DIASORIN LIAISON EBNA IGG, LIAISON VCA IGG, LIAISON VCA IGM ASSAYS
Device Facts
| Record ID | K040120 |
|---|---|
| Device Name | DIASORIN LIAISON EBNA IGG, LIAISON VCA IGG, LIAISON VCA IGM ASSAYS |
| Applicant | DiaSorin, Inc. |
| Product Code | LLM · Microbiology |
| Decision Date | Apr 29, 2005 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 866.3235 |
| Device Class | Class 1 |
Intended Use
The LIAISON® VCA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p18 synthetic peptide in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis. The LIAISON® EBV IgM assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of specific IgM antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p18 synthetic peptide in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis. The LIAISON® EBNA IgG assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of specific IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen synthetic peptide (EBNA-1) in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr Viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis.
Device Story
The LIAISON® EBNA IgG, EBV IgM, and VCA IgG assays are chemiluminescence immunoassays (CLIA) performed on the LIAISON® Analyzer. Input: human serum samples. Principle: indirect CLIA using magnetic particles coated with synthetic peptides (EBNA-1 or VCA p-18) and isoluminol-antibody conjugates. The analyzer performs incubation, wash cycles, and starter reagent addition; a photomultiplier measures light signal (RLU) proportional to antibody concentration. Used in clinical laboratories by technicians. Output: qualitative detection of specific IgG or IgM antibodies. Results aid clinicians in diagnosing EBV-associated syndromes and determining immune status. Benefits: provides standardized, automated serological testing for EBV infection.
Clinical Evidence
Clinical trials conducted at two US labs and DiaSorin using prospective and retrospective serum samples. Prospective sample agreement: EBNA IgG (95.3%), EBV IgM (89.4%), VCA IgG (96.1%). Retrospective (VCA IgM-positive) agreement: EBNA IgG (94.3%), EBV IgM (95.7%), VCA IgG (100%). Studies included reproducibility testing across sites and cross-reactivity panels for herpes viruses and other conditions. No conclusive evidence of interference observed.
Technological Characteristics
Indirect chemiluminescence immunoassay (CLIA). Solid phase: magnetic particles coated with synthetic EBV peptides. Conjugate: mouse monoclonal antibody to human IgG/IgM linked to isoluminol derivative. Detection: flash chemiluminescence measured as RLU via photomultiplier. Automated on LIAISON® Analyzer. Qualitative output.
Indications for Use
Indicated for the laboratory diagnosis of EBV-associated infectious mononucleosis in individuals with signs and symptoms consistent with infectious mononucleosis.
Regulatory Classification
Identification
Epstein-Barr virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Epstein-Barr virus in serum. The identification aids in the diagnosis of Epstein-Barr virus infections and provides epidemiological information on diseases caused by these viruses. Epstein-Barr viruses are thought to cause infectious mononucleosis and have been associated with Burkitt's lymphoma (a tumor of the jaw in African children and young adults) and postnasal carcinoma (cancer).
Predicate Devices
- DiaSorin ETI-VCA-G Kit (K946159)
- DiaSorin ETI-EBV-M reverse Kit (K946157)
- DiaSorin ETI-EBNA-G Kit (K946158)
Related Devices
- K060204 — LIAISON EA IGG · DiaSorin, Inc. · Oct 18, 2006
- K162961 — LIAISON® VCA IgG and LIAISON® VCA IgG Serum Control Set; LIAISON® EBNA IgG and LIAISON® EBNA IgG Serum Control Set · DiaSorin, Inc. · Jan 5, 2017
Submission Summary (Full Text)
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| SUBMITTED BY: | David M. Ikeda<br>Regulatory Affairs/Quality Systems Manager<br>DiaSorin Inc.<br>1951 Northwestern Avenue<br>P.O. Box 285<br>Stillwater, MN 55082-0285<br>Phone (651) 351-5592<br>Fax (651) 351-5669<br>E-mail: david.ikeda@diasorin.com |
|--------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NAME OF DEVICE:<br>Trade Name: | DiaSorin LIAISON® EBNA IgG |
| Common Names/Descriptions: | Immunoassay for the detection of IgG antibodies to<br>EBV Nuclear Antigen (EBNA) |
| Classification Names: | TEST, ANTIGEN, NUCLEAR, EPSTEIN-BARR VIRUS |
| Product Code: | LLM |
| PREDICATE DEVICE: | DiaSorin ETI-EBNA-G Kit (K946158) |
#### 6.0 510 (k) SUMMARY
DEVICE DESCRIPTION:
INTENDED USE: The DiaSorin LIAISON® EBNA IgG kit uses chemiluminescence immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative detection of specific IgG antibodies to EBV nuclear antigen synthetic peptide (EBNA) in human serum. When performed in conjunction with other EBV marker tests, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM). LIAISON® Control EBNA IgG kit is used in conjunction with LIAISON® EBNA IgG immunoassay for quality control of assay runs.
KIT DESCRIPTION: The method for qualitative determination of specific IgG to EBNA is an indirect chemiluminescence immunoassay (CLIA). All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the LIAISON® Analyzer. The principal components of the test are magnetic particles (solid phase) coated with EBNA-1 synthetic peptide and a conjugate of mouse monoclonal antibody to human IgG linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, EBNA antibodies present in the calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with EBNA IgG already bound to the solid phase. After each incubation, the unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of the presence of EBNA IgG in calibrators, samples or controls.
