AXSYM CORE-M 2.0 AND AXSYM CORE-M 2.0 CONTROLS
Device Facts
| Record ID | P060009 |
|---|---|
| Device Name | AXSYM CORE-M 2.0 AND AXSYM CORE-M 2.0 CONTROLS |
| Applicant | Abbott Laboratories, Inc. |
| Product Code | LOM · Microbiology |
| Decision Date | Aug 25, 2006 |
| Decision | APWD |
| Regulation | 21 CFR 866.3172 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
AxSYM CORE-M 2.0 is a microparticle enzyme immunoassay (MEIA) intended for the qualitative detection of IgM antibody to hepatitis B virus core antigen (IgM anti-HBc) in adult and pediatric serum (including serum collected in serum separator tubes) or plasma (collected in potassium EDTA, sodium citrate, sodium heparin, lithium heparin, or plasma separator tubes). The assay is used as an aid in the diagnosis of acute or recent hepatitis B virus (HBV) infection in conjunction with other laboratory results and clinical information.
Device Story
AxSYM CORE-M 2.0 is a microparticle enzyme immunoassay (MEIA) for qualitative detection of IgM anti-HBc in serum or plasma. The device uses the AxSYM System, an automated analyzer, to perform sample/reagent transfers, incubations, and optical readings. Principle: direct binding of sample IgM anti-HBc to anti-human IgM coated microparticles; detection via recombinant HBV core antigen and anti-HBc (human):alkaline phosphatase conjugate. Substrate (MUP) addition produces a fluorescent signal measured by the MEIA optical assembly. The system calculates an Index Value by comparing the sample rate to a stored Index Calibrator mean rate. Results are interpreted as reactive (>1.20), gray zone (0.80-1.20), or nonreactive (<0.80). Used in clinical laboratories by technicians; output aids physicians in diagnosing acute/recent HBV infection. Benefits include timely identification of acute HBV, facilitating appropriate clinical management.
Clinical Evidence
Clinical study evaluated 2,352 prospective serum specimens (US and Vietnam populations) and 100 pediatric specimens. Compared AxSYM CORE-M 2.0 to FDA-approved reference IgM anti-HBc assay. Overall positive percent agreement was 100.00% (16/16) and negative percent agreement was 99.50% (1,990/2,000) in the US population. Performance was consistent with known serological profiles across HBV classifications (acute, chronic, recovering, immune, susceptible). Precision studies (within-laboratory and system reproducibility) demonstrated acceptable CVs across multiple sites, instruments, and reagent lots.
Technological Characteristics
MEIA technology; utilizes anti-human IgM coated microparticles, recombinant HBV core antigen, and alkaline phosphatase conjugate. Energy source: AxSYM System optical assembly (fluorescence). Form factor: automated reagent pack for AxSYM analyzer. Connectivity: standalone analyzer. Preservatives: sodium azide, antimicrobial agents. Software: automated data processing and result calculation.
Indications for Use
Indicated for adult and pediatric patients to aid in the diagnosis of acute or recent hepatitis B virus (HBV) infection. Contraindications: None known.
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.
Related Devices
- P060012 — AXSYM CORE 2.0 AND AXSYM CORE 2.0 CONTROLS · Abbott Laboratories, Inc. · Sep 8, 2006
- P010053 — IMMULITE 2000 XPI ANTI-HBC IMG · Siemens Healthcare Diagnostics Products, Ltd. · Jul 26, 2002
- P060035 — ARCHITECT CORE-M REAGENT KIT/CALIBRATORS/CONTROLS · Abbott Laboratories · Nov 6, 2007
- P110025 — ELECSYS ANTI-HBC IGM IMMUNOASSAY & ELECSYS PREICONTROL ANTI-HBC IGM FOR USE ON THE MODULAR ANAYTICS E170 IMMUNOASSAY ANA · Roche Diagnostics Corp. · Dec 14, 2011
Submission Summary (Full Text)
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# Summary of Safety and Effectiveness Data
## I. GENERAL INFORMATION:
Device Generic Name: IgM Antibody to Hepatitis B Virus Core Antigen (IgM anti-HBc)
Device Trade Name: AxSYM CORE-M™ 2.0
AxSYM CORE-M 2.0 Controls
Name and Address of Applicant: Abbott Laboratories
Abbott Diagnostics Division
100 Abbott Park Road
Abbott Park, IL 60064-3500
Date of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P060009
Date of Notice of Approval to the Applicant: August 25, 2006
## II. INDICATIONS FOR USE:
AxSYM CORE-M 2.0 Reagent Kit
AxSYM CORE-M 2.0 is a microparticle enzyme immunoassay (MEIA) intended for the qualitative detection of IgM antibody to hepatitis B virus core antigen (IgM anti-HBc) in adult and pediatric serum (including serum collected in serum separator tubes) or plasma (collected in potassium EDTA, sodium citrate, sodium heparin, lithium heparin, or plasma separator tubes). The assay is used as an aid in the diagnosis of acute or recent hepatitis B virus (HBV) infection in conjunction with other laboratory results and clinical information.
AxSYM CORE-M 2.0 Controls
The AxSYM CORE-M 2.0 Controls are used for monitoring the performance of the AxSYM System (reagent and instrument) when used for the qualitative detection of IgM antibody to hepatitis B virus core antigen (IgM anti-HBc) when using the AxSYM CORE-M 2.0 Reagent Pack. The performance of the AxSYM CORE-M 2.0 Controls has not been established with any other IgM anti-HBc assays.
## III. CONTRAINDICATIONS: None known.
## IV. WARNINGS AND PRECAUTIONS: For in vitro diagnostic use only.
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Warnings and precautions for the AxSYM CORE-M™ 2.0 Reagent Kit and AxSYM CORE-M 2.0 Controls are stated in the respective product labeling.
## V. DEVICE DESCRIPTION:
### Kit Configurations and Components
The AxSYM CORE-M 2.0 Reagent Kit contains one AxSYM CORE-M 2.0 Reagent Pack and one bottle of Index Calibrator. The AxSYM CORE-M 2.0 Reagent Pack holds the following four reagents:
- 1 Bottle (17.6 mL) Hepatitis B Virus Core Antigen (E. coli, Recombinant) in TRIS buffer with protein (10% bovine) stabilizer. Minimum concentration: 0.175 µg/mL. Preservatives: 0.1% Sodium Azide and Antimicrobial Agents. (Reagent Bottle 1)
- 1 Bottle (12.2 mL) Antibody to Hepatitis B Virus Core Antigen (Human): Alkaline Phosphatase Conjugate in TRIS buffer with protein (1% bovine) stabilizer. Minimum concentration: 0.1 µg/mL. Preservatives: 0.1% Sodium Azide and Antimicrobial Agents. (Reagent Bottle 2)
- 1 Bottle (10.5 mL) Antibody to Human IgM (Goat) Coated Microparticles in TRIS buffer with protein (0.05% porcine) stabilizer. Minimum concentration: 0.06% solids. Preservative: 0.1% Sodium Azide. (Reagent Bottle 3)
- 1 Bottle (50.2 mL) Specimen Diluent containing 0.3 M Sodium Chloride in TRIS buffer. Preservatives: 0.1% Sodium Azide and Antimicrobial Agents. (Reagent Bottle 4)
The Index Calibrator is used to determine the cutoff rate of the AxSYM CORE-M 2.0 assay and contains the following:
- 1 Bottle (5.5 mL) AxSYM CORE-M 2.0 Index Calibrator. Recalcified human plasma reactive for IgM anti-HBc and nonreactive for HIV-1 Ag or HIV-1 RNA, anti-HIV-1/HIV-2, and anti-HCV. Plasma is also tested for HBsAg and may be either nonreactive or reactive. Minimum titer = 1:1. Preservative: 0.1% Sodium Azide. Dye: Green (Acid Yellow No. 23 and Acid Blue No. 9).
The AxSYM CORE-M 2.0 Controls are packaged and sold separately and contain the following:
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- 1 Bottle (7.4 mL) Negative Control. Recalcified human plasma nonreactive for HBsAg, HIV-1 Ag or HIV-1 RNA, anti-HIV-1/HIV-2, anti-HCV, anti-HBc, and anti-HBs. Preservative: 0.1% Sodium Azide.
