | 0 | 0 | 2 | 1301 | 1303 |
| Not Interpretable | 0 | 1 | 0 | 8 | 9 |
| Total | 283 | 5 | 6 | 2788 | 3082 |

PMA P190017: FDA Summary of Safety and Effectiveness Data

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Table 13: Cumulative Adult and Pediatric Clinical Agreement (Combined Prospective and Retrospective)

| HBV Classification | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| Acute | 106/109 (97.2%)
95% CI: 92.2% to 99.1% | N/A |
| Late Acute | 33/34 (97.1%)
95% CI: 85.1% to 99.5% | N/A |
| Chronic | 144/144 (100.0%)
95% CI: 97.4% to 100.0% | N/A |
| Early Recovery | N/A | 57/57 (100.0%)
95% CI: 93.7% to 100.0% |
| Recovery | N/A | 163/167 (97.6%)
95% CI: 94.0% to 99.1% |
| Immune Due to Natural Infection | N/A | 107/107 (100.0%)
95% CI: 96.5% to 100.0% |
| HBV Vaccine Response | N/A | 1152/1152 (100.0%)
95% CI: 99.7% to 100.0% |
| Not Previously Infected | N/A | 1301/1303 (99.8%)
95% CI: 99.4% to 100.0% |
| Not Interpretable | 0/1 (0.0%)
95% CI: 0.0% to 79.3% | 8/8 (100.0%)
95% CI: 67.6% to 100.0% |
| Total | 283/288 (98.3%)
95% CI: 96.0% to 99.3% | 2788/2794 (99.8%)
95% CI: 99.5% to 99.9% |

Table 14: Prospective Pregnancy Cohort Clinical Agreement by Trimester

| Pregnancy (Trimester) | Reference HBsAg assay | | | | Total |
| --- | --- | --- | --- | --- | --- |
| | Reactive | | Nonreactive | | |
| | LIAISON® XL MUREX HBsAg Qual | | LIAISON® XL MUREX HBsAg Qual | | |
| | Reactive | Non reactive | Reactive | Non reactive | |
| First | 2 | 0 | 0 | 380 | 382 |
| Second | 0 | 0 | 0 | 193 | 193 |
| Third | 1 | 0 | 0 | 189 | 190 |
| Unknown | 1 | 0 | 0 | 34 | 35 |
| Total | 4 | 0 | 0 | 796 | 800 |

PMA P190017: FDA Summary of Safety and Effectiveness Data

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Table 15: Prospective Pregnancy Cohort Clinical Agreement by Trimester

| Pregnancy (Trimester) | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| First | 2/2 (100.0%)
95% CI: 34.2% to 100.0% | 380/380 (100.0%)
95% CI: 99.0% to 100.0% |
| Second | N/A | 193/193 (100.0%)
95% CI: 98.0% to 100.0% |
| Third | 1/1 (100.0%)
95% CI: 20.7% to 100.0% | 189/189 (100.0%)
95% CI: 98.0% to 100.0% |
| Unknown | 1/1 (100.0%)
95% CI: 20.7% to 100.0% | 34/34 (100.0%)
95% CI: 89.8% to 100.0% |
| Total | 4/4 (100.0%)
95% CI: 51.0% to 100.0% | 796/796 (100.0%)
95% CI: 99.5% to 100.0% |

Table 16: Cumulative Pediatric Agreement Summary (Combined Prospective and Retrospective)

| HBV Classification | Positive Percent Agreement (PPA) | Negative Percent Agreement (NPA) |
| --- | --- | --- |
| Acute | 20/20 (100.0%)
95% CI: 83.9% to 100.0% | N/A |
| Late Acute | 7/7 (100.0%)
95% CI: 64.6% to 100.0% | N/A |
| Chronic | 7/7 (100.0%)
95% CI: 64.6% to 100.0% | N/A |
| Early Recovery | N/A | 1/1 (100.0%)
95% CI: 20.7% to 100.0% |
| Recovery | N/A | 5/5 (100.0%)
95% CI: 56.6% to 100.0% |
| Immune Due to Natural Infection | N/A | 3/3 (100.0%)
95% CI: 43.9% to 100.0%N/A |
| HBV Vaccine Response | N/A | 63/63 (100.0%)
95% CI: 94.3% to 100.0% |
| Not Previously Infected | N/A | 84/84 (100.0%)
95% CI: 95.6% to 100.0% |
| Not Interpretable | N/A | 2/2 (100.0%)
95% CI: 34.2% to 100.0% |
| Total | 34/34 (100%)
95% CI:89.5% to 100.0% | 158/158 (100%)
95% CI: 97.6% to 100.0% |