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## PERFORMANCE DATA:
COMPARATIVE CLINICAL TRIALS: The clinical trials were conducted at two external US laboratories and at DiaSorin. Testing was performed on repository and prospective samples as defined below. The samples were tested by LIAISON® EBNA IgG and comparison assay, at the trial sites per the manufacturers' instructions for use.
| Prospective Samples: Subjects Sent to the Laboratory for EBV Testing: | | | | | |
|-----------------------------------------------------------------------|--|--|--|--|--|
|-----------------------------------------------------------------------|--|--|--|--|--|
| LIAISON®<br>EBNA IgG | DiaSorin ETI-EBNA-G | | | | Percent Agreement | | Exact 95%<br>confidence interval | |
|--------------------------------|---------------------|----------|-------|----------|-------------------|-----------|----------------------------------|--|
| | Positive | Negative | Total | Positive | 95.9% | (632/659) | 94.1 - 97.3% | |
| Positive (≥22.0 U/mL) | 632 | 9 | 641 | Negative | 92.7% | (152/164) | 87.6 - 96.2% | |
| Equivocal (18.0-<br>21.9 U/mL) | 2 | 3 | 5 | Overall | 95.3% | (784/823) | 93.6 - 96.6% | |
| Negative (<18.0<br>U/mL) | 25 | 152 | 177 | | | | | |
| Total | 659 | 164 | 823 | | | | | |
Using the results for the prospective samples in three reference assays (VCA IgG, EBNA-1 IgG, VCA IgM ELISA), the samples were grouped into serological categories. Four samples tested in v of the LIAISON® EBNA IgG assay had insufficient volume for the entire test profile and are omitted from this analysis. The profiles and number of occurrences are presented in the following table:
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| | VCA IgG | VCA IgM | EBNA-1 IgG | Total |
|------------------|---------|---------|------------|-------|
| EBV seronegative | - | - | - | 62 |
| Acute infection | + | + | - | 29 |
| Past infection | + | - | + | 573 |
| Indeterminate | | | | |
| VCA IgG only | + | - | - | 67 |
| VCA IgM only | - | + | - | 5 |
| EBNA IgG only | - | - | + | 10 |
| Convalescent | + | + | + | 73 |
Based on these serological classifications, the LIAISON® EBNA IgG results for the prospective samples were compared with those obtained with the reference assay (EBNA-1 IgG ELISA).
| | Percent Agreement | | 95% confidence interval |
|---------------------|-------------------|-----------|-------------------------|
| Acute infection | 100.0% | (29/29) | 90.2 - 100.0% |
| Past infection | 98.1% | (562/573) | 96.6 - 99.0% |
| EBV<br>seronegative | 100.0% | (62/62) | 95.3 - 100.0% |
| Indeterminate | 81.9% | (127/155) | 75.0 - 87.7% |
| Overall | 95.2% | (780/819) | 93.6 - 96.6% |
Retrospective Samples: VCA IgM-positive Samples
| LIAISON®<br>EBNA IgG | DiaSorin ETI-EBNA-G | | Total |
|----------------------------|---------------------|----------|-------|
| | Positive | Negative | |
| Positive (≥22.0 U/mL) | 61 | 2 | 63 |
| Equivocal (18.0-21.9 U/mL) | 0 | 2 | 2 |
| Negative (<18.0 U/mL) | 0 | 5 | 5 |
| Total | 61 | 9 | 70 |
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| | Percent Agreement | Exact 95%<br>confidence interval | |
|----------|-------------------|----------------------------------|---------------|
| Positive | 100.0% | (61/61) | 94.1 - 100.0% |
| Negative | N.C.* | (7/9) | N.C.* |
| Overall | 94.3% | (66/70) | 86.0 - 98.4% |
*N.C. - Not Calculated - inadequate sample number
Using the results for the retrospective samples in three reference assays (VCA IgG, EBNA-1 IgG, VCA IgM ELISA), the samples were grouped into serological categories. The profiles and number of occurrences are presented in the following table:
| | VCA IgG | VCA IgM | EBNA-1 IgG | Total |
|------------------|---------|---------|------------|-------|
| EBV seronegative | - | - | - | 0 |
| Acute infection | + | + | - | 9 |
| Past infection | + | - | + | 0 |
| Indeterminate | | | | |
| VCA IgG only | + | - | - | 0 |
| VCA IgM only | - | + | - | 0 |
| EBNA IgG only | - | - | + | 0 |
| Convalescent | + | + | + | 61 |
Based on these serological classifications, the LIAISON® EBNA IgG results for the retrospective Based on these compared with the reference assay (EBNA-1 IgG ELISA).