- 1 Bottle (7.4 mL) Positive Control. Recalcified human plasma reactive for IgM anti-HBc and nonreactive for HIV-1 Ag or HIV-1 RNA, anti-HIV-1/HIV-2, and anti-HCV. Plasma is also tested for HBsAg and may be either nonreactive or reactive. Preservative: 0.1% Sodium Azide.
In addition, the following components are required:
- The AxSYM System is an automated immunoassay analyzer designed for the performance of routine immunoassays and analyte determinations via random access, continuous access, and STAT test processing. The analyzer performs sample and reagent transfers, incubations, optical readings, data processing, and printing of assay reports and screen displays.
- AxSYM Probe Cleaning Solution containing 2% Tetraethylammonium Hydroxide (TEAH).
- Solution 1 (MUP) containing 4-Methylumbelliferyl Phosphate, 1.2 mM, in AMP buffer. Preservative: 0.1% Sodium Azide.
- Solution 3 (Matrix Cell Wash) containing 0.3 M Sodium Chloride in TRIS buffer. Preservatives: 0.1% Sodium Azide and Antimicrobial Agents.
- Solution 4 (Line Diluent) containing 0.1 M Phosphate buffer. Preservatives: 0.1% Sodium Azide and Antimicrobial Agent.
## Assay Principle and Format
AxSYM CORE-M 2.0 is based on MEIA technology and utilizes the principle of direct binding of the IgM anti-HBc in the sample to anti-human IgM coated microparticles, and detection of the IgM anti-HBc by rHBcAg, followed by anti-HBc (human):alkaline phosphatase conjugate. The Matrix Cell is washed with Matrix Cell Wash to remove materials not bound to the microparticles. The substrate (MUP), is added and the fluorescent product is measured by the MEIA optical assembly on the AxSYM System.
The presence or absence of IgM anti-HBc in the sample is determined by comparing the rate of formation of fluorescent product to the mean Index Calibrator rate, which is calculated from a previous AxSYM CORE-M 2.0 Index Calibration, to determine an Index Value. Samples with Index Values greater than 1.20 are considered reactive by AxSYM CORE-M 2.0. Samples with Index Values from 0.80 to 1.20 are considered gray zone reactive by AxSYM CORE-M 2.0. Samples with Index Values less than 0.80 are considered nonreactive by AxSYM CORE-M 2.0.
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# Results
The AxSYM System calculates the mean rate of the Index Calibrator replicates and stores the result. The AxSYM CORE M 2.0 assay protocol calculates a result based on the ratio of the sample rate to the stored Index Calibrator mean rate for each sample and control.
Index Value = Sample Rate / Index Calibrator Mean Rate
## Interpretation of Results
| AxSYM CORE-M 2.0 | | Interpretation |
| --- | --- | --- |
| Index Value | Instrument Interpretation | |
| >1.20 | REACTIVE | Presumptive evidence of IgM anti-HBc. |
| 0.80 to 1.20 | GRAYZONE REACTIVE^{a} | Presumptive evidence of IgM anti-HBc. Patients with specimens exhibiting gray zone reactive test results should be retested at approximately one-week intervals. |
| <0.80 | NONREACTIVE | IgM anti-HBc not detected. Does not exclude the possibility of exposure to or infection with HBV. |
a The word “GRAYZONE” will appear in the interpretation field on the printout.
- Monitoring the level of IgM anti-HBc by retesting at approximately one-week intervals will distinguish rapidly rising IgM anti-HBc levels associated with early acute hepatitis B infection from gradually decreasing or unchanging IgM anti-HBc levels often associated with late acute stage of HBV infection, 6 to 9 months from the appearance of HBsAg.
- Immunosuppressed or immunocompromised individuals may not produce IgM anti-HBc above the detection limit of the AxSYM CORE-M 2.0 assay.
## VI. ALTERNATIVE PRACTICES AND PROCEDURES
The patient’s medical history and thorough physical examination, including hepatitis serology, determination of liver enzyme levels, and biopsy of the liver, will provide further information on the status of a hepatitis B viral infection. Alternative procedures for the detection of HBV in human serum and plasma depend on the detection of HBV deoxyribonucleic acid (DNA) by research polymerase chain reaction (PCR) assays or nucleic acid testing (NAT), or the detection of HBV antigens and antibodies by commercially-available assays that are licensed or approved in the United States.
## VII. MARKETING HISTORY
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AxSYM CORE-M 2.0 (List No. 8B89), has not been marketed in any other country.
## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
The main risk involved in the use of the AxSYM CORE-M 2.0 assay is one associated with any available IgM anti-HBc immunoassay: A nonreactive test result does not exclude the possibility of exposure to or infection with HBV. Levels of IgM anti-HBc may be undetectable in both the early and late stages of infection. For diagnostic purposes, IgM anti-HBc reactivity should be correlated with the overall clinical picture, including the presence or absence of other hepatitis markers.
Other than the circumstances mentioned above, there is no known potential adverse effect on the health of the patient or user if this in vitro device is used according to the AxSYM CORE-M 2.0 package insert instructions.
## IX. SUMMARY OF NONCLINICAL STUDIES
Nonclinical laboratory studies were performed at Abbott Laboratories to evaluate the performance characteristics of the AxSYM CORE-M 2.0 assay. The studies are summarized below.
### Cutoff Rationale
The AxSYM CORE-M 2.0 assay results are expressed as an Index Value, which is calculated by dividing the sample rate by the mean rate of two replicates of the AxSYM CORE-M 2.0 Index Calibrator. The Index Calibrator contains recalcified human plasma positive for IgM anti-HBc. Because the assay cutoff is determined by the mean rate of the Index Calibrator, the concentration of IgM anti-HBc in the Index Calibrator will affect the ability of the assay to detect the early acute and late acute/early recovery stages of HBV infection. Therefore, a study was conducted to select an appropriate IgM anti-HBc concentration range for the Index Calibrator.
Index Calibrator was prepared at various IgM anti-HBc concentrations ranging from 45 to 138 Abbott Units per mL (AU/mL) by adding recalcified human plasma positive for IgM anti-HBc to recalcified nonreactive human plasma. The Index Calibrators and three HBV seroconversion panels from three HBV-infected individuals were tested using AxSYM CORE-M 2.0. The ability of the assay to detect the early acute and late acute/early recovery stages of HBV infection was evaluated at each Index Calibrator concentration level.
The results of this study demonstrated that setting the Index Calibrator concentration range from 45 to 138 AU/mL and using an assay cutoff of 0.80 Index Value allowed appropriate detection of the early acute and late acute/early recovery stages of HBV infection by the AxSYM CORE-M 2.0 assay.
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## Sample Handling and Collection
## Sample Types (Serum and Plasma)
A study was conducted to evaluate which specimen collection tube types are acceptable for use with the AxSYM CORE-M 2.0 assay. Sets of specimens assumed to be nonreactive for IgM anti-HBc were collected in the control specimen collection tube type (serum in glass) and the specimen collection tube types selected for evaluation. The specimens were spiked with human plasma positive for IgM anti-HBc to prepare high nonreactive samples (0.6 Index Value target) and low reactive samples (1.0 Index Value target), and all samples were tested.
On average, the tube types evaluated showed less than a 10% difference when compared to the control tube type (serum in glass), with the exception of sodium citrate, which showed a 12% difference when compared to the control tube type. The distribution of the % difference values for each tube type are summarized in Table 1.
The data support the use of the AxSYM CORE-M 2.0 assay with serum specimens, specimens collected in serum separator tubes (SST®) or plasma separator tubes (PST), and specimens collected in tubes containing the following anticoagulants:
- potassium ethylenediaminetetraacetic acid (EDTA)
- sodium citrate
- sodium heparin
- lithium heparin
Table 1
AxSYM CORE-M 2.0
Sample Types (Serum and Plasma) Study
Summary of Results
| Evaluation Tube Type | Distribution of %Differences | | |
| --- | --- | --- | --- |
| | 0% to ≤ 10% | >10% to ≤ 20% | >20% |
| Serum in plastic | 83.3%
(35/42) | 9.5%
(4/42) | 7.1%
(3/42) |
| SST in glass | 88.1%
(37/42) | 7.1%
(3/42) | 4.8%
(2/42) |
| SST in plastic | 88.1%
(37/42) | 4.8%
(2/42) | 7.1%
(3/42) |
| PST | 90.5%
(38/42) | 4.8%
(2/42) | 4.8%
(2/42) |
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| Evaluation Tube Type | Distribution of %Differences | | |
| --- | --- | --- | --- |
| | 0% to ≤ 10% | >10% to ≤ 20% | >20% |
| Potassium EDTA | 85.7%
(36/42) | 7.1%
(3/42) | 7.1%
(3/42) |
| Sodium Citrate^{a} | 61.9%
(26/42) | 26.2%
(11/42) | 11.9%
(5/42) |
| Sodium Heparin | 90.5%
(38/42) | 4.8%
(2/42) | 4.8%
(2/42) |
| Lithium Heparin | 88.1%
(37/42) | 7.1%
(3/42) | 4.8%
(2/42) |
a Sodium citrate tubes have been shown to increase the Index Values in specimens near the assay cutoff in a positive direction. Low positive results (0.80 to 0.90 Index Value) obtained on samples collected with this anticoagulant should be interpreted accordingly.
