ADVIA Centaur Anti-HBc Total (HBcT2) and Atellica IM Anti-HBc Total (HBcT2)
Device Facts
| Record ID | P210019S002 |
|---|---|
| Device Name | ADVIA Centaur Anti-HBc Total (HBcT2) and Atellica IM Anti-HBc Total (HBcT2) |
| Applicant | Siemens Healthcare Diagnostics, Inc. |
| Product Code | LOM · Microbiology |
| Decision Date | Apr 28, 2023 |
| Decision | APPR |
| Regulation | 21 CFR 866.3172 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
The ADVIA Centaur® HBc Total 2 (HBcT2) assay is an in vitro diagnostic immunoassay for use in the qualitative determination of total antibodies to the core antigen of the hepatitis B virus (HBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA, lithium heparin, and sodium heparin) using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems. This assay can be used as an aid in the diagnosis of acute or chronic hepatitis B virus (HBV) infection, and in the determination of the clinical status of HBV-infected individuals in conjunction with other HBV serological markers, for the laboratory diagnosis of HBV disease associated with HBV infection. This assay can also be used as an aid in the differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown. This assay is not intended for screening donors of blood or blood products or human cells, tissues, and cellular and tissue-based products (HCT/Ps).
Device Story
In vitro diagnostic immunoassay; detects total antibodies (IgM and IgG) to hepatitis B core antigen (HBcAg) in human serum/plasma. Uses antigen sandwich format; solid phase consists of streptavidin-coated microparticles with biotinylated recombinant HBc antigen; Lite Reagent contains acridinium ester-labeled recombinant HBc antigen and anti-human IgG Fab monoclonal antibody. System automates sample/reagent dispensing, incubation at 37°C, and wash cycles. Chemiluminescent reaction initiated by Acid/Base reagents; relative light units (RLUs) measured. Results reported as Index Values (Reactive ≥ 1.0; Nonreactive < 1.0). Used in clinical laboratories on ADVIA Centaur or Atellica IM analyzers. Output aids clinicians in diagnosing HBV infection, determining disease status, and differential diagnosis. Benefits include improved patient management, monitoring, and potential reduction in disease transmission.
Clinical Evidence
Prospective multisite study (N=1595) including 139 pediatric subjects (2-21 years). Compared against FDA-approved reference assay. Pediatric PPA 100% (4/4), NPA 99.3% (134/135). Overall study PPA 97.7% (433/443), NPA 98.5% (1135/1152). Spiking study (N=60 pediatric samples) confirmed performance consistency with adults (98.3% of samples showed <20% bias).
Technological Characteristics
Antigen sandwich immunoassay; chemiluminescent detection. Solid phase: streptavidin-coated microparticles with biotinylated recombinant HBc antigen. Lite Reagent: acridinium ester-labeled recombinant HBc antigen and anti-human IgG Fab monoclonal antibody. Automated platform (ADVIA Centaur/Atellica IM). Two-point calibration with factory-set Master Curve. Qualitative result based on Index Value.
Indications for Use
Indicated for qualitative detection of total antibodies to hepatitis B core antigen (anti-HBc) in human serum and plasma (EDTA, lithium heparin, sodium heparin) for pediatric (2-21 years) and adult patients. Used as an aid in diagnosis of acute/chronic HBV infection, determination of clinical status, and differential diagnosis of hepatitis of unknown etiology. 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: Antibodies to Hepatitis B Core Antigen Assay
Device Trade Name: ADVIA Centaur® HBc Total 2 (HBcT2)
ADVIA Centaur® HBc Total 2 Quality Control (HBcT2 QC)
Atellica IM® HBc Total 2 (HBcT2)
Atellica IM® HBc Total 2 Quality Control (HBcT2 QC)
Device Procode: LOM
Applicant’s Name and Address: Siemens Healthcare Diagnostics Inc
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P210019/S002
Date of FDA Notice of Approval: April 28, 2023
The original PMA (P210019) was approved on July 27, 2022 and is indicated for ADVIA Centaur® HBc Total 2 (HBcT2) and Atellica IM® HBc Total 2 (HBcT2) on ADVIA Centaur XP/XPT and Atellica IM Analyzers in human adult serum and plasma (EDTA, lithium heparin, and sodium heparin) using ADVIA Centaur XP, ADVIA Centaur CPT, and Atellica IM. This assay can be used as an aid in the diagnosis of adults with acute or chronic hepatitis B virus (HBV) infection, and in the determination of the clinical status of HBV-infected individuals in conjunction with other HBV serological markers, for the laboratory diagnosis of HBV disease associated with HBV infection. This assay can also be used as an aid in the differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown.
The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indication for the
Inclusion of pediatric subjects in intended use population for the ADVIA Centaur® HBc Total 2 (HBcT2) on ADVIA Centaur XP/XPT, and ADVIA Centaur CP Analyzers, and Atellica IM® HBc Total 2 (HBcT2) on Atellica IM Analyzer.
