(272 days)
The ADVIA Centaur EBV-VCA IgM (EBVM) assay is for in vitro diagnostic use in the qualitative detection of lgM antibodies to the viral capsid antigen (VCA) of the Epstein-Barr virus (EBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.
The ADVIA Centaur EBV-VCA IgM assay is a fully automated 2-step sandwich immunoassay using acridinium ester chemiluminescent technology. The specimen is incubated with the Ancillary Well Reagent and the Solid Phase, which contains an EBV-VCA IgM specific antigen. Antigen-antibody complexes will form if anti EBV-VCA IgM antibody is present in the specimen. The Lite Reagent contains monoclonal anti-human IgM labeled with acridinium ester and is used to detect EBV-VCA IgM in the specimen.
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:
Device: ADVIA Centaur EBV-VCA IgM
1. Table of Acceptance Criteria and Reported Device Performance:
The document implicitly defines acceptance criteria through the reported performance metrics. For a diagnostic device intended to aid in the diagnosis of infection, common acceptance criteria would include achieving certain levels of Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a reference method, especially in relevant clinical populations (e.g., primary acute infection). Precision and reproducibility are also key acceptance criteria for laboratory assays.
| Acceptance Criteria Category | Specific Metric (Implicit) | Acceptance Range (Implicit based on predicate or general expectations for diagnostic assays) | Reported Device Performance |
|---|---|---|---|
| Clinical Performance (Overall Population) | NPA (Negative Percent Agreement) | High agreement with reference assay for negative samples (e.g., >95%) | 96.7% (95% CI: 95.6% - 97.5%) |
| PPA (Positive Percent Agreement) | Good agreement with reference assay for positive samples (e.g., >60-70%) | 68.9% (95% CI: 58.7% - 77.5%) | |
| Clinical Performance (Primary Acute Infection) | PPA (Positive Percent Agreement) | High agreement in acute cases (e.g., >90%) | 90.6% (95% CI: 79.7% - 95.9%) |
| Clinical Performance (Pediatric Population) | NPA (Negative Percent Agreement) | High agreement for negative pediatric samples | 95.3% (95% CI: 92.8% - 96.9%) |
| PPA (Positive Percent Agreement) | Good agreement for positive pediatric samples | 84.2% (95% CI: 72.6% - 91.5%) | |
| Clinical Performance (Pediatric Primary Acute Infection) | PPA (Positive Percent Agreement) | High agreement in acute pediatric cases | 91.3% (95% CI: 79.7% - 96.6%) |
| Analytical Precision (Total Precision) | CV (Coefficient of Variation) | Typically <10-15% for quantitative assays. For qualitative, generally assessed by consistency. | Ranged from 7.0% to 11.6% for serum, and 7.7% to 10.2% for plasma samples at various index levels. Specific controls had N/A CVs. |
| Analytical Reproducibility | CV (Coefficient of Variation) | Typically <10-15% overall. Acceptable up to 20% for >0.80 Index. | Ranged from 3.4% to 4.7% for serum, and 3.7% to 4.9% for plasma samples. Control 2 showed 9.3% CV. |
| Specimen Equivalency (Correlation Coefficient) | Correlation coefficient (r) | Close to 1.00 for equivalent matrices | 1.00 for EDTA plasma vs. serum, and 1.00 for lithium heparin plasma vs. serum. |
| Interference | Bias | Reactive samples: ±10% bias. Nonreactive samples: ±0.10 Index. | Substances tested were found not to interfere within specified limits. |
| Cross-reactivity | Low reactivity in presence of other infections/conditions | Minimal false positives | Out of 371 samples with other conditions, 348 were nonreactive (93.8%), and 23 were reactive (6.2%). The comparative assay found 353 nonreactive (95.1%) and 16 reactive (4.3%). This suggests generally low cross-reactivity, with some instances where both the new device and the comparative assay show reactivity. |
| Stability (Onboard Reagent) | Duration (days) | A specified period for practical use | 28 days |
| Stability (Onboard Calibrators) | Duration (hours) | A specified short period | 8 hours |
| Stability (Opened Vial Calibrators) | Duration (days) | A specified period for practical use | 60 days (at 2-8°C) |
2. Sample Size and Data Provenance:
- Clinical Study Test Set:
- Total Study Population: 1428 leftover samples (Population 1) + 202 samples with known EBV VCA IgM positive result (Population 2). Total = 1630 samples.