## Sample Storage Conditions
The Clinical Laboratory Standards Institute (CLSI, formerly NCCLS) document H18-A3³ guidelines provides the following recommendations for storing blood specimens:
- Store samples at 22°C (72°F) for no longer than 8 hours.
- If the assay will not be completed within 8 hours, refrigerate the sample at 2 to 8°C (36 to 46°F).
- If the assay will not be completed within 48 hours, freeze at or below -20°C (-4°F).
## Sample Freeze/Thaw
Sets of specimens from individuals assumed to be nonreactive for IgM anti-HBc were collected in all recommended specimen collection tube types (serum, and potassium EDTA, sodium citrate, sodium heparin, or lithium heparin plasma). Tubes from each set were spiked with human plasma positive for IgM anti-HBc to prepare high nonreactive samples (0.6 Index Value target) and low reactive samples (1.2 Index Value target). The samples were tested on Day 0 (within eight hours of draw) and after being subjected to one and two freeze/thaw cycles.
The data support the use of the AxSYM CORE-M 2.0 assay with specimens collected in all recommended collection tubes that have undergone up to two freeze/thaw cycles.
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## Analytical Specificity
A study was conducted to characterize the performance of the AxSYM CORE-M 2.0 assay when used to test specimens from individuals with medical conditions unrelated to HBV infection.
All 185 specimens (100.0%) were nonreactive by AxSYM CORE-M 2.0. The results are summarized in Table 2.
## Table 2
## AxSYM CORE-M 2.0
Analytical Specificity Study: Specimens from Individuals with
Medical Conditions Unrelated to HBV Infection
Summary of Results
| Category | Number of Specimens Tested | AxSYM CORE-M 2.0 Nonreactive | AxSYM CORE-M 2.0 Gray Zone Reactive | AxSYM CORE-M 2.0 Reactive |
| --- | --- | --- | --- | --- |
| Hepatitis A Virus | 12 | 12 | 0 | 0 |
| Hepatitis C Virus | 10 | 10 | 0 | 0 |
| Human Immunodeficiency Virus | 10 | 10 | 0 | 0 |
| Human T-Lymphotropic Virus | 9 | 9 | 0 | 0 |
| Cytomegalovirus | 10 | 10 | 0 | 0 |
| Epstein-Barr Virusb | 10 | 10 | 0 | 0 |
| Herpes Simplex Virusb | 10 | 10 | 0 | 0 |
| Rubellab | 10 | 10 | 0 | 0 |
| Systemic Lupus Erythematosus | 10 | 10 | 0 | 0 |
| Rheumatoid Arthritis Diseasec | 10 | 10 | 0 | 0 |
| Elevated IgG | 10 | 10 | 0 | 0 |
| Elevated IgM | 10 | 10 | 0 | 0 |
| Influenza Vaccine Recipients | 10 | 10 | 0 | 0 |
| HBV Vaccine Recipients | 5 | 5 | 0 | 0 |
| Toxoplasmosisb | 4 | 4 | 0 | 0 |
| Alcoholic Liver Disease | 10 | 10 | 0 | 0 |
| Fatty Liver Disease | 15 | 15 | 0 | 0 |
| Obstructive Jaundice | 15 | 15 | 0 | 0 |
| Hepatocellular Carcinoma | 5 | 5 | 0 | 0 |
| Total (%) | 185 | 185/185 (100.0%) | 0/185 (0.0%) | 0/185 (0.0%) |
a Information about age and gender of the individuals is not available.
b Only IgG antibodies are present
c Both IgG and IgM antibodies are present for eight out of ten specimens. The remaining two specimens were categorized based on clinical diagnosis.
Potentially Interfering Substances – Triglycerides, Total Protein, Bilirubin, and
Hemoglobin
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Human serum nonreactive for IgM anti-HBc was spiked with human plasma positive for IgM anti-HBc to prepare high nonreactive samples (0.6 Index Value target) and low reactive samples (1.0 Index Value target). A triglyceride test sample was prepared by supplementing the high nonreactive and low reactive samples with LIPOSYN® II to a minimum triglyceride concentration of 3,000 mg/dL. A total protein test sample was prepared by supplementing the high nonreactive and low reactive samples with human albumin powder to a minimum concentration of 12 g/dL. A bilirubin (unconjugated) test sample was prepared by supplementing the high nonreactive and low reactive samples with unconjugated bilirubin stock prepared in 0.1 N sodium hydroxide to a minimum concentration of 20 mg/dL. A hemoglobin test sample was prepared by supplementing the high nonreactive and low reactive samples with hemoglobin stock solution to a minimum concentration of 500 mg/dL. Control samples were prepared for each interferent. The controls and samples were tested.
The data support the use of the AxSYM CORE-M 2.0 assay with specimens that contain up to 3,000 mg/dL of triglycerides, up to 12 g/dL of total protein, up to 20 mg/dL of bilirubin (unconjugated), and up to 500 mg/dL of hemoglobin.
At the concentrations listed below, total bilirubin (unconjugated), hemoglobin, total protein, and triglycerides showed less than 0.08 index value interference in the AxSYM CORE-M 2.0 assay for high negative (0.6 Index Value target) serum samples and less than or equal to 10% interference in the AxSYM CORE-M 2.0 assay for low positive (1.0 Index Value target) serum samples:
- Total Bilirubin (≤ 20 mg/dL)
- Hemoglobin (≤ 500 mg/dL)
- Total Protein (≤ 12 g/dL)
- Triglycerides (≤ 3000 mg/dL)
## Within-Laboratory (20-day) Precision
A 20-day precision study was conducted based on guidance from Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS) document EP5-A2¹ to evaluate the precision performance of the AxSYM CORE-M 2.0 assay.
Testing was performed using two AxSYM CORE-M 2.0 Reagent Kit lots and one AxSYM CORE-M 2.0 Control lot on each of two AxSYM instruments. Testing included two precision runs per day for each reagent kit lot, on each instrument, on each of 20 days. Each precision run included two replicates of the AxSYM CORE-M 2.0 Index Calibrator, Negative Control, and Positive Control, and each of two members of a precision panel with Index Values of 0.6 and 1.0. Panel members were prepared by adding recalcified human plasma reactive for IgM anti-HBc to nonreactive human serum.
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The data demonstrated the acceptable precision of the AxSYM CORE-M 2.0 assay. The results are summarized in Tables 3 and 4.