## II. INDICATIONS FOR USE
The ADVIA Centaur® HBc Total 2 (HBcT2):
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The ADVIA Centaur® HBc Total 2 (HBcT2) assay is an in vitro diagnostic immunoassay for use in the qualitative determination of total antibodies to the core antigen of the hepatitis B virus (HBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA, lithium heparin, and sodium heparin) using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems.
This assay can be used as an aid in the diagnosis of acute or chronic hepatitis B virus (HBV) infection, and in the determination of the clinical status of HBV-infected individuals in conjunction with other HBV serological markers, for the laboratory diagnosis of HBV disease associated with HBV infection. This assay can also be used as an aid in the differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown.
This assay is not intended for screening donors of blood or blood products or human cells, tissues, and cellular and tissue-based products (HCT/Ps).
#### ADVIA Centaur® HBc Total 2 Quality Control (HBcT2 QC)
The ADVIA Centaur® HBc Total 2 (HBcT2) Quality Control material is for in vitro diagnostic use for monitoring the performance of the ADVIA Centaur HBc Total 2 (HBcT2) assay using the ADVIA Centaur systems.
The performance of the ADVIA Centaur HBcT2 Quality Control material has not been with any other anti-HBc Total assay.
#### The ADVIA Centaur® HBc Total 2 (HBcT2):
The ADVIA Centaur® HBc Total 2 (HBcT2) assay is an in vitro diagnostic immunoassay for use in the qualitative determination of total antibodies to the core antigen of the hepatitis B virus (HBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA, lithium heparin, and sodium heparin) using the ADVIA Centaur® CP systems.
This assay can be used as an aid in the diagnosis of acute or chronic hepatitis B virus (HBV) infection, and in the determination of the clinical status of HBV-infected individuals in conjunction with other HBV serological markers, for the laboratory diagnosis of HBV disease associated with HBV infection. This assay can also be used as an aid in the differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown.
This assay is not intended for screening donors of blood or blood products or human cells, tissues, and cellular and tissue-based products (HCT/Ps).
#### ADVIA Centaur® HBc Total 2 Quality Control (HBcT2 QC)
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The ADVIA Centaur® HBc Total 2 (HBcT2) Quality Control material is for in vitro diagnostic use for monitoring the performance of the ADVIA Centaur HBc Total 2 (HBcT2) assay using the ADVIA Centaur systems.
The performance of the ADVIA Centaur HBcT2 Quality Control material has not been with any other anti-HBc Total assay.
# The Atellica IM HBc Total 2 (HBcT2):
The ADVIA Centaur® HBc Total 2 (HBcT2) assay is an in vitro diagnostic immunoassay for use in the qualitative determination of total antibodies to the core antigen of the hepatitis B virus (HBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA, lithium heparin, and sodium heparin) using the Atellica IM Analyzer.
This assay can be used as an aid in the diagnosis of acute or chronic hepatitis B virus (HBV) infection, and in the determination of the clinical status of HBV-infected individuals in conjunction with other HBV serological markers, for the laboratory diagnosis of HBV disease associated with HBV infection. This assay can also be used as an aid in the differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown.
This assay is not intended for screening donors of blood or blood products or human cells, tissues, and cellular and tissue-based products (HCT/Ps).
# Atellica IM® HBc Total 2 Quality Control (HBcT2 QC)
The Atellica IM HBc Total 2 (HBcT2) Quality Control material is for in vitro diagnostic use for monitoring the performance of the Atellica IM HBc Total 2 (HBcT2) assay using the Atellica IM systems.
The performance of the Atellica IM HBcT2 Quality Control material has not been with any other anti-HBc Total assay.
### III. CONTRAINDICATIONS
There are no known contraindications.
### IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the device labeling.
### V. DEVICE DESCRIPTION
There have been no changes to the device associated with the addition of pediatric populations to the intended use.
Assay Principle and Format
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The ADVIA Centaur/Atellica Anti-HBcT2 assay is a 2-wash antigen sandwich immunoassay in which antigens are bridged by antibody present in the patient sample. The Solid Phase contains a preformed complex of streptavidin-coated microparticles and biotinylated recombinant HBc antigen and is used to capture anti-HBc in the patient sample.
The Lite Reagent contains recombinant HBc antigen labeled with acridinium ester and anti-human IgG Fab monoclonal antibody labeled with acridinium ester and is used to detect anti-HBc in the sample.
The Ancillary Reagent, Solid Phase, and Ancillary Well Reagent are added to the sample, followed by Lite Reagent. Antibody-antigen complexes will form if anti-HBc antibodies (IgM and IgG) are present in the sample.
A direct relationship exists between the amount of anti-HBc antibodies present in the patient sample and the amount of relative light units (RLUs) detected by the system. A result of reactive or nonreactive is determined according to the Index Value established with the calibrators.
Assay procedure:
The ADVIA Centaur system automatically performs the following actions:
1. Dispenses 50 μL of sample into a cuvette.
2. Dispenses 100 μL of Ancillary Reagent and incubates the mixture for 6 minutes at 37°C.
3. Dispenses 100 μL of Ancillary Well Reagent and 125 μL of Solid Phase, and incubates the mixture for 18 minutes at 37°C.