- Population 1: Collected over a contiguous time period from individuals for whom an EBV test was ordered.
- Population 2: Samples with a known EBV VCA IgM positive result.
- Pediatric Population: 479 samples (from Population 1) + 155 samples (from Population 2). Total = 634 samples.
- Data Provenance: The document states "leftover samples were collected over a contiguous time period" and "multisite clinical study," suggesting diverse geographical sources and a real-world setting. It does not explicitly state country of origin but implies a clinical laboratory setting. The samples are retrospective (leftover samples).
- Total Study Population: 1428 leftover samples (Population 1) + 202 samples with known EBV VCA IgM positive result (Population 2). Total = 1630 samples.
3. Number of Experts and Qualifications for Ground Truth:
- This information is not explicitly provided in the document. The comparison is made against an "FDA-cleared EBV VCA IgM reference assay."
- For equivocal reference assay results, the ground truth was "resolved by 2 other comparative assays." This implies an algorithmic or rule-based resolution rather than human expert consensus for these specific cases.
4. Adjudication Method for the Test Set:
- The document states: "Equivocal reference assay results were resolved by 2 other comparative assays." This indicates a form of algorithmic or rule-based adjudication rather than a human expert consensus method (like 2+1 or 3+1). If the two additional comparative assays agreed, that would constitute a form of resolution. If they disagreed, the method for final resolution is not detailed.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay, not an imaging device or a device requiring human interpretation as part of its primary function where reader performance would be a direct outcome. The performance is assessed by comparing the assay's output to a reference method, not by how human readers improve with or without AI assistance.
6. Standalone (Algorithm Only) Performance:
- Yes, a standalone performance study was done. The entire clinical and analytical performance evaluation describes the ADVIA Centaur EBV-VCA IgM assay's performance independently (as an algorithm/assay) against a reference standard or for its inherent analytical characteristics (precision, reproducibility). There is no "human-in-the-loop" component described for the assay's function itself; it is an automated immunoassay.
7. Type of Ground Truth Used:
- The primary ground truth was established by an "FDA-cleared EBV VCA IgM reference assay."
- For cases where the reference assay was equivocal, "2 other comparative assays" were used for resolution.
- For defining "primary acute infection," the presence of "either EBV IgM or heterophile antibodies, and the absence of EBNA IgG" was used – this relies on a combination of other serological markers/tests.
8. Sample Size for the Training Set:
- The document does not provide information on the training set for the ADVIA Centaur EBV-VCA IgM assay. As a chemical immunoassay, its "training" involves the development and optimization of its chemical components, reagents, and detection parameters, using internal development studies that are typically not detailed as "training sets" in the same way as machine learning models. The reported studies are for validation/testing.
9. How the Ground Truth for the Training Set Was Established:
- As the document does not mention a "training set" in the context of machine learning, this question is not applicable/not addressed by the provided text. The development process for such an immunoassay typically involves extensive R&D, analytical characterization, and optimization using well-characterized samples, but this is distinct from establishing ground truth for a machine learning training dataset.
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August 07, 2024
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Biokit S.A. Dominique Monferrer Regulatory Affairs Director Av. Can Montcau 7 Llicà d'Amunt. 08186 Spain
Re: K233606
Trade/Device Name: ADVIA Centaur EBV-VCA IgM Regulation Number: 21 CFR 866.3235 Regulation Name: Epstein-Barr Virus Serological Reagents Regulatory Class: Class I, reserved Product Code: LSE Dated: July 29, 2024 Received: July 29, 2024
Dear Dominique Monferrer:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
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Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Bhawna Poonia -S
for Maria Garcia, Ph.D. Assistant Director Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
Submission Number (if known)
Device Name
ADVIA Centaur EBV-VCA IgM (10720837)
| Indications for Use (Describe) | |
|---|---|
| -------------------------------- | -- |
The ADVIA Centaur EBV-VCA IgM (EBVM) assay is for in vitro diagnostic use in the qualitative detection of lgM antibodies to the viral capsid antigen (VCA) of the Epstein-Barr virus (EBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis.
Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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510(k) SUMMARY
This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and 21 CFR 807.92.
| 1. Submitter's Information | Biokit, S.A.Av. Can Montcau, 7Lliçà d'Amunt 08186Barcelona (Spain) |
|---|---|
| ---------------------------- | -------------------------------------------------------------------------------- |
| 2. Contact Person | Dominique Monferrer, Regulatory Affairs DirectorPhone: +34 93 860 90 00Email: dmonferrer@werfen.com |
|---|---|
| ------------------- | ------------------------------------------------------------------------------------------------------------- |
| 3. Preparation Date | 2023-Nov-09 |
|---|---|
| --------------------- | ------------- |
| 4. Device TradeName | ADVIA Centaur EBV-VCA IgM |
|---|---|
| -------------------------- | --------------------------- |
| 5. RegulatoryInformation | Regulation Number | 21 CFR 866.3235 |
|---|---|---|
| Regulation Description | Epstein-Barr Virusserological reagents | |
| Classification | Class I (generalcontrols) | |
| Product Code | LSE | |
| Classification Panel | Microbiology |
| 6. Predicate Device | K040120 (LIAISON EBV IgM) |
|---|---|
| --------------------- | --------------------------- |
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| 7. Indications forUse / IntendedUse | The ADVIA Centaur EBV-VCA IgM (EBVM) assayis for in vitro diagnostic use in the qualitativedetection of IgM antibodies to the viral capsidantigen (VCA) of the Epstein-Barr virus (EBV) inhuman pediatric (2-21 years old) and adultserum and plasma (EDTA and lithium heparin)using the ADVIA Centaur XP system. When usedin conjunction with other EBV markers, this assayis intended for use as an aid in the diagnosis ofEpstein-Barr virus infection, such as infectiousmononucleosis. |
|---|---|
| --------------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
| 8. Principles of theprocedure | The ADVIA Centaur EBV-VCA IgM assay is a fullyautomated 2-step sandwich immunoassay usingacridinium ester chemiluminescent technology.The specimen is incubated with the Ancillary WellReagent and the Solid Phase, which contains anEBV-VCA IgM specific antigen. Antigen-antibodycomplexes will form if anti EBV-VCA IgM antibodyis present in the specimen. The Lite Reagentcontains monoclonal anti-human IgM labeled withacridinium ester and is used to detect EBV-VCAIgM in the specimen. |
|---|---|
| ----------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ |
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| COMPARISON PREDICATE | ||
|---|---|---|
| Item | Predicate | New Device |
| Trade Names | LIAISON EBV IgM | ADVIA Centaur EBV-VCA IgM |
| 510K no. | K040120 | K233606 |
| Manufacturer | DiaSorin, S.p.A.Via Crescentino, snc13040 Saluggia (Vercelli) Italy | Siemens HealthcareDiagnostics Inc.511 Benedict Avenue,Tarrytown, NY 10591 USA |
| Intended use | The LIAISON EBV IgM assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON Analyzer family* 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.*(LIAISON and LIAISON XL) | The ADVIA Centaur EBV-VCA IgM (EBVM) assay is for in vitro diagnostic use in the qualitative detection of IgM antibodies to the viral capsid antigen (VCA) of the Epstein-Barr virus (EBV) in human pediatric (2-21 years old) and adult serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP system. When used in conjunction with other EBV markers, this assay is intended for use as an aid in the diagnosis of Epstein-Barr virus infection, such as infectious mononucleosis. |
| Similarities | ||
| Measurand | Epstein Barr Virus IgM to Viral Capsid Antigen | To detect IgM antibodies to the viral capsid antigen (VCA) of Epstein Barr virus (EBV). |
| Regulation Section | 21 CFR 866.3235 | Same |
| Product Code | LLM, LSE | LSE |
| Classification | Class I (general controls) | Same |
| Assay Type | Qualitative | Same |
| Technology | Chemiluminescentimmunoassay (CLIA) | Same |
| Antigen | p18 | Same |
| Differences | ||
| Sample type | Human serum | Human serum and plasma(EDTA and lithium heparin) |
| TargetPopulation | Adults | Pediatric and adult |
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9. Performance Summary
Clinical Study
A multisite clinical study to compare the reference method with ADVIA Centaur EBV-VCA IgM was performed.
Comparison of Results: Total Study Population
A total of 1428 leftover samples were collected over a contiguous time period from individuals for whom an EBV test was ordered (population 1). Of these, 188 were from unclassified serostatus individuals. Two hundred and two (202) samples with a known EBV VCA IgM positive result (population 2) were evaluated as well. Of these, 4 were from unclassified serostatus individuals. The study results otherwise showed that these populations included individuals with acute infection, past infection, or no serologic evidence of EBV infection.