## Clinical Endpoints

As an in vitro diagnostic test, the LIAISON XL MUREX HBsAg Qual test involves taking a sample of plasma or serum from a patient. The test, therefore, presents no more safety hazard to an individual being tested than other tests where blood samples are drawn. Safety issues regarding false positive and negative test results are discussed in section VIII.

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With regards to effectiveness, the clinical performance of the LIAISON XL MUREX HBsAg Qual was evaluated versus an FDA approved HBsAg 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 98.3% and a negative percent agreement (NPA) of 99.8% among subjects in various states of HBV infection.

## B. Accountability of PMA Cohort

The clinical agreement study involved the testing of 3082 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 determine the HBV classification for each of the samples tested.

The samples were collected from 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 HBsAg detection study performed in the US.

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.
- Subjects showing signs or symptoms and individuals living in an area with a higher probability of HBV infection.

The tables below shows the demographic distribution of the cohort.

Table 17: 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% |

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Table 18: 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 | 12.9% | 0 | 0.0% | 0 | 0.0% |
| Native Hawaiian or Other Pacific | 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 pregnancy cohort clinical agreement.

## D. Safety and Effectiveness Results

1. **Safety Results**
With regard to safety, as an in vitro diagnostic test, the LIAISON XL MUREX HBsAg Qual 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 Section X above.

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

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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 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.

## 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 HBsAg Qual test for the qualitative detection of hepatitis-B antigen in human serum and plasma, lithium heparin, sodium citrate, and dipotassium EDTA) 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 98.3% with a two-sided 95% confidence interval (CI) of 96.0%-99.3% and the NPA of 99.8% with a two-sided 95% CI of 99.5%-99.9%.

### 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 HBsAg Qual when used according to the manufacturer's instructions can aid the physician in the diagnosis of HBV infection. The PPA of the assay is 98.3% with a two-sided 95% confidence interval (CI) of 96.0%-99.3% and the NPA of 99.8% with a two-sided 95% CI of 99.5%-99.9%.

### 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 as part of a hepatitis B panel, the appropriate diagnosis and treatment of hepatitis B infection. 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

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appropriate treatment for hepatitis B infection can potentially decrease transmission and disease burden in the general population and particularly in populations at high risk for hepatitis B infection. While the performance of the device in the clinical study suggests that patients will benefit from the assay, low prevalence of certain HBV classifications is a source of potential uncertainty when analyzing the samples. The wide confidence intervals for those subgroups is expected due to the biology of hepatitis B infection and is acceptable.

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

Risks of a false positive test include improper patient management, including further investigation of hepatitis B infection with other laboratory tests to determine if a patient is acutely or chronically infected. It is possible that a clinician would decide to treat hepatitis B infection with antiviral medications in a patient without hepatitis B infection. Antiviral medication 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. These risks are mitigated by the fact that this test would then be part of a panel, and incongruous test results in a hepatitis panel would lead a clinician to retest the patient before starting treatment.

Risks of a false negative test include improper patient management, including missing the opportunity to treat chronic Hepatitis B infection. A clinician may falsely believe that a patient is not acutely or chronically infected, but rather is currently susceptible or immune to the infection. False negative results may lead a clinician to vaccinate an infected patient. This risk is likely mitigated by the fact that this test is usually ordered as part of a panel of hepatitis B tests, and incongruous test results in a hepatitis panel would lead a clinician to retest the patient. A false negative result may alternatively result in a clinician missing the opportunity to further investigate and initiate treatment in a patient in whom treatment is otherwise be recommended, as HBsAg is often the first test sent as part of the evaluation of hepatitis B infection.

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.

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

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probable clinical benefits outweigh the potential 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 implementation 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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