4. Washes the cuvette with ADVIA Centaur Wash 1.
5. Resuspends with 250 μL of ADVIA Centaur Wash 1 and incubates the mixture for 6 minutes at 37°C.
6. Dispenses 100 μL of Lite Reagent and incubates the mixture for 18 minutes at 37°C.
7. Washes the cuvette with ADVIA Centaur Wash 1.
8. Dispenses 300 μL of ADVIA Centaur Acid Reagent and 300 μL of ADVIA Centaur Base Reagent to initiate the chemiluminescent reaction.
9. Reports results.
The Atellica IM automatically performs the following actions:
1. Dispenses 50 μL of sample into a cuvette.
2. Dispenses 100 μL of Ancillary Reagent into a cuvette, then incubates for 6 minutes at 37°C.
3. Dispenses 100 μL of Ancillary Well Reagent and 125 μL of Solid Phase, then incubates for 18 minutes at 37°C.
4. Performs a wash sequence using Atellica IM Wash.
5. Resuspends the particles in 250 μL of Atellica IM Wash.
6. Dispenses 100 μL of Lite Reagent, then incubates for 18 minutes at 37°C.
7. Performs a wash sequence using Atellica IM Wash.
8. Dispenses 300 μL each of Atellica IM Acid and Atellica IM Base to initiate the chemiluminescent reaction.
9. Reports results.
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## Calibration
The ADVIA Centaur/Atellica Anti-HBcT2 assay utilizes two-point calibration (Low Calibrator, High Calibrator). The assay utilizes a factory-set Master Curve. The Master Curve values are contained on the Master Curve card provided with each kit. The Master Curve and calibration are lot specific. The barcode reader or keyboard is used to enter the Master Curve values on the system. The two calibrators in the kit are run when the lot is first used or after expiration of the calibration interval. If the calibration run is valid as determined by prearranged parameters, the values are stored and used to “normalize” test values to the Master Curve.
The Index value of the sample or control is read off the Master Curve. Individuals whose samples read at or above an Index of 1.0 are considered to be reactive for HBcT2.
## Controls
The ADVIA Centaur HBcT2 QC and Atellica IM HBcT2 QC set contains Negative control (2 vials with 7 mL) and Positive control (2 vials with 7 mL). The performance of the ADVIA Centaur and Atellica IM HBcT2 assay is monitored by the use of ADVIA Centaur HBcT2 or Atellica IM HBcT2 QC Quality Controls at least once during each day when samples are analyzed or after a successful calibration.
## Interpretation of Results
The system reports HBcT2 assay results in Index Values and as Nonreactive or Reactive:
- Nonreactive: < 1.0 Index. These samples are considered negative.
- Reactive: ≥ 1.0 Index. These samples are considered positive.
## VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are several other alternatives for the determination of HBV infection and its disease stage. Detection of anti-HBcT in patients who may be infected with the hepatitis B virus may also be accomplished with any commercially available FDA approved serological tests. This assay is one of several hepatitis marker assays that are often used together and in conjunction with clinical assessment and other laboratory test results in the diagnosis of the HBV infection.
## VII. MARKETING HISTORY
ADVIA Centaur HBc Total 2 (HBcT2) assay and ADVIA Centaur HBc Total 2 Quality Control (HBcT2 QC) are marketed globally in several countries. The device has not been withdrawn to date from the market in any country for reasons relating to safety and effectiveness of the device.
| Austria | Belgium | Switzerland | Czech Republic |
| --- | --- | --- | --- |
| Germany | Denmark | Estonia | Spain |
| Finland | France | United Kingdom | Greece |
| Croatia | Hungary | Ireland | Iceland |
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| Italy | Liechtenstein | Lithuania | Luxembourg |
| --- | --- | --- | --- |
| Latvia | North Macedonia | Malta | Netherlands |
| Norway | Poland | Romania | Serbia |
| Sweden | Slovenia | Slovakia | Afghanistan |
| Ukraine | United Arab Emirates | Cyprus | Hong Kong |
| India | Iraq | Turkey | Saudi Arabia |
| Singapore | Malaysia | Canada | Chile |
| Chile | Peru | South Africa | Zimbabwe |
| Madagascar | Bahrain | Pakistan | |
## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**
Below is a list of the potential adverse effects associated with the use of the device.
Failure of the product to perform as indicated, or human error in use of the product may lead to a false result. Repeatedly erroneous false positive or false negative anti-HBc results could lead to inappropriate initiation or cessation of antiviral therapy.
The risk of incorrect test results is inherent with all in vitro diagnostic products. Therefore, the above potential risks are not unusual in the laboratory setting and should be evaluated in conjunction with other clinical indicators.
When used according to the instructions in the package insert, there are no known direct adverse effects of this device on the health of the user. Standard good laboratory practices are considered sufficient to minimize risks to the end user.
## **IX. SUMMARY OF NONCLINICAL STUDIES**
The non-clinical studies previously conducted (P210019) continue to be applicable to and supportive of the use of the device in pediatric populations. Siemens conducted additional laboratory studies (summarized below) to confirm continued performance of the device in pediatric populations.
