← Product Code [LLM](/submissions/MI/subpart-d%E2%80%94serological-reagents/LLM) · K233605

# ADVIA Centaur EBV-EBNA IgG (K233605)

_Biokit, S.A. · LLM · Aug 7, 2024 · Microbiology · SESE_

**Canonical URL:** https://fda.innolitics.com/submissions/MI/subpart-d%E2%80%94serological-reagents/LLM/K233605

## Device Facts

- **Applicant:** Biokit, S.A.
- **Product Code:** [LLM](/submissions/MI/subpart-d%E2%80%94serological-reagents/LLM.md)
- **Decision Date:** Aug 7, 2024
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.3235
- **Device Class:** Class 1
- **Review Panel:** Microbiology
- **Attributes:** Pediatric

## Intended Use

The ADVIA Centaur EBV-EBNA IgG (EBVnaG) assay is for in vitro diagnostic use in the qualitative detection of IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen (EBNA) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.

## Device Story

The ADVIA Centaur EBV-EBNA IgG is an in vitro diagnostic assay for the qualitative detection of IgG antibodies to EBV nuclear antigen (EBNA). It utilizes chemiluminescent immunoassay (CLIA) technology on the ADVIA Centaur XP system. The device processes human serum or plasma (EDTA or lithium heparin) samples. The system performs the assay and provides qualitative results to the clinician. It is intended for use in clinical laboratories by trained personnel. The output serves as an aid in the diagnosis of EBV infection, such as infectious mononucleosis, when used in conjunction with other EBV markers. The device benefits patients by providing diagnostic information to support clinical decision-making regarding EBV infection status.

## Clinical Evidence

Clinical study evaluated 1428 samples (Population 1) and 167 negative samples (Population 2). In the total population, PPA was 99.4% (95% CI: 98.8-99.7%) and NPA was 92.8% (95% CI: 89.6-95.1%). In the pediatric subset, PPA was 98.4% (95% CI: 96.0-99.4%) and NPA was 97.3% (95% CI: 94.3-98.8%). Precision and reproducibility were assessed per CLSI EP05-A3, showing acceptable CVs. Specimen equivalency between serum, EDTA plasma, and lithium heparin plasma was confirmed via weighted Deming regression.

## Technological Characteristics

Fully automated 2-step sandwich immunoassay; acridinium ester chemiluminescent detection. System: ADVIA Centaur XP. Sample volume: 20 µL. Incubation: 18 minutes at 37°C. Reagents: EBV-EBNA IgG specific antigen solid phase, acridinium ester-labeled monoclonal anti-human IgG. Connectivity: Integrated with ADVIA Centaur XP system. Calibration: Master curve card entry, 28-day interval. Sterilization: Not applicable (reagent kit).

## Regulatory Identification

Epstein-Barr virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Epstein-Barr virus in serum. The identification aids in the diagnosis of Epstein-Barr virus infections and provides epidemiological information on diseases caused by these viruses. Epstein-Barr viruses are thought to cause infectious mononucleosis and have been associated with Burkitt's lymphoma (a tumor of the jaw in African children and young adults) and postnasal carcinoma (cancer).

## Predicate Devices

- LIAISON EBNA IgG (k040120)

## Submission Summary (Full Text)

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>
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FDA

U.S. FOOD & DRUG

ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K233605

B Applicant

Biokit S.A.

C Proprietary and Established Names

ADVIA Centaur EBV-EBNA IgG

D Regulatory Information

|  Product Code(s) | Classification | Regulation Section | Panel  |
| --- | --- | --- | --- |
|  LSE | Class I, reserved | 21 CFR 866.3235 - Epstein-Barr Virus Serological Reagents | MI - Microbiology  |

## II Submission/Device Overview:

A Purpose for Submission:

To obtain clearance for a new device

B Measurand:

Epstein Barr Virus IgG to Nuclear Antigen (EBV-EBNA IgG)

C Type of Test:

The ADVIA Centaur EBV-EBNA IgG assay is a fully automated 2-step sandwich immunoassay using acridinium ester chemiluminescent technology.

## III Intended Use/Indications for Use:

A Intended Use(s):

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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The ADVIA Centaur EBV-EBNA IgG (EBVnaG) assay is for in vitro diagnostic use in the qualitative detection of IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen (EBNA) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.