## Table 3
### AxSYM CORE-M 2.0
### Within-Laboratory (20 Day) Precision Study
### Overall Precision—Two Instruments, Two Reagent Lots
| Panel Members/Controls | Total No. Reps | Grand Mean Index Value | Within-Run | | Within-Day | | Within-Laboratory Precision (Total) | | | Precision With Additional Component of Between-Lot | | Precision With Additional Component of Between-Instrument | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | CL | SD | %CV | SD | %CV |
| Panel 1 | 320 | 0.62 | 0.019 | 3.1 | 0.022 | 3.5 | 0.028 | 4.6 | 5.0 | 0.035 | 5.6 | 0.029 | 4.7 |
| Panel 2 | 320 | 0.99 | 0.026 | 2.6 | 0.030 | 3.0 | 0.041 | 4.1 | 4.5 | 0.051 | 5.2 | 0.043 | 4.3 |
| NC | 320 | 0.03 | 0.003 | 10.2 | 0.003 | 10.8 | 0.004 | 11.2 | 12.0 | 0.004 | 13.7 | 0.004 | 11.2 |
| PC | 320 | 1.55 | 0.043 | 2.8 | 0.047 | 3.1 | 0.062 | 4.0 | 4.4 | 0.081 | 5.2 | 0.062 | 4.0 |
| Index Calibrator | Total No. Reps | Grand Mean Rate | Within-Run | | Within-Day | | Within-Laboratory Precision (Total) | | | Precision With Additional Component of Between-Lot | | Precision With Additional Component of Between-Instrument | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | CL | SD | %CV | SD | %CV |
| IC | 320 | 272.22 | 7.426 | 2.7 | 7.967 | 2.9 | 10.632 | 3.9 | 4.3 | 10.632 | 3.9 | 10.950 | 4.0 |
Reps = Replicates, SD = Standard Deviation, CV = Coefficient of Variation, CL = Upper One-sided 95% Confidence Limit
## Table 4
### AxSYM CORE-M 2.0
### Within-Laboratory (20-day) Precision Study
### Individual Component Analysis—Two Instruments, Two Reagent Lots
| Panel Members/Controls | Total No. Reps | Grand Mean Index Value | Within-Run | | Between-Run | | Between-Day | | Between-Lot | | Between-Instrument | | Total^{a} | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Panel 1 | 320 | 0.62 | 0.019 | 3.1 | 0.010 | 1.7 | 0.018 | 3.0 | 0.020 | 3.3 | 0.006 | 0.9 | 0.028 | 4.6 |
| Panel 2 | 320 | 0.99 | 0.026 | 2.6 | 0.016 | 1.6 | 0.027 | 2.8 | 0.031 | 3.1 | 0.013 | 1.3 | 0.041 | 4.1 |
| NC | 320 | 0.03 | 0.003 | 10.2 | 0.001 | 3.5 | 0.001 | 3.0 | 0.003 | 7.9 | 0.000 | 0.0 | 0.004 | 11.2 |
| PC | 320 | 1.55 | 0.043 | 2.8 | 0.019 | 1.2 | 0.041 | 2.6 | 0.052 | 3.4 | 0.004 | 0.3 | 0.062 | 4.0 |
| Index Calibrator | Total No. Reps | Grand Mean Index Value | Within-Run | | Between-Run | | Between-Day | | Between-Lot | | Between-Instrument | | Total^{a} | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| IC | 320 | 272.22 | 7.426 | 2.7 | 2.886 | 1.1 | 7.040 | 2.6 | 0.000 | 0.0 | 2.620 | 1.0 | 10.632 | 3.9 |
a Total variability contains within-run, between-run, and between-day variance components.
Seroconversion Detectability
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A study was conducted to demonstrate the ability of the AxSYM CORE-M 2.0 assay to detect the early acute and late acute/early recovery stages of HBV infection when used to test serial bleed specimens from HBV-infected individuals.
Seven seroconversion panels (a total of 181 serial bleed specimens) from seven HBV-infected individuals were obtained from two commercial vendors and tested. The AxSYM CORE-M 2.0 results were compared to the historical results from FDA-approved or FDA-licensed assays for HBsAg, IgM anti-HBc, anti-HBc, and anti-HBs.
IgM anti-HBc was detected by AxSYM CORE-M 2.0 coincident with the reference IgM anti-HBc assay in six panels, and two days later than the reference IgM anti-HBc assay in one panel. In this panel, the initial IgM anti-HBc reactive specimen was also reactive for HBsAg.
One seroconversion panel showed sustained HBsAg reactivity for longer than six months without detectable anti-HBs, which is indicative of an acute HBV infection progressing to a potential chronic HBV infection. The profiles of the remaining six seroconversion panels were characteristic of an acute HBV infection progressing to eventual recovery and immunity to HBV. AxSYM CORE-M 2.0 detected IgM anti-HBc following detection of HBsAg in all panels during the acute stage of disease. IgM anti-HBc remained detectable over a period of seven months after the appearance of HBsAg in the single panel from an acute HBV infection progressing to a potential chronic infection, and over a range of two to eleven months in the other six panels. The overall AxSYM CORE-M 2.0 results were consistent with the known serological profile of each panel.
These data demonstrate the ability of the AxSYM CORE-M 2.0 assay to detect the early acute and late acute/early recovery stages HBV infection when used to test serial bleed specimens from HBV-infected individuals.
## High Dose Hook Effect
A study was conducted to characterize the performance of the AxSYM CORE-M 2.0 assay when used to test a high-titer IgM anti-HBc specimen that has the potential to cause a high dose hook effect.
High-titer IgM anti-HBc reactive human plasma (titer > 1:256) was serially diluted and tested. The mean Index Value of the neat sample was greater than the mean Index Value of the diluted samples, indicating that no high dose hook effect was observed in the AxSYM CORE-M 2.0 assay.
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## Within- and Between-assay Sample Carryover
Studies were conducted to evaluate the susceptibility of the AxSYM CORE-M 2.0 assay to sample carryover within the assay or from other AxSYM assays when processing samples containing high concentrations of IgM anti-HBc.
Carryover events were modeled by testing human plasma nonreactive for IgM anti-HBc to mimic a sample that was not exposed to potential sample carryover (protected negative), followed by a human plasma sample containing a high concentration of IgM anti-HBc (2.50 Index Value), followed again by human plasma nonreactive for IgM anti-HBc to mimic a sample exposed to potential sample carryover (unprotected negative).
For the within-assay carryover study, the difference between the protected negative and unprotected negative mean or median Index Values was 0.00, indicating that no within-assay sample carryover was present within the AxSYM CORE-M 2.0 assay.
For the between-assay carryover study, the difference between the protected negative and unprotected negative mean or median Index Values ranged from 0.00 to 0.02 in the Sampling Center, and the difference between the protected negative and unprotected negative mean or median Index Values ranged from 0.00 to 0.02 in the Processing Center. These results indicate that no between-assay sample carryover was present between the AxSYM CORE-M 2.0 assay and any of the potential contaminator assays evaluated.
## Microbial Challenge Studies
Studies were conducted to establish the level of antimicrobial protection provided by the preservative system used in the components of the AxSYM CORE-M 2.0 Reagent Kit and Controls, and to determine the effect of bioburden and/or its by-products on assay performance.
Components of the AxSYM CORE-M 2.0 Reagent Kit and Controls were inoculated with the following groups of microorganisms at concentrations between $10^{5}$ to $10^{6}$ colony forming units/mL (CFU/mL): Spore (Baccillus subtilis, Candida albicans), Mold (Aspergillus niger), vegetative (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus), and environmental (Psuedomonas [fluorescent group]). The inoculated materials were evaluated for microbial growth over a period of 15 months.
Components of the AxSYM CORE-M 2.0 Reagent Kit and Controls were inoculated with the following microorganisms at concentrations between $10^{2}$ to $10^{3}$ CFU/mL and at concentrations between $10^{3}$ to $10^{4}$ CFU/mL: Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and
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Psuedomonas (fluorescent group). The inoculated materials were evaluated for assay performance after a period of 35 days.
No growth of the challenge organisms was observed during the study, with the exception of the rHBcAg reagent inoculated with the spore group, which demonstrated growth between Month 12 and Month 15. However, the bioburden count at Month 15 was below the bioburden count observed at Day 0 by more than one log and was within one log of the bioburden count observed for all other time points. Assay performance of the inoculated components was acceptable. The data demonstrate that the AxSYM CORE-M 2.0 Reagent Kit and Controls are adequately protected by the preservative system used.
## Recommended Storage Stability - Reagent Kit and Controls
Real-time stability studies are being conducted to demonstrate the shelf-life integrity of the AxSYM CORE-M 2.0 Reagent Kit and Controls at the recommended storage condition (2 to 8°C).
Three lots of AxSYM CORE-M 2.0 Reagent Kits and Controls were stored at the recommended storage condition of 2 to 8°C. The AxSYM CORE-M 2.0 Reagent Kits and Controls were tested at Month 0 and monthly thereafter. The stability studies are ongoing and are scheduled to continue for a maximum of 20 months (minimum of seven months). At this time, the data for the first eight months of testing is complete.
The data presented demonstrate that the evaluation criteria were met for both the AxSYM CORE-M 2.0 Reagent Kits and Controls at the recommended storage condition (2 to 8°C) for eight months. Additional data will be submitted at a later date.