| | Percent Agreement | | 95% confidence interval |
|---------------------|-------------------|---------|-------------------------|
| Acute infection | 55.6% | (5/9) | 21.2 – 86.3% |
| Past infection | N/A | | N/A |
| EBV<br>seronegative | N/A | | N/A |
| Indeterminate | 100.0% | (61/61) | 95.2 – 100.0% |
| Overall | 94.3% | (66/70) | 86.0 - 98.4% |
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REPRODUCIBILITY: Reproducibility studies were performed at 4 sites using a coded panel comprised of 9 frozen repository serum samples. The serum panel was prepared to represent complious or of rozen repositive analyte level. The same coded panel was tested at all sites, in three replicates per run for ten runs. Results expressed in U/mL are summarized in the following table.
| ID# | N | mean<br>(U/mL) | within<br>run<br>S.D. | within<br>run<br>%CV | between<br>run<br>S.D. | between<br>run<br>%CV | between<br>site<br>S.D. | between<br>site<br>%CV | overall<br>S.D. | overall<br>%CV |
|------|----|----------------|-----------------------|----------------------|------------------------|-----------------------|-------------------------|------------------------|-----------------|----------------|
| EBS1 | 90 | 28.5 | 0.73 | 2.57 | 1.04 | 2.70 | 0.83 | 2.90 | 1.24 | 4.35 |
| EBS2 | 90 | 62.2 | 4.81 | 6.94 | 8.84 | 11.78 | 3.70 | 5.95 | 15.02 | 24.15 |
| EBS3 | 90 | 290.4 | 12.18 | 4.27 | 26.81 | 6.02 | 24.49 | 8.43 | 29.04 | 10.00 |
| EB1 | 90 | 72.2 | 1.81 | 2.48 | 3.32 | 2.82 | 3.12 | 4.32 | 3.72 | 5.15 |
| EB2 | 90 | 71.0 | 2.12 | 3.01 | 5.45 | 3.86 | 5.74 | 8.09 | 5.73 | 8.08 |
| EB3 | 90 | 52.6 | 1.71 | 3.27 | 3.06 | 4.30 | 2.53 | 4.81 | 3.45 | 6.55 |
| EB4 | 90 | 48.6 | 1.51 | 3.17 | 3.30 | 4.72 | 2.93 | 6.04 | 3.57 | 7.34 |
| EB5 | 90 | 59.9 | 1.76 | 2.98 | 3.10 | 4.35 | 2.18 | 3.63 | 3.53 | 5.88 |
| EB6 | 90 | 51.6 | 1.69 | 3.33 | 2.61 | 4.61 | 1.46 | 2.83 | 3.06 | 5.94 |
INTERFERENCE: Controlled studies of potentially interfering substances showed that the assay performance was not affected by hemolysis (at 1000 mg/dL hemoglobin), lipemia (at 3000 mq/dL triglycerides) and icterus (at 10 mg/dL bilirubin).
CROSS-REACTIVITY: The cross-reactivity studies for the LIAISON® EBNA IgG assay were designed to evaluate potential interference from IgG immunoglobulins directed against closelyrelated members of the herpes virus family (HSV-1, HSV-2, VZV, CMV, HHV6), from other organisms that may cause symptoms similar to EBV (Toxoplasma gondii, rubella virus) and from other conditions that may result from atypical immune system activity (rheumatoid factor (RF), anti-nuclear antibodies (ANA)). Samples for these studies were selected using commercially available devices.
| Organism / condition | Number of<br>Samples | Positive<br>LIAISON®<br>EBNA IgG<br>Result |
|--------------------------|----------------------|--------------------------------------------|
| CMV IgG | 19 | (0/19) |
| VZV IgG | 7 | (0/7) |
| HSV-1 IgG | 19 | (1/19) |
| HSV-2 IgG | 3 | (0/3) |
| HHV6 IgG | 1 | (0/1) |
| Toxoplasma gondii<br>IgG | 7 | (0/7) |
| Rubella virus IgG | 30 | (1/30) |
| ANA | 1 | (0/1) |
| RF | 4 | (0/4) |
| Total | 91 | (2/91) |
{5}------------------------------------------------
Two specimens out of 91 total specimens tested from the disease panel were positive. There was no conclusive evidence of interference observed, however due to the limited availability of was no onehaller of onas-reactivity of cross-reactivity cannot be excluded. The user is advised to perform other EBV serology assays to confirm EBV-associated infectious mononucleosis.
WARNING: Assay interference due to circulating antibodies against HIV and Hepatitis A, Heratitis B and Hepatitis C viruses has not been evaluated. The user is responsible for establishing cross-reactivity performance with these infectious agents.
## CONCLUSION
The LIAISON® EBNA IgG assay showed equivalent performance to the corresponding FDAcleared assay. The DiaSorin LIAISON® EBNA IgG assay demonstrated agreement with the comparison method higher then 95% among prospectively collected samples and 94% oompanoon monou higher selected samples. The results demonstrated that LIAISON® EBNA IgG assay can be used with the LIAISON® Analyzer for the qualitative detection of IgG antibodies to EBNA and can be intended for use as an aid in the determination of immune status to EBV.