### **A. Laboratory Studies**
#### **Precision**
Precision study on ADVIA Centaur Anti-HBcT2 assay on ADVIA Centaur CP analyzer:
The ADVIA Centaur Anti-HBcT2 assay precision was examined in a 20-day precision protocol using one reagent lot. Two controls and 5 specimens in 2 matrices (serum and EDTA plasma) were used to measure the precision of the assay at different Index levels. The specimens were assayed in duplicate with 2 runs per day for 20 days (N = 80 for each sample). Table 1 below show the results of precision study
Table 1: ADVIA Centaur CP Precision study results
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| Specimen Type | N^{a} | Mean | Repeatability | | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | SD^{b} | CV^{c} | SD | CV^{c} |
| | | (Index) | (Index) | (%) | (Index) | (%) |
| Plasma A | 80 | 0.21 | 0.02 | N/A^{d} | 0.05 | N/A |
| Plasma B | 80 | 0.68 | 0.04 | N/A | 0.08 | N/A |
| Plasma C | 80 | 1.6 | 0.07 | 4.4 | 0.14 | 8.9 |
| Plasma D | 80 | 2.22 | 0.09 | 4.1 | 0.21 | 9.6 |
| Plasma E | 80 | 7.66 | 0.39 | 5.1 | 0.89 | 11.6 |
| Serum A | 80 | 0.13 | 0.02 | N/A | 0.06 | N/A |
| Serum B | 80 | 0.56 | 0.03 | N/A | 0.07 | N/A |
| Serum C | 80 | 1.49 | 0.07 | 4.4 | 0.15 | 10.3 |
| Serum D | 80 | 2.22 | 0.09 | 3.9 | 0.2 | 9 |
| Serum E | 80 | 6.71 | 0.36 | 5.3 | 0.68 | 10.1 |
| Control 1 (negative) | 80 | 0.21 | 0.02 | N/A | 0.06 | N/A |
| Control 2 (positive) | 80 | 3.12 | 0.13 | 4.2 | 0.27 | 8.5 |
$^{a}$Number of measurements
$^{b}$Standard deviation
$^{c}$Coefficient of variation
$^{d}$Samples recovering below 0.70 Index are not included in analysis
### System Reproducibility
Reproducibility study of ADVIA Centure Anti-HBcT2 on ADIVIA Centaur CP analyzer:
A six-member panel, and QC1 and QC2 were assayed in triplicate for five days, two runs per day, at the three sites. The end of the first run on a testing day was separated from the start of the second run by approximately two hours. Each site ran three reagent lots with their respective calibrators and controls. The system reproducibility was determined in accordance with CLSI Document EP05-A3A reproducibility study was conducted at 3 sites, with each site evaluating 3 reagent lots. The protocol was run over 5 days, 2 runs per day. There were 3 replicates per run for each sample, for a total 270 replicates per sample (N = 270). Results were established using the ADVIA Centaur CP system. The following results are representative of the performance of the assay.
Table 2: ADVIA Centaur CP Reproducibility study across sites and reagent lots
| Sample | Mean | Repeatability (Within-Run) | | Between Run | | Between Day | | Between Lot | | Within Laboratory | | Between Site | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Type | | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| (N = 270) | Index | Index | % | Index | % | Index | % | Index | % | Index | % | Index | % | Index | % |
| Serum A | 0.4 | 0.02 | N/A^{d} | 0.02 | N/A | 0.02 | N/A | 0.06 | N/A | 0.04 | N/A | 0 | N/A | 0.07 | N/A |
| Serum B | 0.71 | 0.03 | N/A | 0.03 | N/A | 0.03 | N/A | 0.06 | N/A | 0.05 | N/A | 0 | N/A | 0.08 | N/A |
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| Serum C | 1.34 | 0.05 | 3.6 | 0.04 | 2.8 | 0.04 | 2.8 | 0.12 | 8.8 | 0.07 | 5.3 | 0.02 | 1.5 | 0.14 | 10.4 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Serum D | 2.41 | 0.08 | 3.3 | 0.07 | 3.1 | 0.08 | 3.4 | 0.18 | 7.4 | 0.14 | 5.6 | 0.02 | 0.7 | 0.23 | 9.3 |
| Serum E | 5.28 | 0.22 | 4.1 | 0.19 | 3.6 | 0.16 | 3.1 | 0.36 | 6.8 | 0.33 | 6.2 | 0.12 | 2.2 | 0.5 | 9.5 |
| Serum F | 8.66 | 0.33 | 3.9 | 0.27 | 3.1 | 0.37 | 0.3 | 0.56 | 6.5 | 0.38 | 4.4 | 0.12 | 1.4 | 0.69 | 8 |
| Control 1 (negative) | 0.19 | 0.02 | N/A | 0.02 | N/A | 0.01 | N/A | 0.03 | N/A | 0.04 | N/A | 0.02 | N/A | 0.05 | N/A |
| Control 2 (positive) | 3.28 | 0.11 | 3.4 | 0.06 | 1.8 | 0.11 | 3.4 | 0.23 | 7.1 | 0.17 | 5.1 | 0.08 | 2.3 | 0.3 | 9.1 |
### Sensitivity Study with HBV WHO First International Standard
The analytical sensitivity of the ADVIA Centaur/Atellica Anti-HBcT2 assay was evaluated using the World Health Organization (WHO) First International Standard for anti-Hepatitis B core antigen (anti-HBc).