## B Indication(s) for Use:
Not applicable

## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only

## D Special Instrument Requirements:
The assay is intended for use on the fully automated ADVIA Centaur XP system manufactured by Siemens Healthcare Diagnostics Inc.

## IV Device/System Characteristics:

### A Device Description:
The ADVIA Centaur EBV-EBNA IgG assay detects IgG antibodies to the Epstein-Barr virus nuclear antigen (EBNA) in adults and pediatric serum, EDTA plasma and Lithium-Heparin Plasma. This assay is run on the fully automated ADVIA Centaur XP system. The results are intended for use in conjunction with other EBV markers as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.

The ADVIA Centaur EBV-EBNA IgG assay kit consists of the following components:

- 1 ADVIA Centaur EBVnaG ReadyPack containing EBVnaG Lite Reagent, Solid Phase, and Ancillary Well Reagent.
- 1 vial x 2.0 mL EBVnaG CAL low calibrator.
- 1 vial x 2.0 mL EBVnaG CAL high calibrator.
- ADVIA Centaur EBVnaG CAL calibrator assigned value cards and barcode labels.
- ADVIA Centaur EBVnaG master curve card.
- ADVIA Centaur Wash 1

The controls are available separately:

ADVIA Centaur EBV-EBNA IgG Quality Control has the following:

- Negative control
- Positive control

### B Principle of Operation:

K233605 - Page 2 of 15

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The ADVIA Centaur EBV-EBNA IgG is a fully automated 2-step sandwich immunoassay using acridinium ester chemiluminescent technology. The specimen is incubated with the Ancillary Well Reagent and the Solid Phase, which contains an EBV-EBNA IgG specific antigen. Antigen-antibody complexes will form if anti-EBV-EBNA IgG antibody is present in the specimen. The Lite Reagent contains monoclonal anti-human IgG labeled with acridinium ester and is used to detect EBV-EBNA IgG in the specimen.

## Assay Procedure:

The system automatically performs the following steps:

1. Dispenses 20 µL of sample into a cuvette.
2. Dispenses 250 µL of Solid Phase and 90 µL of Ancillary Well Reagent into a cuvette, then incubates for 18 minutes at 37°C.
3. Performs a wash sequence using ADVIA Centaur Wash 1.
4. Dispenses 100 µL of Lite Reagent, then incubates for 18 minutes at 37°C.
5. Performs a wash sequence using ADVIA Centaur Wash 1.
6. Dispenses 300 µL of ADVIA Centaur Acid Reagent and 300 µL of ADVIA Centaur Base Reagent to initiate the chemiluminescent reaction.
7. Reports results.

## Results interpretation:

The system reports ADVIA Centaur EBV-EBNA IgG assay results in Index values and as Nonreactive or Reactive:

Nonreactive: < 1.00 Index value. These samples are considered negative.

Reactive: ≥ 1.00 Index value. These samples are considered positive.

Results of this assay should always be interpreted in conjunction with the patient's medical history, clinical presentation, and other findings.

## C Instrument description Information

1. Instrument Name:

ADVIA Centaur XP System

2. Specimen Identification:

Serum, EDTA plasma, and lithium heparin plasma are the recommended specimen types for the ADVIA Centaur EBV-EBNA IgG Assay.

3. Specimen Sampling and Handling:

The assay needs 20 µL of sample for a single determination. The instrument performs all handling procedures automatically.

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4. Calibration information:

Calibration frequency is as stated below:
- At the end of the 28-day calibration interval.
- When changing lot numbers of primary reagent packs.
- When indicated by quality control results.
- After major maintenance or service, as indicated by quality control results.

Before initiating calibration on each new lot of reagents, the assay master curve values need to be entered by scanning the master curve card.

5. Quality Control:

External positive and negative controls are available separately. According to the IFU, the controls should be used at least once during each day that samples are analyzed. In addition, quality control is performed:
- Following a valid calibration
- With use of a new lot of reagents
- When troubleshooting test results that do not match clinical conditions or symptoms

Acceptable performance is achieved when the analyte values obtained are within the expected control interval for the system.