{6}------------------------------------------------
| SUBMITTED BY: | David M. Ikeda<br>Regulatory Affairs/Quality Systems Manager<br>DiaSorin Inc.<br>1951 Northwestern Avenue<br>P.O. Box 285<br>Stillwater, MN 55082-0285<br>Phone (651) 351-5592<br>Fax (651) 351-5669<br>E-mail: david.ikeda@diasorin.com |
|--------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NAME OF DEVICE:<br>Trade Name: | DiaSorin LIAISON® EBV IgM |
| Common Names/Descriptions: | Immunoassay for the detection of IgM antibodies to<br>EBV Viral Capsid Antigen (VCA) |
| Classification Names: | EPSTEIN-BARR VIRUS, OTHER |
| Product Code: | LSE |
| PREDICATE DEVICES: | DiaSorin ETI-EBV-M reverse Kit (K946157) |
#### 6.0 510 (k) SUMMARY
## DEVICE DESCRIPTION:
INTENDED USE: The LIAISON® EBV IgM assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of specific IgM antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p-18 synthetic peptide in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM). LIAISON® Control EBV IgM kit is used in conjunction with LIAISON® EBV IgM immunoassay for quality control of assay runs.
## KIT DESCRIPTION:
The method for qualitative determination of specific IgM to Epstein-Barr viral capsid antigens (VCA) is an indirect chemiluminescence immunoassay (CLIA).
All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the LIAISON® Chemiluminescence Analyzer. The principal components of the test are magnetic particles (solid phase) coated with p18 synthetic peptide and a conjugate of mouse monoclonal antibody to human IgM linked to an isoluminol derivative (isoluminolantibody conjugate).
In the first step, samples and controls are diluted with Buffer A, which contains goat IgG to human IgG as an absorbent reagent to curb interference from human IgG specific to VCA or from rheumatoid factor. During the first incubation, VCA IgM antibodies present in the calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with VCA IgM already bound to the solid phase. After each incubation, the unbound material is removed with a wash cycle.
{7}------------------------------------------------
Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured hy a photomultiplier as relative light units (RLU) and is indicative of the presence of VCA IgM in calibrators, samples or controls.
## PERFORMANCE DATA:
COMPARATIVE CLINICAL TRIALS: The clinical trials were conducted at two external US laboratories and at DiaSorin. Testing was performed on repository and prospective samples as lastratories and The samples were tested by LIAISON® EBV IgM and comparison assay (DiaSorin ETI-EBV-M reverse ELISA Kit), at the trial sites per the manufacturers' instructions for use.
| LIAISON®<br>EBV IgM | DiaSorin ETI-EBV-M | | |
|--------------------------------|--------------------|----------|-------|
| | Positive | Negative | Total |
| Positive (≥44.0<br>U/mL) | 58 | 28 | 86 |
| Equivocal (36.0-<br>43.9 U/mL) | 4 | 10 | 14 |
| Negative (<36.0<br>U/mL) | 45 | 674 | 719 |
| Total | 107 | 712 | 819 |
Prospective Samples: Subjects Sent to the Laboratory for EBV Testing:
| | Percent Agreement | Exact 95% confidence interval |
|----------|-------------------|-------------------------------|
| Positive | 54.2% (58/107) | 44.3 - 63.9% |
| Negative | 94.7% (674/712) | 92.8 – 96.2% |
| Overall | 89.4% (732/819) | 87.1 - 91.4% |
Using the results for the prospective samples in three reference assays (VCA IgG, EBNA-1 IgG, VCA IgM ELISA), the samples were grouped into serological categories. The profiles and number of occurrences are presented in the following table:
{8}------------------------------------------------
| | VCA IgG | VCA IgM | EBNA-1 IgG | Total |
|------------------|---------|---------|------------|-------|
| EBV seronegative | - | - | - | 62 |
| Acute infection | + | + | - | 29 |
| Past infection | + | - | + | 573 |
| Indeterminate | | | | |
| VCA IgG only | + | - | - | 67 |
| VCA IgM only | - | + | - | 5 |
| EBNA IgG only | - | - | + | 10 |
| Convalescent | + | + | + | 73 |
Based on these serological classifications, the LIAISON® EBV IgM results for the prospective samples were compared with those obtained with the reference assay (VCA IgM ELISA).
| | Percent Agreement | | 95% confidence interval |
|---------------------|-------------------|-----------|-------------------------|
| Acute infection | 100.0% | (29/29) | 90.2 – 100.0% |
| Past infection | 95.3% | (546/573) | 93.2 – 96.9% |
| EBV<br>seronegative | 93.5% | (58/62) | 84.3 – 98.2% |
| Indeterminate | 63.9% | (99/155) | 55.8 – 71.4% |
| Overall | 89.4% | (732/819) | 87.1 – 91.4% |
Retrospective Samples: VCA IgM-positive Samples
| LIAISON®<br>EBV IgM | DiaSorin ETI-EBV-M | | |
|--------------------------------|--------------------|----------|-------|
| | Positive | Negative | Total |
| Positive (≥44.0<br>U/mL) | 67 | 0 | 67 |
| Equivocal (36.0-<br>43.9 U/mL) | 0 | 0 | 0 |
| Negative (<36.0<br>U/mL) | 3 | 0 | 3 |
| Total | 70 | 0 | 70 |
{9}------------------------------------------------
| | Percent Agreement | Exact 95% confidence interval |
|----------|-------------------|-------------------------------|
| Positive | 95.7% (67/70) | 88.0 – 99.1% |
| Negative | N.C.* (0/0) | N.C.* |
| Overall | 95.7% (67/70) | 88.0 – 99.1% |
*N.C .- Not Calculated - inadequate sample number
Using the results for the retrospective samples in three reference assays (VCA IgG, EBNA-1 IgG and VCA IgM ELISA), the samples were grouped into serological categories. The profiles and number of occurrences are presented in the following table:
| | VCA IgG | VCA IgM | EBNA-1 IgG | Total |
|------------------|---------|---------|------------|-------|
| EBV seronegative | - | - | - | 0 |
| Acute infection | + | + | - | 9 |
| Past infection | + | - | + | 0 |
| Indeterminate | | | | |
| VCA IgG only | + | - | - | 0 |
| VCA IgM only | - | + | - | 0 |
| EBNA IgG only | - | - | + | 0 |
| Convalescent | + | + | + | 61 |
Based on these serological classifications, the LIAISON® EBV IgM results for the retrospective samples were compared with those obtained with the reference assay (VCA IgM ELISA).