The WHO Standard was reconstituted and diluted according to manufacturer's instructions. A stock solution of the standard was used to prepare a dilution series with negative human serum. The first level in the dilution series (A) was prepared by mixing 1 part of the NIBSC 95/522 50 IU/mL stock solution with 1 part of anti-HBc negative serum. The serial dilutions were then prepared by adding anti-HBc negative serum. Each diluted sample was tested in triplicate with the ADVIA Centaur/Atellica Anti-HBcT2 assay using an ADVIA Centaur XP, XPT, ADVIA Centaur CP and Atellica IM instrument. The observed dose was calculated using 2-point calibration. The quantitative value of WHO material detected at cutoff (Index = 1.00) was calculated using linear regression analysis. Analytical sensitivity evaluated with three different reagent lots of ADVIA Centaur/Atellica Anti-HBcT2 assay on ADVIA Centaur XP, XPT, ADVIA Centaur CP and Atellica IM instruments yield only minor differences from the WHO International Standard in all cases, as shown below in Table 3. The WHO 95/522 International Unit per milliliter (IU/mL) concentration at the assay cutoff was determined to be 0.28 IU/mL.
Table 3: Value of WHO material (IU/mL) detected at HBcT2 cutoff (Index = 1.00) and Correlation Coefficient
| Reagent Lot | Platform | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | ADVIA Centaur XP | | ADVIA Centaur XPT | | Atellica IM | | ADVIA Centaur CP | |
| | IU/mL | R^{2} | IU/mL | R^{2} | IU/mL | R^{2} | IU/mL | R^{2} |
| Lot 1 | 0.225 | 0.998 | 0.267 | 0.996 | 0.218 | 0.98 | 0.980 | 0.228 |
| Lot 2 | 0.234 | 0.997 | 0.231 | 0.995 | 0.211 | 0.995 | 0.995 | 0.256 |
| Lot 3 | 0.254 | 0.997 | 0.231 | 0.995 | 0.251 | 0.992 | 0.992 | 0.218 |
### Seroconversion Sensitivity
Seroconversion study on ADVIA Centaur Anti-HBcT2 assay on ADVIA Centaur CP analyzer:
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Commercially available HBV patient seroconversion panels were tested using the ADVIA Centaur Anti-HBcT2 to determine the seroconversion sensitivity of the assay on ADVIA Centaur CP analyzer.
The same 7 commercially available HBV seroconversion panels used in the original PMA P210019 were tested at the same three US clinical sites. Each site tested at least 2 seroconversion panels. The following results were obtained with the ADVIA Centaur CP instrument:
Table 4: Seroconversion Resultson ADVIA Centaur CP HBcT2 versus Referenec assay
| Panel ID | First HBcT2 Reactive Result From Initial Draw Date | | ADVIA Centaur CP HBcT2 versus Reference Assay |
| --- | --- | --- | --- |
| | ADVIA Centaur CP Assay (Days) | Reference Assay (Days) | Difference in Bleed Numbers^{a} |
| HBV6278 | 41 | 41 | 0 |
| HBV6281 | 41 | 41 | 0 |
| HBV9093 | 49 | 49 | 0 |
| HBV9099 | 74 | 74 | 0 |
| PHM941 | 99 | 99 | 0 |
| SCPHBV1 | 29 | 29 | 0 |
| SCPHBV4 | 65 | 71 | +1 |
a The difference in bleed numbers is relative to the reference assay. For example, a “+1” means that the reference assay required 1 additional bleed before reactivity was determined as compared to the time point when the ADVIA Centaur assay confirmed reactive.
Stability for Calibration interval for ADVIA Centaur CP system:
The stability of the working calibration curve was evaluated on the ADVIA Centaur CP instrument with two lots of ADVIA Centaur HBcT2. Reagents were placed on onboard ADVIA Centaur CP for the duration of the study. Testing was performed with calibrators (Low, High) and controls (Control 1, Control 2) run as samples and patient pools spiked with anti-HBc. All samples were tested in replicates of 4. In addition to testing open onboard reagents, fresh static packs were tested at each timepoint. The results support the calibration interval claim of 21 days on ADVIA Centaur CP instrument.
# X. SUMMARY OF PRIMARY CLINICAL STUDY(IES)
Siemens performed a clinical study to establish a reasonable assurance of safety and effectiveness of the ADVIA Centaur/Atellica Anti-HBcT2 assay with samples from pediatric individuals. 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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A summary of the clinical study is presented below on ADVIA Centaur CP analyzer.