## Transport Stability
A study was conducted to evaluate the performance of the AxSYM CORE-M 2.0 Reagent Kit and Controls following a simulation of ambient shipping conditions (transport simulation).
One lot each of the AxSYM CORE-M 2.0 Reagent Kit and Controls was tested after being subjected to a series of storage temperatures simulating transport stress.
The data support ambient shipment of the AxSYM CORE-M 2.0 Reagent Kit and Controls.
## Onboard Reagent Pack Stability
20
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Testing was performed using three lots of AxSYM CORE-M 2.0 Reagent Packs that were stored continuously at 2 to 8°C (recommended storage) and at 31°C (simulated onboard storage) for 24, 48, 72, 96, 120, 144, 192, 240, 288, or 336 hours. The AxSYM CORE-M 2.0 Index Calibrator was not evaluated for onboard stability because this reagent is not left on board the AxSYM System.
The AxSYM CORE-M 2.0 Reagent Pack may be on board the AxSYM System for a maximum of 112 cumulative hours; for example, 14 eight-hour shifts.
## Calibration Stability and Control Frequency
An analysis was performed to determine if an AxSYM CORE-M 2.0 calibration that is stored on the AxSYM System for a minimum of 14 days can be used to generate valid results (calibration stability), and to support a minimum control requirement to test controls once every 24 hours (control frequency).
The validity data generated in the Within-Laboratory (20-day) Precision Study were used for this analysis. The study was conducted using two AxSYM instruments and two AxSYM CORE-M 2.0 Reagent Kit lots for 20 days. A calibration was performed on the first day of testing for each instrument and reagent kit lot combination. The AxSYM CORE-M 2.0 Negative Control and Positive Control were each tested for validity purposes, once per run, twice daily, on each of 20 days, using each instrument and reagent kit lot combination.
## X. SUMMARY OF CLINICAL STUDIES
A multi-center study was conducted to demonstrate that the AxSYM CORE-M 2.0 assay performs as intended in a diagnostic population. The study was designed to measure the precision of the AxSYM CORE-M 2.0 assay and determine the percent agreement between AxSYM CORE-M 2.0 and an FDA-approved IgM anti-HBc reference method.
## System Reproducibility (5-day Precision)
The precision of the AxSYM CORE-M 2.0 assay was evaluated by testing three AxSYM CORE-M 2.0 Reagent Kit and Control master lots at three clinical testing sites for five days. Testing included two precision runs per day (a minimum of two hours apart) for each of three reagent master lots, on each of five days. Each precision run included four replicates of each precision panel member and four replicates each of AxSYM CORE-M 2.0 Index Calibrator, Negative Control, and Positive Control. Panel members were prepared by adding recalcified human plasma reactive for IgM anti-HBc to nonreactive human serum. The analysis method was based on National Committee for Clinical Laboratory Standards (formerly NCCLS) document EP15-A2². The results are presented in Tables 5 through 7.
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## Table 5
AxSYM CORE-M 2.0 System Reproducibility: Overall Precision
Three Reagent Master Lots, Three Clinical Testing Sites
| Panel Members/Controls | Total No. Reps | Grand Mean Index Value | Within-Run | | Within-Day | | Within-Laboratory Precision (Total) | | | Precision With Additional Component of Between-Lot | | Precision With Additional Component of Between-Site | | Precision with Additional Components of Site and Lot (Overall) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | CL | SD | %CV | SD | %CV | SD | %CV |
| Panel 1 | 360 | 0.65 | 0.030 | 4.6 | 0.052 | 8.1 | 0.053 | 8.1 | 9.1 | 0.075 | 11.6 | 0.072 | 11.1 | 0.084 | 13.0 |
| Panel 2 | 360 | 1.03 | 0.028 | 2.8 | 0.038 | 3.7 | 0.042 | 4.0 | 4.4 | 0.082 | 8.0 | 0.091 | 8.8 | 0.107 | 10.4 |
| NC | 360 | 0.03 | 0.003 | 9.9 | 0.003 | 9.9 | 0.003 | 10.5 | 11.3 | 0.005 | 18.2 | 0.003 | 12.1 | 0.005 | 18.6 |
| PC | 360 | 1.58 | 0.037 | 2.4 | 0.049 | 3.1 | 0.052 | 3.3 | 3.6 | 0.083 | 5.2 | 0.126 | 8.0 | 0.126 | 8.0 |
| Index Calibrator | Total No. Reps | Grand Mean Rate | Within-Run | | Within-Day | | Within-Laboratory Precision (Total) | | | Precision With Additional Component of Between-Lot | | Precision With Additional Component of Between-Site | | Precision with Additional Components of Site and Lot (Overall) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | CL | SD | %CV | SD | %CV | SD | %CV |
| IC | 360 | 293.84 | 8.414 | 2.9 | 10.891 | 3.7 | 12.334 | 4.2 | 4.6 | 20.841 | 7.1 | 25.368 | 8.6 | 29.436 | 10.0 |
Reps = Replicates; SD = Standard Deviation; CV = Coefficient of Variation, CL = Upper One-sided 95% Confidence Limit
## Table 6
AxSYM CORE-M 2.0 System Reproducibility: Individual Component Analysis
Three Reagent Master Lots, Three Clinical Testing Sites
| Panel Members/Controls | Total No. Reps | Grand Mean Index Value | Within-Run | | Between-Run | | Between-Day | | Between-Lot | | Between-Site | | Total^{a} | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Panel 1 | 360 | 0.65 | 0.030 | 4.6 | 0.043 | 6.7 | 0.005 | 0.8 | 0.053 | 8.2 | 0.049 | 7.5 | 0.084 | 13.0 |
| Panel 2 | 360 | 1.03 | 0.028 | 2.8 | 0.025 | 2.5 | 0.017 | 1.6 | 0.071 | 6.9 | 0.081 | 7.8 | 0.107 | 10.4 |
| NC | 360 | 0.03 | 0.003 | 9.9 | 0.000 | 0.0 | 0.001 | 3.6 | 0.004 | 14.9 | 0.002 | 5.9 | 0.005 | 18.6 |
| PC | 360 | 1.58 | 0.037 | 2.4 | 0.032 | 2.0 | 0.018 | 1.1 | 0.064 | 4.1 | 0.114 | 7.2 | 0.126 | 8.0 |
| Index Calibrator | Total No. Reps | Grand Mean Index Value | Within-Run | | Between-Run | | Between-Day | | Between-Lot | | Between-Instrument | | Total^{a} | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| IC | 360 | 293.84 | 8.414 | 2.9 | 6.915 | 2.4 | 5.789 | 2.0 | 16.799 | 5.7 | 22.168 | 7.5 | 29.436 | 10.0 |
a Total variability contains within-run, between-run, between-day, between-lot, between-site, and lot-site interaction variance components.
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Table 7
AxSYM CORE-M 2.0 System Reproducibility: By-site Precision
Clinical Testing Sites 1, 2, and 3, Three Reagent Master Lots
| Clinical Testing Site | Panel Members/Controls/ Calibrator | Total No. Reps | Grand Mean Index Value / Rate^{a} | Within-Run | | Within-Day | | Within-Laboratory Precision (Total) | | Precision With Additional Component of Between-Lot | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | Panel 1 | 120 | 0.60 | 0.015 | 2.4 | 0.022 | 3.7 | 0.024 | 4.0 | 0.039 | 6.4 |
| | Panel 2 | 120 | 0.95 | 0.023 | 2.5 | 0.031 | 3.3 | 0.034 | 3.5 | 0.052 | 5.5 |
| | NC | 120 | 0.03 | 0.002 | 6.7 | 0.002 | 6.7 | 0.002 | 6.9 | 0.006 | 21.9 |
| | PC | 120 | 1.46 | 0.032 | 2.2 | 0.037 | 2.5 | 0.045 | 3.1 | 0.087 | 6.0 |
| | IC | 120 | 275.72 | 7.002 | 2.5 | 9.134 | 3.3 | 9.383 | 3.4 | 13.148 | 4.8 |
| | | | | | | | | | | | |
| 2 | Panel 1 | 120 | 0.67 | 0.046 | 6.8 | 0.085 | 12.7 | 0.085 | 12.7 | 0.115 | 17.1 |
| | Panel 2 | 120 | 1.08 | 0.036 | 3.3 | 0.049 | 4.6 | 0.049 | 4.6 | 0.114 | 10.6 |
| | NC | 120 | 0.03 | 0.003 | 11.5 | 0.003 | 11.5 | 0.003 | 11.7 | 0.004 | 15.0 |
| | PC | 120 | 1.65 | 0.044 | 2.7 | 0.060 | 3.6 | 0.060 | 3.6 | 0.102 | 6.2 |
| | IC | 120 | 288.41 | 9.990 | 3.5 | 12.339 | 4.3 | 15.075 | 5.2 | 28.821 | 10.0 |
| | | | | | | | | | | | |
| 3 | Panel 1 | 120 | 0.67 | 0.018 | 2.7 | 0.020 | 3.0 | 0.022 | 3.3 | 0.046 | 6.8 |
| | Panel 2 | 120 | 1.07 | 0.025 | 2.3 | 0.031 | 2.9 | 0.040 | 3.8 | 0.068 | 6.3 |
| | NC | 120 | 0.03 | 0.003 | 10.4 | 0.003 | 10.4 | 0.003 | 11.7 | 0.005 | 17.7 |
| | PC | 120 | 1.63 | 0.034 | 2.1 | 0.044 | 2.7 | 0.051 | 3.1 | 0.051 | 3.2 |
| | IC | 120 | 317.40 | 7.973 | 2.5 | 10.962 | 3.5 | 11.878 | 3.7 | 17.307 | 5.5 |
a Panel 1, Panel 2, NC, and PC are reported in Grand Mean Index Value. The IC is reported in Grand Mean Rate.