V Substantial Equivalence Information:

A Predicate Device Name(s):

Diasorin Liaison Ebna Igg, Liaison Vca Igg, Liaison Vca Igm Assays

B Predicate 510(k) Number(s):

K040120

C Comparison with Predicate(s):

|  Device & Predicate Device(s): | Candidate Device K233605 | Predicate Device K040120  |
| --- | --- | --- |
|  Device Trade Name | ADVIA Centaur EBV-EBNA IgG | LIAISON EBNA IgG  |
|  Intended Use | The ADVIA Centaur EBV-EBNA IgG (EBVnaG) assay is for in vitro diagnostic use in the qualitative detection of IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen (EBNA) in human pediatric (2-21 years old) | The LIAISON EBNA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON Analyzer family* for the qualitative determination of specific IgG antibodies to Epstein-  |

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K233605 - Page 5 of 15
|   | and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis. | Barr virus (EBV) nuclear antigen synthetic peptide (EBNA-1) in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis. *(LIAISON and LIAISON XL)  |
| --- | --- | --- |
|  **General Device Characteristic Similarities** |  |   |
|  |   |   |
|  Measurand | IgG antibodies to the Epstein-Barr virus (EBV) nuclear antigen (EBNA) | IgG antibodies to the Epstein-Barr virus (EBV) nuclear antigen (EBNA.  |
|  Technology | Same | Chemiluminescent immunoassay (CLIA)  |
|  Antigen | Same | EBNA-1  |
|  **General Device Characteristic Differences** |  |   |
|  Sample Type | Human serum and plasma (EDTA and lithium heparin) | Human serum  |
|  Target Population | Adults and pediatrics | Adults  |
|   |  As an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis | As an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis  |

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# VI Standards/Guidance Documents Referenced:

- CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition (Reaffirmed: September 2019).
- CLSI EP09c Measurement Procedure Comparison and Bias Estimation Using Patient Samples - 3rd Edition (2018).
- CLSI EP07 Interference Testing in Clinical Chemistry; Approved Guideline - 3rd Edition (2018).
- CLSI EP37 Supplemental Tables for Interference Testing in Clinical Chemistry - 1st Edition (2018).
- CLSI EP25-A (Replaces EP25-P) Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline (2009).
- CLSI EP12-Ed3 Evaluation of Qualitative, Binary Output Examination Performance (2023).
- CLSI I/LA21-A2 Clinical Evaluation of Immunoassays; Approved Guideline - 2nd Edition.

# VII Performance Characteristics (if/when applicable):

# A Analytical Performance:

# 1. Precision/Reproducibility:

# a. Within-Laboratory Precision Study:

A within laboratory precision study was evaluated using 5 serum, and 5 EDTA plasma samples ranging from low negative to positive with two external controls. Samples were tested in duplicate, two runs a day for 20 days, for a total of 240 replicates per sample across all three-reagent kit lots on the ADVIA Centaur XP system. Within laboratory precision results are reported in Table 1.

Table 1. Within- Laboratory Precision results- EBV-EBNA IgG

|  Sample ID | Mean (Index) | Na | Repeatability |   | Between-Run |   | Between-Day |   | Between-Lot |   | Within-Laboratory (Total)  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |  SDb | CVc(%) | SD | %CV | SD | %CV | SD | %CV | SD | %CV  |
|  Serum A | 0.69 | 240 | 0.015 | 2.1% | 0.026 | 3.8% | 0.000 | 0.0% | 0.006 | 0.9% | 0.030 | 4.4%  |
|  Serum B | 1.01 | 240 | 0.019 | 1.8% | 0.029 | 2.8% | 0.000 | 0.0% | 0.092 | 9.0% | 0.098 | 9.7%  |
|  Serum C | 1.34 | 240 | 0.024 | 1.8% | 0.029 | 2.2% | 0.047 | 3.5% | 0.167 | 12.5% | 0.178 | 13.3%  |
|  Serum D | 4.98 | 240 | 0.074 | 1.5% | 0.084 | 1.7% | 0.166 | 3.3% | 0.326 | 6.5% | 0.382 | 7.7%  |
|  Serum E | 8.54 | 240 | 0.164 | 1.9% | 0.195 | 2.3% | 0.145 | 1.7% | 0.187 | 2.2% | 0.348 | 4.1%  |
|  Plasma A | 0.71 | 240 | 0.015 | 2.1% | 0.024 | 3.4% | 0.005 | 0.7% | 0.009 | 1.3% | 0.030 | 4.3%  |
|  Plasma B | 0.95 | 240 | 0.019 | 2.1% | 0.028 | 2.9% | 0.009 | 0.9% | 0.083 | 8.8% | 0.090 | 9.5%  |
|  Plasma C | 1.33 | 240 | 0.025 | 1.9% | 0.047 | 3.6% | 0.021 | 1.6% | 0.000 | 0.0% | 0.058 | 4.3%  |