| | Percent Agreement | | 95% confidence interval |
|---------------------|-------------------|---------|-------------------------|
| Acute infection | 77.8% | (7/9) | 40.0 – 97.2% |
| Past infection | N/A | | N/A |
| EBV<br>seronegative | N/A | | N/A |
| Indeterminate | 98.4% | (60/61) | 91.2 – 100.0% |
| Overall | 95.7% | (67/70) | 88.0 – 99.1% |
REPRODUCIBILITY: Reproducibility studies were performed at 3 sites using a coded panel comprised of 9 frozen repository serum samples. The serum panel was prepared to represent from low- to mid-positive analyte level. The same coded panel was tested at all sites, in three replicates per run for ten runs. Results expressed in U/mL are summarized below.
{10}------------------------------------------------
| ID# | N | mean (U/mL) | within run S.D. | within run %CV | between run S.D. | between run %CV | between site S.D. | between site %CV | overall S.D. | overall %CV |
|------|----|-------------|-----------------|----------------|------------------|-----------------|-------------------|------------------|--------------|-------------|
| EMS1 | 90 | 67.2 | 2.22 | 3.30 | 3.36 | 4.26 | 2.21 | 3.28 | 3.92 | 5.83 |
| EMS2 | 89 | 89.7 | 4.00 | 4.55 | 6.90 | 5.16 | 6.26 | 6.98 | 7.79 | 8.70 |
| EMS3 | 90 | <10.0 | 69.6* | 7.15* | 83.6* | 6.50* | 69.5* | 7.35* | 115.7* | 12.24* |
| EM1 | 90 | 36.4 | 2.79 | 7.88 | 4.93 | 5.50 | 5.43 | 14.92 | 5.52 | 15.16 |
| EM2 | 90 | 37.2 | 2.23 | 6.09 | 5.43 | 6.17 | 5.91 | 15.90 | 5.77 | 15.52 |
| EM3 | 90 | 79.5 | 6.22 | 7.79 | 12.04 | 5.63 | 13.16 | 16.55 | 13.25 | 16.67 |
| EM4 | 89 | 65.9 | 4.34 | 6.60 | 8.95 | 5.35 | 9.95 | 15.10 | 9.77 | 14.83 |
| EM5 | 89 | 37.1 | 2.65 | 7.27 | 4.25 | 6.92 | 4.14 | 11.16 | 4.88 | 13.18 |
| EM6 | 90 | 64.6 | 4.26 | 6.65 | 6.07 | 6.58 | 5.36 | 8.30 | 7.18 | 11.11 |
*EMS3 dose was below the reading range of the assay. Precision calculations are based on signal (RLU) for this sample.
INTERFERENCE: Controlled studies of potentially interfering substances showed that the assay performance was not affected by hemolysis (at 1000 mg/dL hemoglobin), lipemia (at 3000 mg/dL triglycerides) and icterus (at 20 mg/dL bilirubin).
CROSS-REACTIVITY: The cross-reactivity studies for the LIAISON® EBV IgM assay were designed to evaluate potential interference from IgM immunoglobulins directed against closelyrelated members of the herpes virus family (HSV-1, HSV-2, VZV, CMV), from other organisms that may cause symptoms similar to EBV (Toxoplasma gondii, rubella virus, rubeola virus, mumps virus, hepatitis A virus, hepatitis B virus) and from other conditions that may result from atypical immune system activity (rheumatoid factor (RF), anti-nuclear antibodies (ANA)), Samples for these studies were selected using commercially available devices.
| Organism / condition | Number of<br>Samples | Positive<br>LIAISON® EBV<br>IgM Result |
|---------------------------------|----------------------|----------------------------------------|
| CMV IgM | 29 | (2/29) |
| VZV IgM | 16 | (1/16) |
| HSV-1 IgM | 2 | (0/2) |
| HSV-2 IgM | 7 | (0/7) |
| Hepatitis A virus IgM | 10 | (0/10) |
| Hepatitis B virus (core)<br>IgM | 23 | (0/23) |
| Toxoplasma gondii<br>IgM | 12 | (0/12) |
| Rubella virus IgM | 11 | (0/11) |
| Rubeola virus IgM | 3 | (0/3) |
| Mumps virus IgM | 2 | (1/2) |
| RF | 6 | (0/6) |
| ANA Ig | 10 | (0/10) |
| Total | 131 | (4/131) |
Four specimens out of 131 total specimens tested from the disease panel were positive. There was no conclusive evidence of interference observed, however due to the limited availability of certain samples, the possibility of cross-reactivity cannot be excluded. Other EBV serology
{11}------------------------------------------------
assays should be performed to confirm EBV-associated infectious mononucleosis.