## Method Comparison
### Clinical Performance
The clinical specimens used in the study were obtained from six specimen collection sites and three specimen vendors. A total of 2,352 linked serum specimens were prospectively collected and tested. In addition, 100 specimens from a surplus pediatric population were obtained.
The specimens included the following categories:
### Specimens Collected From Individuals Living in the United States (US) (Population 1)
- 1,313 specimens from individuals at increased risk of hepatitis B virus (HBV) infection
- 703 specimens from individuals with signs and symptoms of hepatitis infection
- 11 specimens from individuals diagnosed with acute HBV infection
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- 25 preselected IgM anti-HBc positive specimens
- 100 specimens from a pediatric population (This population included specimens from children > 2 to 12 years of age and adolescents > 12 to 19 years of age.)
## Specimens Collected From Individuals Living in Vietnam (Population 2)
- 100 specimens from individuals at increased risk of HBV infection
- 200 specimens from individuals with signs and symptoms of hepatitis infection
Three AxSYM CORE-M 2.0 Reagent Kit and Control master lots were used in the percent agreement evaluation. Three clinical testing sites performed AxSYM CORE-M 2.0 testing. Specimens were sent to an external reference laboratory for reference IgM anti-HBc assay testing. A summary of the percent agreement results for all specimen categories is presented in Table 8.
### Table 8 Summary of Percent Agreement Between AxSYM CORE-M 2.0 and the Reference IgM Anti-HBc Assay
| Specimen Category | Number of Specimens Tested | Positive Percent Agreement | Negative Percent Agreement^{a} |
| --- | --- | --- | --- |
| Individuals at Increased Risk of HBV Infection and Individuals With Signs and Symptoms of Hepatitis Infection (US Population) | 2,016 | 100.00% (16/16) | 99.50% (1,990/2,000) |
| Individuals at Increased Risk of HBV Infection and Individuals With Signs and Symptoms of Hepatitis Infection (Vietnam Population) | 300 | NA | 99.00% (297/300) |
| Individuals Diagnosed With Acute HBV Infection | 11 | 100.00% (11/11) | NA |
| Preselected IgM Anti-HBc Positive Specimens | 25 | 100.00% (23/23) | 0.00% (0/2) |
| Pediatric Population | 100 | NA | 100.00% (100/100) |
NA = Not Applicable
a Of the 15 discordant specimens, 11 were classified as chronic based on the four-marker HBV reference results.
24
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The 2,316 specimens from individuals at increased risk of HBV infection and individuals with signs and symptoms of hepatitis infection (Populations 1 and 2) were also sent to an external reference laboratory for HBV reference marker testing by FDA-approved reference assays for the detection of HBsAg, anti-HBc IgM, total anti-HBc, and anti-HBs. These specimens were assigned an HBV classification using the results for the four HBV reference markers and the modification of the serological criteria established by the National Center of Infectious Diseases (CDC) for diagnosing HBV infection.
The number of specimens in each HBV classification category is presented in Tables 9 and 10. A comparison of AxSYM CORE-M 2.0 results versus the reference IgM anti-HBc assay results by HBV classification category is presented in Tables 11 and 12. The percent agreement between AxSYM CORE-M 2.0 and the reference IgM anti-HBc assay by HBV classification category is summarized in Tables 13 and 14.
Two thousand sixteen specimens were prospectively collected in the United States at specimen collection sites located in Galveston, TX (39.29%); Dallas, TX (5.80%); Miami, FL (4.51%); St. Petersburg, FL (4.17%); Chicago, IL (8.18%); and Denver, CO (6.10%); or were obtained from a specimen vendor at the following three locations: Colton, CA (5.85%); Plymouth, MA (16.91%); and High Point, NC (9.18%) (Population 1). Three hundred specimens were also prospectively collected in Vietnam (Population 2) by a specimen vendor.
Population 1 was 52.83% Caucasian, 28.52% African American, 14.68% Hispanic, 1.98% Asian, and 0.45% American Indian/Alaska Native, with the remaining 1.54% represented by other ethnic groups. The population was 52.53% female and 47.47% male and ranged in age from 18 to 83 years. Testing of these specimens occurred at Clinical Testing Site 1 located in Port Jefferson, NY (39.29%); Clinical Testing Site 2 located in Dallas, TX (40.13%); and Clinical Testing Site 3 located in Raritan, NJ (20.59%).
Population 2 was Vietnamese (100.00%). The population was 53.33% female and 46.67% male and ranged in age from 18 to 68 years. Testing of these specimens occurred at a clinical testing site located in Raritan, NJ.
Table 9
HBV Classification for Individuals at Increased Risk of HBV Infection and Individuals With Signs and Symptoms of Hepatitis Infection (Population 1)
| HBV Reference Markers | | | | | HBV Classification |
| --- | --- | --- | --- | --- | --- |
| Number of Specimens | HBsAg | Anti-HBc IgM | Total Anti-HBc | Anti-HBs | |
| 2 | + | - | - | - | Early Acute |
| 7 | + | + | + | - | Acute |
| 1 | + | + | + | 1 | Chronic |
| 2 | + | - | + | + | Chronic |
| 35 | + | - | + | - | Chronic |
| 1 | + | - | - | + | Chronic |
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| 2 | + | - | + | I | Chronic |
| --- | --- | --- | --- | --- | --- |
| 1 | + | + | + | + | Late Acute/Recovering |
| 4 | - | + | + | + | Recovering Acute |
| 3 | - | + | + | I | Early Recovery |
| 193 | - | - | + | + | Immune Due to Natural Infection |
| 31 | - | - | + | I | Distantly Immune/Anti-HBs Unknown |
| 107 | - | - | + | - | Distantly Immune/Anti-HBs Not Detected |
| 507 | - | - | - | + | Immune Due to HBV Vaccination |
| 66 | - | - | - | I | Unknown |
| 1,054 | - | - | - | - | Susceptible |
| 2,016 | | | | | Total |
I = Indeterminate
Table 10
HBV Classification for Individuals at Increased Risk of HBV Infection and Individuals With Signs and Symptoms of Hepatitis Infection (Population 2)
| HBV Reference Markers | | | | | HBV Classification |
| --- | --- | --- | --- | --- | --- |
| Number of Specimens | HBsAg | Anti-HBc IgM | Total Anti-HBc | Anti-HBs | |
| 1 | + | - | - | - | Early Acute |
| 3 | + | - | + | + | Chronic |
| 119 | + | - | + | - | Chronic |
| 2 | + | - | - | + | Chronic |
| 3 | + | - | + | I | Chronic |
| 72 | - | - | + | + | Immune Due to Natural Infection |
| 5 | - | - | + | I | Distantly Immune/Anti-HBs Unknown |
| 15 | - | - | + | - | Distantly Immune/Anti-HBs Not Detected |
| 41 | - | - | - | + | Immune Due to HBV Vaccination |
| 39 | - | - | - | - | Susceptible |
| 300 | | | | | Total |
I = Indeterminate
Table 11
Comparison of AxSYM CORE-M 2.0 Results With Reference IgM Anti-HBc Assay Results by HBV Classification (Population 1)
| HBV Classification | Reference IgM Anti-HBc Assay Resulta | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | + | | | - | | | |
| | AxSYM CORE-M 2.0 Result | | | | | | |
| | + | GZR | - | + | GZR | - | |
| Early Acute | 0 | 0 | 0 | 0 | 0 | 2 | 2 |
| Acute | 7 | 0 | 0 | 0 | 0 | 0 | 7 |
| Chronic | 1 | 0 | 0 | 1b | 5c | 34 | 41 |
| Late Acute/Recovering | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
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| Recovering Acute | 3 | 1 | 0 | 0 | 0 | 0 | 4 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Early Recovery | 3 | 0 | 0 | 0 | 0 | 0 | 3 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 0 | 2^{c} | 191 | 193 |
| Distantly Immune/Anti-HBs Unknown | 0 | 0 | 0 | 0 | 0 | 31 | 31 |
| Distantly Immune/Anti-HBs Not Detected | 0 | 0 | 0 | 0 | 1^{c} | 106 | 107 |
| Immune Due to HBV Vaccination | 0 | 0 | 0 | 0 | 0 | 507 | 507 |
| Unknown | 0 | 0 | 0 | 0 | 1^{f} | 65 | 66 |
| Susceptible | 0 | 0 | 0 | 0 | 0 | 1,054 | 1,054 |
| Total | 15 | 1 | 0 | 1 | 9 | 1,990 | 2,016 |
GZR = Gray Zone Reactive
a Includes retesting performed according to the package insert, if required.