### A. Study Design
A multisite study was conducted to evaluate the performance of the ADVIA Centaur/Atellica Anti-HBcT2 assay. The study consists of a Qualitative Method Comparison Agreement with a reference assay (FDA-approved Anti-HBcT assay).
Subjects were assessed for hepatitis markers using commercially available, FDA-approved reference assays. The serological assessment included the following 6 HBV markers: hepatitis B virus surface antigen (HBsAg), hepatitis B e antigen (HBeAg), IgM antibody to hepatitis B core antigen (anti-HBc IgM), total antibody to hepatitis B virus core antigen (anti-HBc Total), hepatitis B e antibody (anti-HBe , and antibody to hepatitis B virus surface antigen (anti-HBs).
Testing was conducted at three US sites with three reagent lots.
### B. Accountability of PMA Cohort
A total of 1595 prospective subjects were enrolled for this study. The study population was considered either at risk for hepatitis B (due to lifestyle, behavior, occupation, or known exposure events) or had signs-and-symptoms of hepatitis B infection. Among 1595 specimens, 139 were from pediatric and non-pregnant adolescent subjects. The population analysis was stratified by the following age groups: 2-12 years (n=30) and 13-21 years (n=109).
### C. Study Population Demographics and Baseline Parameters
Table 5. Pediatric subjects Demographics
| Subject Demographics* | Prospective Patient | | |
| --- | --- | --- | --- |
| | | N | (%) |
| **Characteristic** | **Population** | 139 | 100% |
| Category | Pediatric Patient | 139 | 100% |
| Gender | Female | 72 | 51.8% |
| | Male | 67 | 48.2% |
| State of Residence | California | 36 | 25.9% |
| | Florida | 61 | 43.9% |
| | Minnesota | 41 | 29.5% |
| | New Jersey | 1 | 0.7% |
| Continent of Origin†† | Africa | 1 | 0.7% |
| | Asia | 1 | 0.7% |
| | Caribbean | 4 | 2.9% |
| | Central America | 1 | 0.7% |
| | Mexico | 2 | 1.4% |
| | North America | 128 | 92.1% |
| | South America | 2 | 1.4% |
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| Ethnicity | Hispanic/Latino | 21 | 15.1% |
| --- | --- | --- | --- |
| | Non-Hispanic/Non-Latino | 118 | 84.9% |
| Race | White | 30 | 21.6% |
| | Black or African American | 92 | 66.2% |
| | Asian | 6 | 4.3% |
| | Native Am/Alaska Native | 2 | 1.4% |
| | multi-race | 8 | 5.8% |
| | unknown/declined | 1 | 0.7% |
| Age (Years) | Mean | 16.9 | |
| | Median | 19 | |
| | SD | 4.8 | |
| | Min | 2 | |
| | Max | 21 | |
*Across sites;†† When subjects were asked to list their country of origin, there were 10 countries represented by the study population. The 10 countries were: Bahamas (1), Brazil (1), China (1), Colombia (1), Cuba (1), Haiti (2), Honduras (1), Mexico (2), Nigeria (1), United States (128).
### Percent Agreement on ADVIA Centaur CP analyzer:
ADVIA Centaur Anti-HBcT2 assay was tested on ADVIA Centaur CP system and the agreement calculated against an FDA-approved anti-HBcT reference assay. The Percent Positive Agreement (PPA) and Negative Percentage of Agreement (NPA) versus the reference assay on the different instrument systems is in Table 6.
Table 6: Agreement Table with ADVIA Centaur CP
| ADVIA Centaur CP HBcT2 | Reference Assay | | Total |
| --- | --- | --- | --- |
| | Reactive | Nonreactive | |
| Reactive | 433 | 17 | 450 |
| Nonreactive | 10 | 1135 | 1145 |
| Total | 443 | 1152 | 1595 |
% Positive Agreement = 97.7% (433/443)
95% Confidence Interval = 95.9%–98.8%
% Negative Agreement = 98.5% (1135/1152)
95% Confidence Interval = 97.6%–99.1%
### Expected Values
All of the samples from the 1595 unique patients including pregnant women were tested with the ADVIA Centaur/Atellica Anti-HBcT2.
See P210019 SSED for expected values in adults.
The below table 7 shows the expected values form pediatric population (2-21years old)
Table 7: Expected Values with ADVIA Centaur XP Pediatric population
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| Age Range (Years) | Reactive | | Nonreactive | | Total Number Tested |
| --- | --- | --- | --- | --- | --- |
| | N | % | N | % | |
| 2-12 | 1 | 3.4% | 29 | 96.7% | 30 |
| 13-21 | 4 | 3.8% | 105 | 96.3% | 109 |
| Total | 5 | 3.7% | 134 | 96.4% | 139 |
#### D. Safety and Effectiveness Results
##### 1. Safety Results
The safety of this device is related to the efficacy described below as incorrect results may lead to patient mismanagement.