Samples were tested using the ADVIA Centaur EBVM assay and an FDA-cleared EBV VCA IgM reference assay. Equivocal reference assay results were resolved by 2 other comparative assays. The results obtained are presented in the following tables:
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| Population 1 | ||||
|---|---|---|---|---|
| ADVIA CentaurEBVM Assay | Reference Assay | |||
| Negative | Equivocal | Positive | Total | |
| Nonreactive | 1294 | 2 | 26 | 1322 |
| Reactive | 41 | 3 | 62 | 106 |
| Total | 1335 | 5 | 88 | 1428 |
| NPAa=96.7% | PPAc=68.9% | |||
| (1294/1338) | (62/90) | |||
| 95% CIb: 95.6% - | 95% CI: 58.7% - | |||
| 97.5% | 77.5% |
a Negative percent agreement.
b Confidence interval.
് Positive percent agreement.
Out of 90 samples that were positive on the reference assay, 53 were primary acute, and of those, 48 samples were positive on the ADVIA Centaur EBVM assay.
% Positive Agreement for primary acute patients = 90.6 % (48 / 53) 95% Confidence Interval = 79.7 % - 95.9 %
In this study, primary acute infection was defined by the presence of either EBV IgM or heterophile antibodies, and the absence of EBNA IgG.
| Population 2 | ||||
|---|---|---|---|---|
| ADVIA CentaurEBM Assay | Negative | Equivocal | Positive | Total |
| Nonreactive | 0 | 0 | 0 | 0 |
| Reactive | 0 | 0 | 202 | 202 |
| Total | 0 | 0 | 202 | 202 |
| N/Aa | PPAb=100% (202/202)95% CIc: 98.1% - 100% |
a Not applicable.
ե Positive percent agreement.
Confidence interval.
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Percent of Agreement: Pediatric Population
The agreement between the ADVIA Centaur EBVM assay and the reference EBV VCA IgM assay in the pediatric subjects from Population 1 and 2 is presented in the tables below.
Population 1 included samples from subjects with signs and symptoms for whom an EBV antibody test was ordered. Of these, 84 were from unclassified serostatus individuals. The study results otherwise showed that this population included individuals with acute, past, or no serologic evidence of EBV infection. Population 2 included samples with a known EBV VCA IgM positive result to supplement numbers for positive EBV VCA IqM. Of these, 3 were from unclassified serostatus individuals.
| Population 1 | ||||
|---|---|---|---|---|
| ADVIA CentaurEBVM Assay | Reference AssayNegative | Equivocal | Positive | Total |
| Nonreactive | 402 | 0 | 9 | 411 |
| Reactive | 19 | 1 | 48 | 68 |
| Total | 421 | 1 | 57 | 479 |
| NPAa=95.3%(402/422)95% CIb: 92.8% -96.9% | PPAc=84.2%(48/57)95% CI: 72.6% -91.5% |
a Negative percent agreement.
b Confidence interval.
C Positive percent agreement.
Out of 57 pediatric subject samples that were positive on the reference assay, 46 were primary acute, and of those, 42 samples were positive on the ADVIA Centaur EBVM assay.
% Positive Agreement for primary acute patients = 91.3 % (42 / 46) 95% Confidence Interval = 79.7 % - 96.6 %
In this study, primary acute infection was defined by the presence of either EBV IgM or heterophile antibodies, and the absence of EBNA IqG.
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| Population 2 | ||||
|---|---|---|---|---|
| ADVIA CentaurEBVM Assay | Reference Assay | |||
| Negative | Equivocal | Positive | Total | |
| Nonreactive | 0 | 0 | 0 | 0 |
| Reactive | 0 | 0 | 155 | 155 |
| Total | 0 | 0 | 155 | 155 |
| N/Aa | PPAb=100% (155/155)95% CIc: 97.6% - 100% |
a Not applicable.
b Positive percent agreement.
Confidence interval.