b This specimen was tested and determined to be positive for anti-HBe and HBV DNA.
c Three specimens were tested and determined to be positive for HBeAg and HBV DNA; two specimens were positive for anti-HBe and HBV DNA.
d These specimens were tested and determined to be positive for anti-HBe and gray zone reactive by an FDA-approved IgM anti-HBc assay.
e This specimen was tested and determined to be positive for anti-HBe and gray zone reactive by an FDA-approved IgM anti-HBc assay.
f This specimen was tested and determined to be reactive by an FDA-approved IgM anti-HBc assay.
Table 12 Comparison of AxSYM CORE-M 2.0 Results with Reference IgM Anti-HBc Assay Results by HBV Classification (Population 2)
| HBV Classification | Reference IgM Anti-HBc Assay Result^{a} | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | + | | | - | | | |
| | AxSYM CORE-M 2.0 Result | | | | | | |
| | + | GZR | - | + | GZR | - | |
| Early Acute | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Chronic | 0 | 0 | 0 | 0 | 3^{b} | 124 | 127 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 0 | 0 | 72 | 72 |
| Distantly Immune/Anti-HBs Unknown | 0 | 0 | 0 | 0 | 0 | 5 | 5 |
| Distantly Immune/Anti-HBs Not Detected | 0 | 0 | 0 | 0 | 0 | 15 | 15 |
| Immune Due to HBV Vaccination | 0 | 0 | 0 | 0 | 0 | 41 | 41 |
| Susceptible | 0 | 0 | 0 | 0 | 0 | 39 | 39 |
| Total | 0 | 0 | 0 | 0 | 3 | 297 | 300 |
GZR = Gray Zone Reactive
a Includes retesting performed according to the package insert, if required.
b Two specimens were tested and determined to be positive for HBeAg and HBV DNA, and one specimen was positive for anti-HBe and HBV DNA.
Table 13 Percent Agreement between AxSYM CORE-M 2.0 Results and Reference IgM Anti-HBc Assay Results Summarized by HBV Classification (Population 1)
| HBV Classification | Positive Percent Agreement | 95% Confidence Interval | Negative Percent Agreement | 95% Confidence Interval |
| --- | --- | --- | --- | --- |
| Early Acute | NA | NA | 2/2 (100.00%) | [15.81%, 100.00%] |
| Acute | 7/7 (100.00%) | [59.04%, 100.00%] | NA | NA |
| Chronic | 1/1 (100.00%) | [2.50%, 100.00%] | 34/40 (85.00%) | [70.16%, 94.29%] |
| Late Acute/Recovering | 1/1 (100.00%) | [2.50%, 100.00%] | NA | NA |
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| Recovering Acute | 4/4 (100.00%) | [39.76%, 100.00%] | NA | NA |
| --- | --- | --- | --- | --- |
| Early Recovery | 3/3 (100.00%) | [29.24%, 100.00%] | NA | NA |
| Immune Due to Natural Infection | NA | NA | 191/193 (98.96%) | [96.31%, 99.87%] |
| Distantly Immune/Anti-HBs Unknown | NA | NA | 31/31 (100.00%) | [88.78%, 100.00%] |
| Distantly Immune/Anti-HBs Not Detected | NA | NA | 106/107 (99.07%) | [94.90%, 99.98%] |
| Immune Due to HBV Vaccination | NA | NA | 507/507 (100.00%) | [99.28%, 100.00%] |
| Unknown | NA | NA | 65/66 (98.48%) | [91.84%, 99.96%] |
| Susceptible | NA | NA | 1,054/1,054 (100.00%) | [99.65%, 100.00%] |
| Overall | 16/16 (100.00%) | [79.41%, 100.00%] | 1,990/2,000 (99.50%) | [99.08%, 99.76%] |
NA = Not Applicable
## Table 14
### Percent Agreement between AxSYM CORE-M 2.0 Results and Reference IgM Anti-HBc Assay Results Summarized by HBV Classification (Population 2)
| HBV Classification | Positive Percent Agreement | 95% Confidence Interval | Negative Percent Agreement | 95% Confidence Interval |
| --- | --- | --- | --- | --- |
| Early Acute | NA | NA | 1/1 (100.00%) | [2.50%, 100.00%] |
| Chronic | NA | NA | 124/127 (97.64%) | [93.25%, 99.51%] |
| Immune Due to Natural Infection | NA | NA | 72/72 (100.00%) | [95.01%, 100.00%] |
| Distantly Immune/Anti-HBs Unknown | NA | NA | 5/5 (100.00%) | [47.82%, 100.00%] |
| Distantly Immune/Anti-HBs Not Detected | NA | NA | 15/15 (100.00%) | [78.20%, 100.00%] |
| Immune Due to HBV Vaccination | NA | NA | 41/41 (100.00%) | [91.40%, 100.00%] |
| Susceptible | NA | NA | 39/39 (100.00%) | [90.97%, 100.00%] |
| Overall | NA | NA | 297/300 (99.00%) | [97.11%, 99.79%] |
NA = Not Applicable
## Potentially Cross-reacting Subgroups
A total of 492 specimens from Population 1 (US) were identified as anti-HCV reactive, and 11 specimens from Population 2 (Vietnam) were identified as anti-HAV IgM reactive. The AxSYM CORE-M 2.0 results were compared to the results of the reference IgM anti-HBc assay by HBV classification. A comparison of AxSYM CORE-M 2.0 results versus the reference IgM anti-HBc assay results by HBV classification category is presented in Tables 15 and 16.
## Table 15
### Comparison of AxSYM CORE-M 2.0 Results With Reference IgM Anti-HBc Assay Results by HBV Classification (Population 1) Anti-HAV IgM Reactive Specimens
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| HBV Classification | Reference IgM Anti-HBc Assay Result^{a} | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | + | | | - | | | |
| | AxSYM CORE-M 2.0 Result | | | | | | |
| | + | GZR | - | + | GZR | - | |
| Early Acute | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Acute | 2 | 0 | 0 | 0 | 0 | 0 | 2 |
| Chronic | 0 | 0 | 0 | 0 | 0 | 5 | 5 |
| Recovering Acute | 3 | 1 | 0 | 0 | 0 | 0 | 4 |
| Early Recovery | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 0 | 1 | 87 | 88 |
| Distantly Immune/Anti-HBs Unknown | 0 | 0 | 0 | 0 | 0 | 26 | 26 |
| Distantly Immune/Anti-HBs Not Detected | 0 | 0 | 0 | 0 | 1 | 72 | 73 |
| Immune Due to HBV Vaccination | 0 | 0 | 0 | 0 | 0 | 70 | 70 |
| Unknown | 0 | 0 | 0 | 0 | 0 | 15 | 15 |
| Susceptible | 0 | 0 | 0 | 0 | 0 | 207 | 207 |
| Grand Total | 6 | 1 | 0 | 0 | 2 | 483 | 492 |
GZR = Gray Zone Reactive
a Includes retesting performed according to the package insert as required.