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|  Plasma D | 4.93 | 240 | 0.108 | 2.2% | 0.122 | 2.5% | 0.132 | 2.7% | 0.121 | 2.5% | 0.242 | 4.9%  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Plasma E | 8.76 | 240 | 0.155 | 1.8% | 0.239 | 2.7% | 0.116 | 1.3% | 0.254 | 2.9% | 0.399 | 4.6%  |
|  Negative Control | 0.32 | 240 | 0.007 | 2.1% | 0.007 | 2.1% | 0.009 | 2.6% | 0.006 | 1.9% | 0.014 | 4.4%  |
|  Positive Control | 3.16 | 240 | 0.051 | 1.6% | 0.065 | 2.1% | 0.079 | 2.5% | 0.061 | 1.9% | 0.130 | 4.1%  |

a Number of measurements.
b Standard deviation.
Coefficient of variation.

# b. Reproducibility:

Reproducibility of the ADVIA Centaur EBV-EBNA IgG assay was evaluated using 5 serum and 5 EDTA plasma samples with 2 external controls, in duplicate, twice a day, over 5 days, at three sites located in the US, using one reagent lot. Reproducibility results are reported for EBV-EBNA IgG in Table 2.

Table 2. Reproducibility results- EBV-EBNA IgG

|  Sample | Mean (Index) | N | Within-Run |   | Between-Runs |   | Between-Days |   | Between-Sites |   | Reproducibility  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |  \( SD^a \) | \( CV^b \)(%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%)  |
|  Serum A | 0.77 | 90 | 0.023 | 3.0 | 0.023 | 2.9 | 0.010 | 1.3 | 0.034 | 4.4 | 0.048 | 6.3  |
|  Serum B | 1.07 | 90 | 0.066 | 6.1 | 0.051 | 4.7 | 0.000 | 0.0 | 0.065 | 6.0 | 0.105 | 9.8  |
|  Serum C | 1.40 | 90 | 0.031 | 2.2 | 0.012 | 0.9 | 0.028 | 2.0 | 0.036 | 2.6 | 0.056 | 4.0  |
|  Serum D | 4.99 | 90 | 0.103 | 2.1 | 0.119 | 2.4 | 0.077 | 1.6 | 0.255 | 5.1 | 0.310 | 6.2  |
|  Serum E | 8.85 | 90 | 0.173 | 2.0 | 0.316 | 3.6 | 0.185 | 2.1 | 0.490 | 5.5 | 0.635 | 7.2  |
|  Plasma A | 0.78 | 90 | 0.025 | 3.2 | 0.001 | 0.2 | 0.017 | 2.2 | 0.032 | 4.1 | 0.044 | 5.7  |
|  Plasma B | 1.06 | 90 | 0.024 | 2.3 | 0.016 | 1.5 | 0.025 | 2.3 | 0.037 | 3.5 | 0.053 | 5.0  |
|  Plasma C | 1.39 | 90 | 0.032 | 2.3 | 0.014 | 1.0 | 0.022 | 1.6 | 0.068 | 4.9 | 0.080 | 5.7  |
|  Plasma D | 5.06 | 90 | 0.104 | 2.1 | 0.061 | 1.2 | 0.103 | 2.0 | 0.258 | 5.1 | 0.303 | 6.0  |
|  Plasma E | 8.75 | 90 | 0.824 | 9.4 | 0.093 | 1.1 | 0.148 | 1.7 | 0.404 | 4.6 | 0.934 | 10.7  |
|  Negative Control | 0.36 | 90 | 0.010 | 2.7 | 0.009 | 2.5 | 0.000 | 0.0 | 0.017 | 4.7 | 0.022 | 6.0  |
|  Positive Control | 3.31 | 90 | 0.057 | 1.7 | 0.043 | 1.3 | 0.000 | 0.0 | 0.113 | 3.4 | 0.134 | 4.0  |

a Standard deviation of mean concentration (Index)
b Coefficient of variation
$\% \mathrm{CV} = (\mathrm{SD} / \mathrm{Mean})^{*}100$