WARNING: Assay interference due to circulating antibodies against HIV and Hepatitis C virus has not been evaluated. The user is responsible for establishing cross-reactivity performance with these infectious agents.
## CONCLUSION
The LIAISON® EBV IgM assay showed equivalent performance to the corresponding FDAcleared assay. The DiaSorin LIAISON® EBV IgM assay demonstrated agreement with the comparison method higher than 89% among prospectively collected samples and 95% agreement among retrospective selected samples. The results demonstrated that LIAISON® EBV IgM assay can be used with the LIAISON® Analyzer for the qualitative detection of IgM antibodies to EBV and can be intended for use as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM).
{12}------------------------------------------------
| SUBMITTED BY: | David M. Ikeda<br>Regulatory Affairs/Quality Systems Manager<br>DiaSorin Inc.<br>1951 Northwestern Avenue<br>P.O. Box 285<br>Stillwater, MN 55082-0285<br>Phone (651) 351-5592<br>Fax (651) 351-5669<br>E-mail: david.ikeda@diasorin.com |
|--------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NAME OF DEVICE:<br>Trade Name: | DiaSorin LIAISON® VCA IgG |
| Common Names/Descriptions: | Immunoassay for the detection of IgG antibodies to<br>EBV viral capsid antigens (VCA) |
| Classification Names: | EPSTEIN-BARR VIRUS, OTHER |
| Product Code: | LSE |
| PREDICATE DEVICE: | DiaSorin ETI-VCA-G Kit (K946159) |
#### 6.0 510 (k) SUMMARY
DEVICE DESCRIPTION:
INTENDED USE: The DiaSorin LIAISON® VCA IgG kit uses chemiluminescence immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative detection of specific IqG antibodies to EBV viral capsid antigen (VCA) p-18 synthetic peptide in human serum. When performed in conjunction with other EBV marker tests, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM). LIAISON® Control VCA IgG kit is used in conjunction with LIAISON® VCA IgG immunoassay for quality control of assay runs.
KIT DESCRIPTION: The method for qualititative determination of specific IgG to EBV viral capsid antigen (VCA) is an indirect chemiluminescence immunoassay (CLIA). All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the LIAISON® Analyzer. The principal components of the test are magnetic particles (solid phase) coated with EBV VCA p-18 synthetic peptide and a conjugate of mouse monoclonal antibody to human IgG linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, VCA IgG antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with VCA IgG antibodies that are already bound to the solid phase. After each incubation, unbound material is removed Subsequently, the starter reagents are added and a flash with a wash cycle. chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and
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is indicative of the presence of EBV VCA IgG antibodies present in calibrators, samples or controls.
## PERFORMANCE DATA:
COMPARATIVE CLINICAL TRIALS: The clinical trials were conducted at two external US laboratories and at DiaSorin. Testing was performed on repository and prospective samples as laborator below. The samples were tested by LIAISON® VCA IgG and comparison assay (DiaSorin ETI-VCA-G ELISA Kit), at the trial sites per the manufacturers' instructions for use.
Prospective Samples: Subjects Sent to the Laboratory for EBV Testing:
| | LIAISON®<br>VCA IgG | DiaSorin ETI-VCA-G | | Total |
|----------|--------------------------------|--------------------|----------|-------------------------------|
| | | Positive | Negative | |
| | Positive (≥22.0<br>U/mL) | 717 | 4 | 721 |
| | Equivocal (18.0-<br>21.9 U/mL) | 5 | 0 | 5 |
| | Negative (<18.0<br>U/mL) | 23 | 74 | 97 |
| | Total | 745 | 78 | 823 |
| | | Percent Agreement | | Exact 95% confidence interval |
| Positive | | 96.2% (717/745) | | 94.6 - 97.5% |
| Negative | | 94.9% (74/78) | | 87.4 - 98.6% |
| Overall | | 96.1% (791/823) | | 94.6 - 97.3% |
Using the results for the prospective samples in three reference assays (VCA IgG, EBNA-1 IgG and VCA IgM ELISA), the samples were grouped into serological categories. Four samples tested in the LIAISON® VCA IgG assay had insufficient volume for the entire test profile and are omitted from this analysis. The profiles and number of occurrences are presented in the following table:
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| | VCA IgG | VCA IgM | EBNA-1 IgG | Total |
|------------------|---------|---------|------------|-------|
| EBV seronegative | - | - | - | 62 |
| Acute infection | + | + | - | 29 |
| Past infection | + | - | + | 573 |
| Indeterminate | | | | |
| VCA IgG only | + | - | - | 67 |
| VCA IgM only | - | + | - | 5 |
| EBNA IgG only | - | - | + | 10 |
| Convalescent | + | + | + | 73 |
Based on these serological classifications, the LIAISON® VCA IgG results for the prospective samples were compared with those obtained with the reference assay (VCA IgG ELISA).