Table 16 Comparison of AxSYM CORE-M 2.0 Results With Reference IgM Anti-HBc Assay Results by HBV Classification (Population 2) Anti-HAV IgM Reactive Specimens
| HBV Classification | Reference IgM Anti-HBc Assay Result^{a} | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | + | | | - | | | |
| | AxSYM CORE-M 2.0 Result | | | | | | |
| | + | GZR | - | + | GZR | - | |
| Chronic | 0 | 0 | 0 | 0 | 0 | 3 | 3 |
| Immune Due to Natural Infection | 0 | 0 | 0 | 0 | 0 | 4 | 4 |
| Immune Due to HBV Vaccination | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Susceptible | 0 | 0 | 0 | 0 | 0 | 3 | 3 |
| Grand Total | 0 | 0 | 0 | 0 | 0 | 11 | 11 |
GZR = Gray Zone Reactive
a Includes retesting performed according to the package insert as required.
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# Expected Results
Expected results were determined using the AxSYM CORE-M 2.0 results for individuals at increased risk of HBV infection living in the United States.
Of the prospective subjects participating in the investigation, 55.82% (1,313/2,352) were from individuals, living in the United States, who were at increased risk of HBV infection. All subjects were at risk of HBV infection due to lifestyle, behavior, occupation, or known exposure event but were asymptomatic and reported no current signs or symptoms of hepatitis. The population ranged in age from 18 to 75 years. A demographic summary of this population is presented in the following table:
| | Total Number of Specimens (%) |
| --- | --- |
| Ethnicity: | |
| Caucasian | 47.60 |
| African American | 36.25 |
| Hispanic | 12.72 |
| Asian | 1.45 |
| American Indian/Alaska Native | 0.46 |
| Other | 1.52 |
| Gender: | |
| Female | 62.15 |
| Male | 37.85 |
The AxSYM CORE-M 2.0 assay was reactive or gray zone reactive in 0.61% (8/1,313) of the individuals in this population. The percent of individuals at increased risk of HBV infection enrolled at each location and the percent of AxSYM CORE-M 2.0 reactive results observed from each location are presented in Table 17. The percent AxSYM CORE-M 2.0 reactive, gray zone reactive, and nonreactive results by age range and gender is presented in Table 18.
Table 17 AxSYM CORE-M 2.0 Reactive Results by Specimen Collection Site or Specimen Vendor for Individuals at Increased Risk of HBV Infection
| Specimen Collection Site/ Specimen Vendor | Percent of Individuals at Increased Risk of HBV Infection Enrolled at Each Location | Percent of AxSYM CORE-M 2.0 Reactivea Results Observed From Each Location |
| --- | --- | --- |
| Site 1, Galveston, TX | 56.51 (742/1,313) | 0.54 (4/742) |
| Site 2, Dallas, TX | 4.49 (59/1,313) | 0.00 (0/59) |
| Site 3, Miami, FL | 3.96 (52/1,313) | 1.92 (1/52) |
| Site 4, St. Petersburg, FL | 4.27 (56/1,313) | 1.79 (1/56) |
| Site 5, Chicago, IL | 0.61 (8/1,313) | 0.00 (0/8) |
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| Site 6, Denver, CO | 2.74 (36/1,313) | 0.00 (0/36) |
| --- | --- | --- |
| Specimen Vendor 1 | | |
| Location: | | |
| Colton, CA | 5.79 (76/1,313) | 0.00 (0/76) |
| Plymouth, MA | 7.54 (99/1,313) | 1.01 (1/99) |
| High Point, NC | 14.09 (185/1,313) | 0.54 (1/185) |
* Includes gray zone reactives.
Table 18 AxSYM CORE-M 2.0 Results by Age Range and Gender for Individuals at Increased Risk of HBV Infection
| Age Range | Gender | AxSYM CORE-M 2.0 Result | | | Total |
| --- | --- | --- | --- | --- | --- |
| | | + Number of Specimens (%) | GZR Number of Specimens (%) | - Number of Specimens (%) | |
| 10 to 19 | Female | 0 (0.00) | 0 (0.00) | 14 (100.00) | 14 |
| | Male | 0 (0.00) | 0 (0.00) | 11 (100.00) | 11 |
| 20 to 29 | Female | 0 (0.00) | 1 (0.54) | 183 (99.46) | 184 |
| | Male | 1 (1.03) | 0 (0.00) | 96 (98.97) | 97 |
| 30 to 39 | Female | 0 (0.00) | 0 (0.00) | 184 (100.00) | 184 |
| | Male | 1 (0.93) | 0 (0.00) | 106 (99.07) | 107 |
| 40 to 49 | Female | 1 (0.40) | 1 (0.40) | 249 (99.20) | 251 |
| | Male | 0 (0.00) | 0 (0.00) | 159 (100.00) | 159 |
| 50 to 59 | Female | 0 (0.00) | 1 (0.73) | 136 (99.27) | 137 |
| | Male | 1 (0.93) | 1 (0.93) | 106 (98.15) | 108 |
| 60 to 69 | Female | 0 (0.00) | 0 (0.00) | 35 (100.00) | 35 |
| | Male | 0 (0.00) | 0 (0.00) | 12 (100.00) | 12 |
| 70 to 79 | Female | 0 (0.00) | 0 (0.00) | 8 (100.00) | 8 |
| | Male | 0 (0.00) | 0 (0.00) | 3 (100.00) | 3 |
| Unknown* | Female | 0 (0.00) | 0 (0.00) | 3 (100.00) | 3 |
| Total | | 4 (0.30) | 4 (0.30) | 1,305 (99.39) | 1,313 |
GZR = Gray Zone Reactive
* Age was not provided for three subjects.
# XI. CONCLUSIONS DRAWN FROM THE STUDIES
The data from the nonclinical studies demonstrated acceptable precision, analytical specificity, and seroconversion panel detection of the AxSYM CORE-M 2.0 assay when used according to the instructions for use as stated in the labeling, the warnings and precautions, and the Specimen Collection and Preparation for Analysis and Limitations sections of the labeling.
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The clinical studies in this application indicate that the AxSYM CORE-M 2.0 assay is safe and effective when used according to the directions for use in the labeling.
## RISK BENEFIT ANALYSIS
As a diagnostic test, the AxSYM CORE-M 2.0 assay involves removal of blood from an individual for testing purposes. This test presents no more of a safety hazard to an individual than is presented to an individual who is having their blood drawn for any other diagnostic evaluation. The benefits to HBV-infected individuals tested by the assay outweigh any potential adverse event or risk to the patient or user due to assay malfunction or operator error.
The potential risks encountered with this in vitro diagnostic test are not unusual in the clinical laboratory setting. Appropriate warnings for these risks are contained in the labeling and package inserts for the device. Standard good laboratory practices are considered sufficient to mitigate the risks to the end user.
## SAFETY
Based on the results of the preclinical and clinical laboratory studies, the AxSYM CORE-M 2.0 assay, when used according to the provided directions and in conjunction with other serological and clinical information, should be safe and effective and pose minimal risk to the patient due to false test results.
## EFFECTIVENESS
The effectiveness of the AxSYM CORE-M 2.0 assay has been demonstrated for use in determining if IgM antibodies to hepatitis B virus core antigen (IgM anti-HBc) are present in an individual’s serum or plasma. A reasonable determination of effectiveness of the AxSYM CORE-M 2.0 assay for aiding in the diagnosis of acute or recent HBV infection in conjunction with other laboratory results and clinical information in suspected individuals has been demonstrated.
## XII. PANEL RECOMMENDATIONS
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Microbiology Advisory Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.
32
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## XIII. CDRH DECISION
FDA issued an approval order on August 25, 2006.
The applicant’s manufacturing facility was inspected on 5/8/06 (N. Chicago), 5/16/06 (Abbott Park), and 5/19/06 (Puerto Rico) and found to be in compliance with the Quality Systems Regulation (21 CFR 820).
## XIV. APPROVAL SPECIFICATIONS
Directions for use: See the labeling.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions and Adverse Events in the labeling.
Postapproval Requirements and Restrictions: See approval order.