Precision
Precision was determined in accordance with CLSI EP05-A3 using the Negative and Positive Controls as well as 5 serum samples and 5 EDTA plasma samples prepared at different levels across the assay range. Samples (N=240) were assayed in replicates of 2 with 2 runs per day using three reagent lots in a 20day protocol.
| Sample | MeanValue(Index) | Repeatability | Between Run | Between Day | Between Lot | TotalPrecision | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SDb(Index) | CVc(%) | SD(Index) | CV(%) | SD(Index) | CV(%) | SD(Index) | CV(%) | SD(Index) | CV(%) | ||
| SerumA | 0.75 | 0.019 | 2.5 | 0.018 | 2.4 | 0.017 | 2.3 | 0.081 | 10.9 | 0.087 | 11.6 |
| SerumB | 0.96 | 0.024 | 2.5 | 0.023 | 2.4 | 0.023 | 2.4 | 0.076 | 8.0 | 0.086 | 9.0 |
| SerumC | 1.39 | 0.034 | 2.4 | 0.030 | 2.2 | 0.041 | 2.9 | 0.119 | 8.5 | 0.133 | 9.6 |
| SerumD | 3.16 | 0.075 | 2.4 | 0.053 | 1.7 | 0.101 | 3.2 | 0.173 | 5.5 | 0.221 | 7.0 |
| SerumE | 7.22 | 0.217 | 3.0 | 0.140 | 1.9 | 0.269 | 3.7 | 0.531 | 7.4 | 0.649 | 9.0 |
| Plasma,EDTA A | 0.74 | 0.019 | 2.6 | 0.026 | 3.4 | 0.023 | 3.0 | 0.048 | 6.4 | 0.062 | 8.3 |
| Plasma,EDTA B | 1.00 | 0.022 | 2.2 | 0.031 | 3.1 | 0.027 | 2.7 | 0.061 | 6.1 | 0.077 | 7.7 |
The following results are representative of the performance of the assay:
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| Sample | MeanValue(Index) | Repeatability | Between Run | Between Day | Between Lot | TotalPrecision | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SDb(Index) | CVc(%) | SD(Index) | CV(%) | SD(Index) | CV(%) | SD(Index) | CV(%) | SD(Index) | CV(%) | ||
| Plasma,EDTA C | 1.40 | 0.029 | 2.1 | 0.045 | 3.2 | 0.041 | 2.9 | 0.118 | 8.4 | 0.136 | 9.7 |
| Plasma,EDTA D | 3.35 | 0.081 | 2.4 | 0.062 | 1.8 | 0.111 | 3.3 | 0.308 | 9.2 | 0.342 | 10.2 |
| Plasma,EDTA E | 7.63 | 0.218 | 2.9 | 0.367 | 4.8 | 0.320 | 4.2 | 0.466 | 6.1 | 0.709 | 9.3 |
| Control1 | 0.28 | 0.012 | N/Ac | 0.014 | N/A | 0.010 | N/A | 0.011 | N/A | 0.024 | N/A |
| Control2 | 3.02 | 0.071 | 2.3 | 0.049 | 1.6 | 0.088 | 2.9 | 0.214 | 7.1 | 0.247 | 8.2 |
a Standard deviation.
b Coefficient of variation.
ς Not applicable.
Reproducibility
Reproducibility was determined in accordance with CLSI EP05-A3. Testing was performed using 3 external sites and 1 reagent lot. A 4-member serum panel and a 4-member plasma EDTA panel were assayed in replicates of 3 with 2 runs per day, over 5 days (N = 90 for each sample).