| | | Percent Agreement | 95% confidence interval |
|---------------------|-------|-------------------|-------------------------|
| Acute infection | 82.8% | (24/29) | 64.2 - 94.2% |
| Past infection | 98.3% | (563/573) | 96.8 - 99.2% |
| EBV<br>seronegative | 98.4% | (61/62) | 91.3 - 100.0% |
| Indeterminate | 89.7% | (139/155) | 83.8 - 94.0% |
| Overall | 96.1% | (787/819) | 94.5 - 97.3% |
Retrospective Samples: VCA IgM-positive Samples
| LIAISON®<br>VCA IgG | DiaSorin ETI-VCA-G | | |
|--------------------------------|--------------------|----------|-------|
| | Positive | Negative | Total |
| Positive (≥22.0<br>U/mL) | 70 | 0 | 70 |
| Equivocal (18.0-<br>21.9 U/mL) | 0 | 0 | 0 |
| Negative (<18.0<br>U/mL) | 0 | 0 | 0 |
| Total | 70 | 0 | 70 |
.
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| | Percent Agreement | Exact 95% confidence interval |
|----------|-------------------|-------------------------------|
| Positive | 100.0% (70/70) | 94.1 - 100.0% |
| Negative | N.C.* (0/0) | N.C.* |
| Overall | 100.0% (70/70) | 94.1 - 100.0% |
* N.C. - Not Calculated - Inadequate sample number
Using the results for the retrospective samples in three reference assays (VCA IgG, EBNA-1 IgG and VCA IgM ELISA), the samples were grouped into serological categories. The profiles and number of occurrences are presented in the following table:
| | VCA IgG | VCA IgM | EBNA-1 IgG | Total |
|------------------|---------|---------|------------|-------|
| EBV seronegative | - | - | - | 0 |
| Acute infection | + | + | - | 9 |
| Past infection | + | - | + | 0 |
| Indeterminate | | | | |
| VCA IgG only | + | - | - | 0 |
| VCA IgM only | - | + | - | 0 |
| EBNA IgG only | - | - | + | 0 |
| Convalescent | + | + | + | 61 |
Based on these serological classifications, the LIAISON® VCA IgG results for the retrospective samples were compared with those obtained with the reference assay (VCA IgG ELISA).
| | Percent Agreement | | 95% confidence interval |
|---------------------|-------------------|---------|-------------------------|
| Acute infection | 100.0% | (9/9) | 71.7 – 100.0% |
| Past infection | N/A | | N/A |
| EBV<br>seronegative | N/A | | N/A |
| Indeterminate | 100.0% | (61/61) | 95.2 – 100.0% |
| Overall | 100.0% | (70/70) | 95.8 – 100.0% |
REPRODUCIBILITY: Reproducibility studies were performed at 3 sites using a coded panel comprised of 9 frozen repository serum samples. The serum panel was prepared to represent from low- to mid-positive analyte level. The same coded panel was tested at all sites, in three replicates per run for ten runs. Results expressed in U/mL are summarized in the following table.
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| ID# | N | mean<br>(U/mL) | within<br>run<br>S.D. | within<br>run<br>%CV | between<br>run<br>S.D. | between<br>run<br>%CV | between<br>site<br>S.D. | between<br>site<br>%CV | overall<br>S.D. | overall<br>%CV |
|------|----|----------------|-----------------------|----------------------|------------------------|-----------------------|-------------------------|------------------------|-----------------|----------------|
| VGS1 | 90 | 266.6 | 9.86 | 3.68 | 23.56 | 7.23 | 12.98 | 4.87 | 25.19 | 9.45 |
| VGS2 | 90 | 52.9 | 1.89 | 3.83 | 3.75 | 5.43 | 2.81 | 5.32 | 4.35 | 8.22 |
| VGS3 | 90 | 145.5 | 7.55 | 5.78 | 11.69 | 7.41 | 4.71 | 3.23 | 15.37 | 10.56 |
| VG1 | 90 | 31.6 | 0.71 | 2.31 | 2.94 | 6.36 | 2.64 | 8.35 | 2.99 | 9.45 |
| VG2 | 90 | 52.2 | 1.09 | 2.06 | 2.88 | 5.43 | 0.97 | 1.82 | 3.07 | 5.89 |
| VG3 | 90 | 61.0 | 1.17 | 1.92 | 3.75 | 5.64 | 2.05 | 3.35 | 3.86 | 6.32 |
| VG4 | 90 | 69.2 | 1.58 | 2.31 | 4.56 | 5.38 | 3.28 | 4.74 | 4.79 | 6.92 |
| VG5 | 90 | 58.0 | 1.21 | 2.11 | 3.07 | 4.08 | 2.47 | 4.26 | 3.27 | 5.63 |
| VG6 | 90 | 49.6 | 1.23 | 2.46 | 3.05 | 5.76 | 1.46 | 2.94 | 3.25 | 6.55 |
INTERFERENCE: Controlled studies of potentially interfering substances showed that the assay performance was not affected by hemolysis (at 1000 mg/dL hemoglobin), lipemia (at 3000 mg/dL triglycerides), icterus (at 20 mg/dL bilirubin).