# 2. Linearity:

Not Applicable

# 3. Analytical Specificity/Interference:

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# 1. Cross reactivity:

Biokit evaluated potential cross-reactivity on the ADVIA Centaur EBV-EBNA IgG by testing at least 10 samples from individuals containing antibodies to other microorganisms or with medical conditions unrelated to EBV infections. The data showed no cross reactivity with various disease status tested except with 4 samples. Among those 4 samples, 2 samples produced equivocal results by comparator device, the LIAISON EBNA IgG. The equivocal results were interpreted as discrepant against candidate device. One sample each containing HSV-1 and HSV-2 IgG produced false nonreactive results (reactive on comparator device) on the ADVIA Centaur EBV-EBNA IgG test. The cross reactivity study results are presented in Table 3.

Table 3. Cross reactivity on the ADVIA Centaur EBV-EBNA IgG

|  Sample type | *Number of samples Tested | ADVIA Centaur EBV-EBNA IgG Assay Results |   | Comparative EBV-EBNA IgG Assay Results  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |   |  Nonreactive | Reactive | Negative | Equivocal | Positive  |
|  Cytomegalovirus (CMV) IgG | 10 | 5 | 5 | 5 | 0 | 5  |
|  Cytomegalovirus (CMV) IgM | 10 | 9 | 1 | 9 | 0 | 1  |
|  Parvovirus B19 IgG | 10 | 5 | 5 | 5 | 0 | 5  |
|  Toxoplasma gondii IgG | 10 | 5 | 5 | 5 | 0 | 5  |
|  Toxoplasma gondii IgM | 10 | 5 | 5 | 5 | 0 | 5  |
|  Rubella IgG | 18 | 7 | 11 | 7 | 0 | 11  |
|  Rubella IgM | 11 | 3 | 8 | 3 | 0 | 8  |
|  Hepatitis B Virus (HBV) IgG | 11 | 6 | 5 | 6 | 0 | 5  |
|  Hepatitis A Virus (HAV) IgG | 11 | 5 | 6 | 5 | 0 | 6  |
|  Hepatitis C Virus (HCV) IgG | 11 | 5** | 6 | 4 | 1 | 6  |
|  Human Immunodeficiency Virus (HIV) | 10 | 4 | 6 | 4 | 0 | 6  |
|  Herpes Simplex Virus (HSV-1) IgG | 11 | 5* | 6 | 4 | 0 | 7  |
|  Herpes Simplex Virus (HSV-2) IgG | 12 | 4* | 8 | 3 | 0 | 9  |
|  Treponema pallidum (Syphilis) | 12 | 3 | 9 | 3 | 0 | 9  |
|  Varicella Zoster Virus (VZV) IgG | 10 | 6 | 4 | 6 | 0 | 4  |
|  Measles virus IgG | 13 | 6 | 7 | 6 | 0 | 7  |
|  Mumps virus IgG | 10 | 4 | 6 | 4 | 0 | 6  |
|  Borrelia burgdorferi IgG (Lyme IgG) | 11 | 3 | 8 | 3 | 0 | 8  |

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|  Influenza virus IgG | 10 | 2 | 8 | 2 | 0 | 8  |
| --- | --- | --- | --- | --- | --- | --- |
|  Mycoplasma pneumoniae IgG | 21 | 14 | 7** | 14 | 1 | 6  |
|  Antinuclear antibodies (ANA) | 10 | 9 | 1 | 9 | 0 | 1  |
|  Rheumatic Factors (RF) | 12 | 3 | 9 | 3 | 0 | 9  |
|  Human Anti-mouse antibodies (HAMA) | 12 | 5 | 7 | 5 | 0 | 7  |
|  Human Herpes Virus (HHV6) | 14 | 10 | 4 | 10 | 0 | 4  |
|  Systemic Lupus Erythematosus (SLE) | 10 | 7 | 3 | 7 | 0 | 3  |
|  Flu vaccinated patients | 10 | 6 | 4 | 6 | 0 | 4  |
|  Elevated IgG | 10 | 3 | 7 | 3 | 0 | 7  |
|  Epstein Barr Virus (EBV) VCA IgG | 10 | 10 | 0 | 10 | 0 | 0  |
|  Epstein Barr Virus (EBV) VCA IgM | 10 | 9 | 1 | 9 | 0 | 1  |
|  Total | 330 | 168 | 162 | 165 | 2 | 163  |