| Sample | Na | Mean(Index) | Within-RunRepeatability | Between-Runs | Between-Days | Between-Sites | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SDb | CVc (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | |||
| Serum A | 90 | 0.85 | 0.023 | 2.7 | 0.028 | 3.3 | 0.004 | 0.5 | 0.017 | 2.0 | 0.040 | 4.7 |
| Serum B | 90 | 1.00 | 0.024 | 2.4 | 0.020 | 2.1 | 0.008 | 0.8 | 0.011 | 1.1 | 0.034 | 3.5 |
| Serum C | 90 | 1.57 | 0.038 | 2.4 | 0.022 | 1.4 | 0.014 | 0.9 | 0.028 | 1.8 | 0.054 | 3.4 |
| Serum D | 90 | 3.30 | 0.099 | 3.0 | 0.025 | 0.8 | 0.009 | 0.3 | 0.081 | 2.5 | 0.131 | 4.0 |
| Plasma,EDTA A | 90 | 0.75 | 0.023 | N/A | 0.026 | N/A | 0.000 | N/A | 0.013 | N/A | 0.037 | N/A |
| Plasma,EDTA B | 90 | 1.00 | 0.035 | 3.5 | 0.023 | 2.3 | 0.000 | 0.0 | 0.009 | 0.9 | 0.043 | 4.3 |
| Plasma,EDTA C | 90 | 1.49 | 0.036 | 2.4 | 0.038 | 2.5 | 0.000 | 0.0 | 0.016 | 1.1 | 0.055 | 3.7 |
| Plasma,EDTA D | 90 | 3.72 | 0.103 | 2.8 | 0.088 | 2.4 | 0.054 | 1.4 | 0.106 | 2.8 | 0.180 | 4.9 |
| Control 1 | 90 | 0.24 | 0.012 | N/A | 0.004 | N/A | 0.006 | N/A | 0.009 | N/A | 0.017 | N/A |
| Control 2 | 90 | 3.20 | 0.248 | 7.8 | 0.000 | 0.0 | 0.075 | 2.3 | 0.145 | 4.5 | 0.297 | 9.3 |
a Number of measurements
b Standard deviation
Coefficient of variation
d Not Applicable
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The assay was designed to have the following reproducibility when using a 5day protocol in accordance with CLSI Document EP05-A3:
| Concentration Interval | Reproducibility |
|---|---|
| $≤$ 0.80 Index | N/Aa |
| > 0.80 Index | $≤$ 20% CV |
ª Not applicable.
Specimen Equivalency
The specimen equivalency study was determined with the weighted Deming regression model using the ADVIA Centaur XP in accordance with CLSI document EP09c-ed3.
This study was performed using 70 sets of matched samples of three matrixes (serum separator tube (SST), EDTA plasma and lithium heparin plasma) from commercial sources.
Samples were analyzed in one replicate in randomized order using one reagent lot.
| Tube (y) vs. Serum (x) | Regression Equation | Sample Interval | Na | rb |
|---|---|---|---|---|
| Plasma, EDTA | $y=1.00x-0.03 Index$ | 0.12-12.35 Index | 70 | 1.00 |
| Plasma, lithium heparin | $y=1.00x-0.05 Index$ | 0.10-11.49 Index | 70 | 1.00 |
a Number of samples tested.
b Correlation coefficient.
The results support that EDTA Plasma and Lithium Heparin Plasma are equivalent matrixes to Serum.
Interferences
Potential interference was evaluated using the ADVIA Centaur XP system in accordance with guidance from the CLSI documents EP07-ed3 and EP-37-ed1.
Three matrixes (serum, EDTA plasma and lithium heparin plasma) have been analyzed in this study. For each sample (nonreactive, low reactive and high reactive) and each interfering substance to test, two samples (Control and Test) were analyzed.
The acceptable difference with respect to the value reported for Control sample from the compounds listed below is ±10 % bias for reactive samples and ±0.10 Index for nonreactive samples.
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The following substances do not interfere with the assay in the different matrixes at the concentrations indicated below:
| Substance | Substance Test Concentration |
|---|---|
| Hemoglobin | 1000 mg/dL |
| Bilirubin, conjugated | 40 mg/dL |
| Bilirubin, unconjugated | 40 mg/dL |
| Lipemia (Intralipid) | 1500 mg/dL |
| Biotin | 3510 ng/mL |
| Cholesterol | 502 mg/dL |
| Protein (hyperproteinemic) | 15 g/dL |
| Protein (hypoproteinemic) | 3 g/dL |
Cross-reactivity
The ADVIA Centaur EBVM assay was evaluated for potential cross-reactivity with other viral antibodies and disease state specimens using the ADVIA Centaur system.
A total of 371 samples were analyzed with ADVIA Centaur EBV-VCA IgM on the ADVIA Centaur XP system and with an EBV VCA IgM comparative assay.