CROSS-REACTIVITY: The cross-reactivity studies for the LIAISON® VCA IgG assay were designed to evaluate potential interference from IgG immunoglobulins directed against closelyrelated members of the herpes virus family (HSV-1, HSV-2, VZV, CMV, HHV6), from other organisms that may cause symptoms similar to EBV (Toxoplasma gondii, rubella virus) and from other conditions that may result from atypical immune system activity (rheumatoid factor (RF)).
| Organism / condition | Number of<br>Samples | Positive<br>LIAISON® VCA<br>IgG Result |
|--------------------------|----------------------|----------------------------------------|
| CMV IgG | 16 | (1/16) |
| VZV IgG | 7 | (0/7) |
| HSV-1 IgG | 18 | (2/18) |
| HSV-2 IgG | 3 | (0/3) |
| HHV6 IgG | 3 | (0/3) |
| Toxoplasma gondii<br>IgG | 8 | (1/8) |
| Rubella virus IgG | 30 | (0/30) |
| RF | 4 | (0/4) |
| Total | 89 | (4/89) |
Four specimens out of 89 total specimens tested from the disease panel were positive. There was no conclusive evidence of interference observed, however due to the limited availability of certain samples, the possibility of cross-reactivity cannot be excluded. The user is advised to perform other EBV serology assays to confirm EBV-associated infectious mononucleosis.
WARNING: Assay interference due to circulating antibodies against HIV and Hepatitis A, Hepatitis B and Hepatitis C viruses has not been evaluated. The user is reponsible for
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establishing cross-reactivity performance with these infectious agents.
### CONCLUSION
The LIAISON® VCA IgG assay showed equivalent performance to the corresponding FDAcleared assay. The DiaSorin LIAISON® VCA IgG assay demonstrated agreement with the comparison method higher then 96% among prospectively collected samples and 100% agreement among retrospective selected samples. The results demonstrated that LIAISON® VCA IgG assay can be used with the LIAISON® Analyzer for the qualitative detection of IgG antibodies to VCA p18 synthetic peptide and can be intended for use as an aid in the clinical lahoratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM)
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Image /page/18/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized image of an eagle with its wings spread, rendered in a simple, bold line drawing.
APR 2 9 2005
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
David M. Ikeda Manager, Regulatory Affairs & Quality Systems DiaSorin Inc. 1951 Northwestern Avenue P.O. Box 285 Stillwater, MN 55082-0285
k040120 Re: -
Trade/Device Name: DiaSorin LIAISON® VCA fgG Assay DiaSorin LIAISON® VCA IgM Assay DiaSorin LIAISON® EBNA IgG Regulation Number: 21 CFR 866.3235 Regulation Name: Epstein-Barr Virus Serological Reagents Regulatory Class: Class I Product Code: LSE, LLM Dated: April 12, 2005 Received: April 14, 2005
Dear Mr. Ikeda:
We have reviewed your Section 510(k) premarket notification of intent to market the device we nave reviewed your becamed the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate for ass surfal in the May 28, 1976, the enactment date of the Medical Device Amendments, or to conniner of Prier to May 2011 11:12 provisions of the Federal Food, Drug, de necs may been routed on t require approval of a premarket approval application (PMA). and Cosmeter For (110) rast the device, subject to the general controls provisions of the Act. The r ou may, dierer exercy mains of the Act include requirements for annual registration, listing of general controls provisions practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device it may be subject to back adde of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean I least of advised that I Drivisation that your device complies with other requirements of the Act that I DA has made a acterimaliations administered by other Federal agencies. You must or any it cacal statutes and regaranents, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice erequirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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Page 2 -
This letter will allow you to begin marketing your device as described in your Section 510(k) I his letter wrif anow you to ought manisang of substantial equivalence of your device to a legally premarket notification: "The sults in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, If you desire specific information and advertising of your device, please contact the Office of In or questions on the promotion and Safety at (240)276-0484. Also, please note the Pill o Duelloode Down Berence to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the rou may oount outer generers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html
Sincerely yours,
Sale, a Forg
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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## Indications for Use
510(k) Number (if known): K040120
LIAISON® VCA IgG Device Name:
The LIAISON® VCA IgG assay uses chemiluminescent Indications For Use: immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of IgG antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p-18 synthetic peptide in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM).
Prescription Use × (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Sagasta
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510(k)________________________________________________________________________________________________________________________________________________________________________
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## Indications for Use
## 510(k) Number (if known): K040120
LIAISON® EBV IgM Device Name:
Indications For Use:
The LIAISON® EBV IgM assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of IgM antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA) p-18 synthetic peptide in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM).
Prescription Use × (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use __ (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Nalez a Mons
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Ko40120 510(k) ___
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# Indications for Use
510(k) Number (if known): K040120
LIAISON® EBNA IgG Device Name:
The LIAISON® EBNA IgG assay uses chemiluminescent Indications For Use: immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of IgG antibodies to Epstein-Barr virus (EBV) nuclear antigen synthetic peptide (EBNA-1) in human serum. When performed in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM).
Prescription Use × (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
```
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510(k)________________________________________________________________________________________________________________________________________________________________________