##### 2. Effectiveness Results
###### *Prospective Population*
The performance of the ADVIA Centaur Anti-HBcT2 assay was evaluated against the risk groups, the disease classification, and the subpopulations. The performance on the ADVIA Centaur CP analyzer is presented below:
###### **By Risk Group**
The performance of the ADVIA Centaur Anti-HBcT2 assay was evaluated in the signs and symptoms prospective populations and compared to the reference assay (Table 8). The percent agreement and confidence intervals for the prospective population by risk group is presented below (Table 9).
##### 1) Signs and Symptom prospective population on ADVIA Centaur CP:
Table 8: ADVIA Centaur CP – Comparison of Results in the Signs and Symptoms Prospective Population
| ADVIA Centaur HBcT2 Assay | Reference Assay | | Total |
| --- | --- | --- | --- |
| | Reactive | Nonreactive | |
| Reactive | 189 | 11 | 200 |
| Nonreactive | 5 | 571 | 576 |
| Total | 194 | 582 | 776 |
% Positive Agreement = 97.4% (189/194)
95% Confidence Interval = 94.1%–98.9%
% Negative Agreement = 98.1% (571/582)
95% Confidence Interval = 96.6%–98.9%
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## 2) High-Risk Prospective Population:
Table 19: ADVIA Centaur CP – Comparison of Results in the High-Risk Prospective Population
| ADVIA Centaur HBcT2 Assay | Reference Assay | | Total |
| --- | --- | --- | --- |
| | Reactive | Nonreactive | |
| Reactive | 244 | 6 | 250 |
| Nonreactive | 5 | 564 | 569 |
| Total | 249 | 570 | 819 |
Positive Percent Agreement: 98.0% (244/249)
95% Confidence Interval: 95.4%–99.1%
Negative Percent Agreement: 98.9% (564/570)
95% Confidence Interval: 97.7%–99.5%
### a. By HBV Serological Classification
A total of 1595 samples including the 35 unclassified serostatus samples were evaluated using the ADVIA Centaur Anti-HBcT2 assay on ADVIA Centaur CP and an FDA approved reference Anti-HBcT assay for each sample classification. The agreement and 95% CIs between the ADVIA Centaur Anti-HBcT2 assay and a reference Anti-HBcT assay for each HBV classification are presented in the Table 10.
Below table 10 shows results on ADVIA Centaur CP systems
Table 10: Positive and Negative Percent Agreements Between ADVIA Centaur CP HBcT2 assay and reference Anti-HBcT assay by HBV Classification
| ADVIA Centaur CP Percent Agreement with Reference Assay | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| HBV Classification | Positive Percent Agreement | | | Negative Percent Agreement | | |
| | (x/N) | % | 95% CI | (x/N) | % | 95% CI |
| Acute, N=3 | (3/3) | 100% | 43.9-100% | NA | NA | NA |
| Chronic, N=77 | (77/77) | 100% | 95.2-100% | NA | NA | NA |
| Early Recovery, N=15 | (15/15) | 100% | 79.6-100% | NA | NA | NA |
| Recovered, N=223 | (207/209) | 99.0% | 96.6-99.7% | (5/14) | 35.7% | 16.3-61.2% |
| Recovery, N=105 | (101/101) | 100% | 96.3-100% | (3/4) | 75.0% | 30.1-95.4% |
| HBV Vaccine Response, N=539 | (19/25) | 76.0% | 56.6-88.5% | (511/514) | 99.4% | 98.3-99.8% |
| Not Previously Infected, N=599 | (3/5) | 60.0% | 23.1-88.2% | (591/594) | 99.5% | 98.5-99.8% |
| Unclassified, N=34 | (8/8) | 100% | 67.6-100% | (25/26) | 96.2% | 81.1-99.3% |
| Total, N=1595 | (433/443) | 97.7% | 95.9-98.8% | (1135/1152) | 98.5% | 97.6-99.1% |
### b. Pediatric population
Pediatric and adolescent (non-pregnant) samples were prospectively collected (N = 139) and tested using the ADVIA Centaur XP system. The population analysis was stratified by the following age groups: 2–12 years and 13–21 years. Results of
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the testing (reactive and nonreactive) were compared using the ADVIA Centaur HBcT2 assay and the reference anti-HBcT assay for pediatric population.
Table 11: Percent Agreement and Confidence Intervals: Pediatric Populations
| Age Range (Years) | Positive Percent Agreement | | Negative Percent Agreement | |
| --- | --- | --- | --- | --- |
| | % (x/n) | 95% Confidence Interval | % (x/n) | 95% CI |
| 2–12 | 100 (1/1) | 20.7–100 | 100 (29/29) | 88.3–100 |
| 13–21 | 100 (3/3) | 43.9–100 | 99.1 (105/106) | 94.8–99.8 |
| **Total** | **100 (4/4)** | **51.0–100** | **99.3 (134/135)** | **95.9–99.9** |
Because few positives were identified (4/139) in pediatric population study, a spiking study was conducted to evaluate the results, when pediatric samples are tested with the ADVIA Centaur HBcT2 assay using the ADVIA Centaur XP system. A total of 60 pediatric (age 2–21 years) and 60 adult serum samples were spiked with unique native anti-HBc positive samples. The mean percent bias between each paired spiked pediatric donor samples versus spiked adult donor samples was analyzed.