The data are summarized in the following table.
| Clinical Category | NumberTested | ADVIA Centaur EBV-VCA IgM Assay Results | Comparative EBV-VCA IgMAssay Results | |||
|---|---|---|---|---|---|---|
| Nonreactive | Reactive | Negative | Equivocal | Positive | ||
| Cytomegalovirus (CMV)IgG | 10 | 10 | 0 | 10 | 0 | 0 |
| Cytomegalovirus (CMV)IgM | 10 | 7 | 3 | 7 | 0 | 3 |
| Parvovirus B19 IgM | 10 | 10 | 0 | 9 | 0 | 1 |
| Toxoplasma gondii IgG | 10 | 10 | 0 | 10 | 0 | 0 |
| Toxoplasma gondii IgM | 28 | 22 | 6 | 24 | 0 | 4 |
| Rubella IgG | 20 | 18 | 2 | 19 | 1 | 0 |
| Rubella IgM | 11 | 11 | 0 | 10 | 1 | 0 |
| Hepatitis B Virus (HBV)IgM | 11 | 11 | 0 | 11 | 0 | 0 |
| Clinical Category | Number Tested | ADVIA Centaur EBV-VCA IgM Assay Results | Comparative EBV-VCA IgM Assay Results | |||
| Hepatitis A Virus (HAV) IgM | 10 | 7 | 3 | 8 | 0 | 2 |
| Hepatitis C Virus (HCV) | 11 | 11 | 0 | 10 | 0 | 1 |
| Human Immunodeficiency Virus (HIV) | 10 | 9 | 1 | 9 | 0 | 1 |
| Herpes Simplex Virus (HSV-1) IgG | 11 | 11 | 0 | 11 | 0 | 0 |
| Herpes Simplex Virus (HSV-1) IgM | 10 | 10 | 0 | 10 | 0 | 0 |
| Herpes Simplex Virus (HSV-2) IgG | 12 | 12 | 0 | 12 | 0 | 0 |
| Herpes Simplex Virus (HSV-2) IgM | 11 | 9 | 2 | 10 | 0 | 1 |
| Treponema pallidum (Syphilis) | 11 | 11 | 0 | 11 | 0 | 0 |
| Varicella Zoster Virus (VZV) IgM | 10 | 9 | 1 | 10 | 0 | 0 |
| Measles virus IgM | 10 | 10 | 0 | 10 | 0 | 0 |
| Mumps virus IgM | 10 | 10 | 0 | 10 | 0 | 0 |
| Borrelia burgdorferi IgM (Lyme IgM) | 11 | 11 | 0 | 11 | 0 | 0 |
| Influenza virus IgM | 10 | 10 | 0 | 10 | 0 | 0 |
| Mycoplasma pneumoniae IgM | 18 | 15 | 3 | 16 | 0 | 2 |
| Antinuclear antibodies (ANA) | 10 | 10 | 0 | 10 | 0 | 0 |
| Rheumatic Factors (RF) | 11 | 10 | 1 | 11 | 0 | 0 |
| Human Anti-mouse antibodies (HAMA) | 10 | 10 | 0 | 10 | 0 | 0 |
| Human Herpes Virus (HHV6) | 14 | 14 | 0 | 14 | 0 | 0 |
| Systemic Lupus Erythematosus (SLE) | 10 | 10 | 0 | 10 | 0 | 0 |
| Flu vaccinated patients | 10 | 10 | 0 | 10 | 0 | 0 |
| Elevated IgG | 10 | 10 | 0 | 10 | 0 | 0 |
| Elevated IgM | 11 | 11 | 0 | 11 | 0 | 0 |
| Epstein Barr Virus (EBV) Viral Capsid Antigen (VCA) IgG | 10 | 10 | 0 | 10 | 0 | 0 |
| Epstein Barr Virus (EBV) Epstein-Barr Nuclear Antigen (EBNA) IgG | 10 | 9 | 1 | 9 | 0 | 1 |
| Total | 371 | 348 | 23 | 353 | 2 | 16 |
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10. Stability
The onboard stability of the ADVIA Centaur EBV-VCA IqM reagent is 28 days with a calibration interval of 28 days. The onboard stability of the ADVIA Centaur EBV-VCA IgM Calibrators is 8 hours. The opened vial stability of the ADVIA Centaur EBV-VCA IgM Calibrators is 60 days when stored at 2-8°C. Unopened reagents and calibrators are stable until the expiration date printed on the box label when stored at 2-8°C.
11. Conclusion
The analytical and clinical study results demonstrate that the ADVIA Centaur EBV-VCA IgM is substantially equivalent to the predicate device, LIAISON EBV IgM (FDA cleared under K040120).
§ 866.3235 Epstein-Barr virus serological reagents.
(a)
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).(b)
Classification. Class I (general controls).