* HSV-1 and HSV-2: For each cross reactants, one sample produced positive results by predicate device. Possible cross reactivity cannot be excluded based on these results. The results should be interpreted in the clinical context including signs, symptoms, and other laboratory information.
** Mycoplasma pneumoniae IgG and HCV IgG: For each cross reactants, one sample gave EQV outcome on predicate device which was taken as discordant with the ADVIA Centaur EBV-EBNA IgG assay. Possible cross reactivity cannot be excluded based on these results. The results should be interpreted in the clinical context including signs, symptoms, and other laboratory information.

# 2. Interference study:

Biokit evaluated the potential interference of commonly found endogenous substances on the ADVIA Centaur EBV-EBNA IgG assay using negative, low positive and high positive serum, EDTA plasma, and lithium heparin plasma samples. No interference was observed at the tested interferents concentrations. The results for interference study are reported in Table 4.

Table 4. Interference study results -The ADVIA Centaur EBV-EBNA IgG

|  Interfering Substances | Concentration  |
| --- | --- |
|  Hemoglobin | 1000 mg/dL  |
|  Conjugated Bilirubin | 40 mg/dL  |
|  Unconjugated Bilirubin | 40 mg/dL  |
|  Triglycerides | 1500 mg/dL  |

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K233605 - Page 10 of 15

|  Total protein (hyperproteinemia) | 15 g/dL  |
| --- | --- |
|  Total protein (hypoproteinemia) | 3 g/dL  |
|  Cholesterol | 502 mg/dL  |
|  Biotin | 3510 ng/mL  |

3. **EBV-EBNA IgG class specificity:**

Biokit performed a class specificity study to demonstrate that the ADVIA Centaur EBV-EBNA IgG assay is specific to EBV-EBNA IgG class. The results demonstrated that the ADVIA Centaur EBV-EBNA IgG assay specifically detects IgG class immunoglobulin.

4. **Assay Reportable Range:**

Not Applicable

5. **Stability:**

**Sample Stability**

The stability of specimens stored under different conditions was evaluated by testing a panel of natural and contrived samples (including Serum Separator Tube (SST), EDTA plasma, Lithium Heparin plasma on the ADVIA Centaur EBV-EBNA IgG assay.

The data support the following storage conditions for the serum, EDTA plasma and lithium heparin plasma on the ADVIA Centaur EBV-EBNA IgG assay. Summary of sample stability is provided in Table 5.

Table 5. Summary of serum, EDTA plasma and lithium heparin plasma stability

|  Stability summary of samples | Stability Claim  |
| --- | --- |
|  Stability Type  |   |
|  Refrigerated (2 °C to 8 °C) Primary containers (on the clot or gel) | 7 Days  |
|  Refrigerated (2 °C to 8 °C) in secondary containers (separated samples) | 7 Days  |
|  Room Temperature (Nominal 15 °C to 30 °C) in secondary containers (separated samples) | 72 hours  |
|  Frozen (Nominal -30 °C to -15 °C) (separated samples) | 12 months  |
|  Freeze-thaw | 5 cycles  |

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# Reagent Stability

The data support the following storage conditions for the ADVIA Centaur EBV-EBNA IgG assay reagents. Summary of reagent stability is in Table 6.

Table 6. Summary of reagent stability -The ADVIA Centaur EBV-EBNA IgG

|  Stability Study | Stability Claim  |
| --- | --- |
|  Reagent On-Board | 28 days  |
|  Reagent Unopened Shelf Life | 12 months at 2-8°C  |
|  Calibrator Unopened Shelf-Life | 12 months at 2-8°C  |
|  Calibrator In-Use/Opened | 60 days at 2-8°C  |
|  Calibrator at room temperature | 8 hours  |
|  Controls Unopened Shelf Life | 13 months at 2-8°C  |
|  Controls In-Use/Opened | 60 days at 2-8°C  |
|  Controls at room temperature | 8 hours  |

6. Sample fresh-frozen study:

Biokit performed sample fresh-frozen study to demonstrate ADVIA Centaur EBV-EBNA IgG detects analyte equivalently in fresh vs. frozen samples. The results showed the EBV-EBNA IgG detection is similar in both fresh and frozen samples.