Out of 60 pediatric samples tested 59 samples showed bias less than 20% (98.3% samples). The distribution of percent bias between the Index values of the spiked pediatric serum samples and the paired adult serum samples are summarized in table 12.
Table 12: Distribution of percent bias in pediatric sample spiking study
| Age Range (Years) | Distribution of Percent Bias | | | |
| --- | --- | --- | --- | --- |
| | Na | ≤ 10% | > 10%– ≤ 20% | > 20%– ≤ 30% |
| 2–12 | 20 | 45.0 (9/20) | 50.0 (10/20) | 5.0 (1/20) |
| 13–21 | 40 | 72.5 (29/40) | 27.5 (11/40) | 0.0 (0/40) |
| **Total** | **60** | **63.3 (38/60)** | **35.0 (21/60)** | **1.7 (1/60)** |
### c. Pregnant Population
4. Pediatric Extrapolation
In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.
E. Financial Disclosure
The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The
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pivotal clinical study included 5 investigators of which 1 was a full-time or part-time employee of the sponsor and none had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below:
- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
- Significant payment of other sorts: 0
- Proprietary interest in the product tested held by the investigator: 0
- Significant equity interest held by investigator in sponsor of covered study: 0
The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. 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 supplement was not referred to Microbiology Devices 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 ADVIA Centaur/Atellica Anti-HBcT2 assay has been demonstrated by the sensitivity and specificity which has been comparable with the current commercially available FDA-approved anti-HBcT assays among all populations tested. The results from both the nonclinical and clinical studies indicate that the ADVIA Centaur/Atellica Anti-HBcT2 assay is safe and effective for the in vitro qualitative detection of total antibodies to the hepatitis B core antigen (Anti-HBc) in serum and plasma (EDTA, lithium heparin, and sodium heparin) collected from pediatric (age 2-21) and adult population.
# B. Safety Conclusions
The risk of the device is based on data collected in the non-clinical and clinical studies conducted to support PMA approval as described above. Based on the results from both studies, the ADVIA Centaur/Atellica Anti-HBcT2 assay, when used according to the provided directions and in conjunction with all relevant clinical and laboratory findings, should be safe to use and poses minimal risk to the patient due to false test results.
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### C. Benefit-Risk Determination
The benefits of the assay are as an aid in the diagnosis of individuals with acute or chronic hepatitis B virus (HBV) infection, and in the determination of the clinical status of HBV-infected individuals in conjunction with other HBV serological markers, for the laboratory diagnosis of HBV disease associated with HBV infection, and as an aid in the differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown.
Test results can facilitate initiation of appropriate monitoring, antiviral medications, and improved patient knowledge regarding the 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. Additionally, diagnosis and appropriate treatment can potentially decrease transmission and disease burden in the general population as well as in populations at high risk for hepatitis B infection.
Accurate diagnosis of HBV infection also leads clinicians to evaluate and subsequently treat patients for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) if indicated as these viruses share common risk factors and modes of transmission with HBV, and patients are often coinfected.
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 false positive tests includes improper patient management, including treatment for hepatitis B with antiviral medication. Antiviral medical has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are co-infected but undiagnosed with other viruses using the same antiviral medication, such as HIV, can lead to viral resistance, however the chance of an undiagnosed co-infection in a patient tested for hepatitis B is exceedingly unlikely. These risks are somewhat mitigated by the fact that this test is generally sent as 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 false negative tests include potentially missing the opportunity to treat a patient who has hepatitis B infection and whose clinical picture warrants antiviral treatment. 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 somewhat 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.
# 1. Patient Perspective
Patient perspectives considered during the review included:
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This submission either did not include specific information on patient perspectives for this device.
In conclusion, given the available information above, the data support that for the qualitative determination of total antibodies to the core antigen of the hepatitis B virus (HBV) in human pediatric (age 2-21 years) and adult serum and plasma, 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 data from the nonclinical studies demonstrated acceptable analytical sensitivity, precision, and analytical specificity of the ADVIA Centaur/Atellica Anti-HBcT2 assay when used according to the instructions for use as stated in the labeling, the warnings, and precautions, and limitations sections of the labeling. The clinical studies have shown that the ADVIA Centaur/Atellica Anti-HBcT2 assay, when compared to the FDA approved comparator, has a similar ability to detect the presence of anti-HBcT antibodies in specimens from individuals with chronic hepatitis B, or those recovered from HBV infection. The assay has also demonstrated that it has no cross-reactivity with viral antibodies or other cross-reactants in the specimens from individuals with medical conditions unrelated to the HBV infection. The probable clinical benefits outweigh the potential risks for the proposed assay considering the performance of the device in the clinical trial and the low risk and associated risk mitigations in clinical practice. The proposed assay labelling will facilitate accurate assay implementation and interpretation of results. The assay may provide substantial benefits to patients as an accurate and sensitive aid in determining HBV seroconversion in conjunction with other diagnostic information
### XIII. CDRH DECISION
CDRH issued an approval order on.
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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