7. Detection Limit:

Not Applicable

8. Assay Cut-Off:

A study to establish the ADVIA Centaur EBV-EBNA IgG cut-off was performed using 393 intended use samples. The cut-off value was determined by performing concordance and Receiver Operator Characteristic (ROC) analysis, using predicate (LIAISON EBNA IgG) results as the standard. The estimated cut-off value for ADVIA Centaur EBV-EBNA IgG assay was established as 1.0 Index value.

9. Accuracy (Instrument):

Not Applicable.

10. Carry-over:

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The ADVIA Centaur EBV-EBNA IgG assay is not susceptible to within-assay sample carryover.

# B Comparison Studies:

# 1. Method Comparison with Predicate Device:

A total of 1428 leftover samples were collected over a contiguous time period from individuals for whom an EBV test was ordered (population 1). Of these, 188 were from unclassified serostatus individuals. One-hundred sixty-seven (167) samples with a known negative result (population 2) were evaluated as well. Of these 14 were from unclassified serostatus individuals. The study results otherwise showed that these populations included individuals with acute infection, past infection, or no serologic evidence of EBV infection.

Testing was conducted at three sites in the U.S. representative of testing environments where the candidate device will be used. Table 7 presents all individual samples tested in population 1 and 2 combined with age category.

Table 7. Total study population by age

|  Total Study Population by Age  |   |   |   |
| --- | --- | --- | --- |
|  Sample Age | All individuals  |   |   |
|   |  (N=1595)  |   |   |
|   |  N | n/N | %  |
|  Overall | 1595 | N/A | 100.00%  |
|  Age 2-21 | 551 | 551/1595 | 34.55%  |
|  Age >21 | 1044 | 1044/1595 | 65.45%  |

The performance of the ADVIA Centaur EBV-EBNA IgG results in population 1(leftover remnants with adults and pediatrics) and in population 2 (selected leftover remnant with a known negative result in adults and pediatrics) for all sites combined are summarized in Tables 8 and 9.

Table 8. Population 1 performance of the ADVIA Centaur EBV-EBNA IgG in adults and pediatrics- all sites combined.

|  Population 1  |   |   |   |   |
| --- | --- | --- | --- | --- |
|  ADVIA Centaur EBV-EBNA IgG | LIAISON EBNA IgG  |   |   |   |
|   |  Negative | Equivocal | Positive | Total  |
|  Nonreactive | 323 | 2 | 4 | 329  |
|  Reactive | 23 | 2 | 1074 | 1099  |
|  Total | 346 | 4 | 1078 | 1428  |
|  Performance | NPA=92.82% (323/348) |  | PPA= 99.44% (1074/1080) |   |
|   | 95% CI: 89.61% - 95.09% |  | 95% CI: 98.79% - 99.75% |   |

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Table 9. Population 2 performance of the ADIVA Centaur EBV-EBNA IgG in adults and pediatrics- all sites combined.

|  Population 2  |   |   |   |   |
| --- | --- | --- | --- | --- |
|  ADVIA Centaur EBV-EBNA IgG | LIAISON EBNA IgG  |   |   |   |
|   |  Negative | Equivocal | Positive | Total  |
|  Nonreactive | 164 | 0 | 0 | 164  |
|  Reactive | 3 | 0 | 0 | 3  |
|  Total | 167 | 0 | 0 | 167  |
|  Performance | NPA=98.2% (164/167) |  | N/A |   |
|  95% CI | 95% CI: 94.85% - 99.39% |  | N/A | N/A  |

The ADVIA Centaur EBV-EBNA IgG results for pediatrics alone on population 1 and 2 are summarized in Table 10 and 11.

Table 10. Population 1 performance of the ADIVA Centaur EBV-EBNA IgG in Pediatrics

|  Population 1-pediatrics  |   |   |   |   |
| --- | --- | --- | --- | --- |
|  ADVIA Centaur EBV-EBNA IgG | LIASON EBNA IgG  |   |   |   |
|   |  Negative | Equivocal | Positive | Total  |
|  Nonreactive | 220 | 2 | 2 | 224  |
|  Reactive | 5 | 1 | 249 | 255  |
|  Total | 225 | 3 | 251 | 479  |
|  Performance | NPA= 97.35% (220/226) |  | PPA= 98.42% (249/253) |   |
|  95% CI | 95% CI: 94.33% - 98.78% |  | 95% CI: 96.01%% - 99.38% |   |

Table 11. Population 2 performance of the ADIVA Centaur EBV-EBNA IgG in Pediatrics

|  Population 2-pediatric  |   |   |   |   |
| --- | --- | --- | --- | --- |
|  ADVIA Centaur EBV-EBNA IgG | LIAISON EBNA IgG  |   |   |   |
|   |  Negative | Equivocal | Positive | Total  |
|  Nonreactive | 72 | 0 | 0 | 72  |
|  Reactive | 0 | 0 | 0 | 0  |
|  Total | 72 | 0 | 0 | 72  |
|   | NPA=100% (72/72) |  | N/A |   |
|   | 95% CI: 94.94% - 100.00% |  |  |   |

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# 2. Matrix Comparison:

The aim of this study was to evaluate the performance of different sample matrices with the ADVIA Centaur EBV-EBNA IgG assay. This study evaluated ninety eight (98) sets of matched samples of Serum (Serum Separator Tube) and EDTA plasma and 97 sets of matched samples of Lithium Heparin plasma with the ADVIA Centaur EBV-EBNA IgG assay on the ADVIA Centaur XP system for matrix equivalency. The samples were analyzed by regression analysis as shown in Table 12.

The data showed that the sample matrices, serum (SST), EDTA plasma and Lithium-Heparin plasma are comparable in performance.

Table 12. Regression analysis on matrix equivalence

|  Tube (y) vs. Serum (x) | Regression Equation | Sample Interval | Na | rb  |
| --- | --- | --- | --- | --- |
|  Plasma, EDTA | y = 1.00x - 0.01 | 0.03-19.86 Index | 98 | 1  |
|   |  Index  |   |   |   |
|  Plasma, lithium heparin | y = 0.98x - 0.01 | 0.03-17.87 Index | 97 | 0.99  |
|   |  Index  |   |   |   |

a Number of samples tested.
b Correlation coefficient.

# C Clinical Studies:

See section B. 1 for clinical study results.

# D Clinical Cut-Off:

Not Applicable

# E Expected Values/Reference Range:

The ADVIA Centaur EBV-EBNA IgG results for the study population 1 (N=1428 samples) for all sites combined by age group and sex are summarized in Table 13.

Table 13. Population 1 (leftover remnant study population) results by age and sex

|  Age Group (Years) | Sex | Reactive |   | Nonreactive |   | Total  |
| --- | --- | --- | --- | --- | --- | --- |
|   |   |  Na | %b | N | %  |   |
|  2-21 | Male | 113 | 49.80% | 114 | 50.20% | 227  |
|   |  Female | 142 | 56.30% | 110 | 43.70% | 252  |
|   |  Overall | 255 | 53.20% | 224 | 46.80% | 479  |
|  >21 | Male | 290 | 86.60% | 45 | 13.40% | 335  |
|   |  Female | 554 | 90.20% | 60 | 9.80% | 614  |
|   |  Overall | 844 | 88.90% | 105 | 11.10% | 949  |
|  Total | Male | 403 | 71.70% | 159 | 28.30% | 562  |

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|   | Female | 696 | 80.40% | 170 | 19.60% | 866  |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Overall | 1099 | 77.00% | 329 | 23.00% | 1428  |

a Number of samples tested.
b Percentages are for the numbers of reactive and nonreactive in a given row.

## VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

## IX Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

K233605 - Page 15 of 15

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**Source:** [https://fda.innolitics.com/submissions/MI/subpart-d%E2%80%94serological-reagents/LLM/K233605](https://fda.innolitics.com/submissions/MI/subpart-d%E2%80%94serological-reagents/LLM/K233605)

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