(94 days)
The ADVIA Centaur® Herpes-2 IgG (HSV2) assay is for in vitro diagnostic use in the qualitative determination of IgG antibodies to herpes simplex virus type 2 (HSV-2) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur systems. The test is indicated for testing sexually active adults or expectant mothers for aiding in the presumptive diagnosis of HSV infection. The predictive value of a positive or negative result depends on the prevalence of HSV-2 infection in the population and the pre-test likelihood of HSV-2 infection.
The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for immunocompromised patients, pediatric patients or matrices other than human serum and plasma (EDTA and lithium heparin).
The ADVIA Centaur Herpes-2 IgG (HSV2) assay is a fully automated two-step sandwich immunoassay using indirect chemiluminometric technology. The specimen is incubated with the Solid Phase, which contains HSV-2-specific recombinant-gG2 antigen. Antigen-antibody complexes will form if anti-HSV-2 antibody is present in the specimen. The Lite Reagent contains monoclonal anti-human IgG labeled with acridinium ester, and is used to detect HSV-2 IgG in the specimen.
The provided document describes the performance of the ADVIA Centaur Herpes-2 IgG (HSV2) assay, which is an in vitro diagnostic device. The study aims to demonstrate that the device meets acceptance criteria for substantial equivalence to a predicate device.
Here's a breakdown of the requested information based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document presents performance characteristics and compares them against design requirements or expected outcomes.
| Acceptance Criteria / Design Requirement | Reported Device Performance (ADVIA Centaur Herpes-2 IgG) |
|---|---|
| Precision | |
| Repeatability (%CV) | |
| < 0.5 Index: NA | Negative Control (Plasma): NA |
| 0.51-0.79 Index: ≤ 10.0% | Plasma 2 (0.63 Index): 2.4% |
| 0.80–1.20 Index: ≤ 6.0% | Serum 3 (1.08 Index): 4.3% |
| 1.21-3.00 Index: ≤ 5.0% | Positive Control (Plasma) (3.09 Index): 2.3%; Serum 4 (2.58 Index): 3.6% |
| 3.01-6.00 Index: ≤ 5.0% | Serum 5 (5.29 Index): 1.7% |
| > 6.00 Index: ≤ 5.0% | Serum 6 (7.62 Index): 2.2% |
| Within-Lab Precision (%CV) | |
| < 0.5 Index: NA | Negative Control (Plasma): NA |
| 0.51-0.79 Index: ≤ 15.0% | Plasma 2 (0.63 Index): 5.9% |
| 0.80–1.20 Index: ≤ 8.0% | Serum 3 (1.08 Index): 7.2% |
| 1.21-3.00 Index: ≤ 8.0% | Positive Control (Plasma) (3.09 Index): 6.5%; Serum 4 (2.58 Index): 7.6% |
| 3.01-6.00 Index: ≤ 7.0% | Serum 5 (5.29 Index): 6.4% |
| > 6.00 Index: ≤ 7.0% | Serum 6 (7.62 Index): 6.1% |
| Multi-site Reproducibility (%CV) | |
| ≥ 0.80 Index: ≤ 15% | Positive Control (3.27 Index): 3.2%; Serum 3 (1.07 Index): 5.2%; Serum 4 (2.47 Index): 7.0%; Serum 5 (5.24 Index): 8.2%; Serum 6 (7.87 Index): 4.6% |
| Sample Matrix Equivalence | Demonstrated equivalence for Serum Separator Tube, EDTA Plasma, and Lithium Heparin Plasma compared to Serum via Deming regression (r values ≥ 0.997). |
| Panel Testing (% Agreement) | |
| ToRCH-mixed Zeptometrix panel: 100% agreement expected with reference assay 1 | 100% total agreement observed with reference assay 1 |
| CDC panel: 100% agreement expected with CDC results | 100% total agreement observed with results provided by the CDC |
| Interferences (≤ 10% change) | Confirmed ≤ 10% change in results for listed interferents up to specified concentrations (e.g., Biotin: 3500 ng/mL, Hemoglobin: 500 mg/dL). |
| Cross-Reactivity (% Total Agreement) | 96.9% for various clinical categories with Comparative Assay/Western Blot. |
| Clinical Performance (Overall) | |
| Sensitivity (vs Comparative Assay/WB) | 95.3% (245/257) with 95% CI: 92.0%-97.3% |
| Specificity (vs Comparative Assay/WB) | 98.5% (598/607) with 95% CI: 97.2%-99.2% |
| Clinical Performance (Pregnant Women) | |
| Sensitivity (vs Comparative Assay/WB) | 100.0% (34/34) with 95% CI: 89.9%-100.0% |
| Specificity (vs Comparative Assay/WB) | 98.3% (236/240) with 95% CI: 95.8%-99.4% |
| Reagents Stability | Onboard stability: 60 days; Calibration interval: 28 days; Opened vial calibrator stability: 65 days; Unopened: until box label date. |
2. Sample Size and Data Provenance
- Precision Study: 6 samples and Negative/Positive Controls. Each material tested in duplicate, twice a day for 20 days.
- N = 80 replicates per level for within-lab precision.
- Sample Matrix Study: 68 sets of matched samples (serum, serum separator tube, EDTA plasma, lithium heparin plasma).
- Panel Testing:
- ToRCH-mixed Zeptometrix panel: 24 characterized HSV samples.
- CDC panel: 100 blind characterized HSV samples.
- Cross-Reactivity Study: 522 specimens across various clinical categories.
- Multi-site Reproducibility: 6 samples and Negative/Positive Controls.
- N = 90 replicates per level (from 3 external sites, 5 days, 2 runs/day, 3 replicates/run).
- Clinical Study:
- Total: 864 specimens (≥ 18 years of age), including 274 pregnant women.
- Data Provenance: Specimens collected within the United States. The study was conducted at 3 independent external laboratories. The nature of the specimen collection implies it was prospective for the purpose of this study, although the individual samples may have been sourced retrospectively from biobanks or collected prospectively for the study itself. The document does not explicitly state "retrospective" or "prospective" for the clinical sample collection, but "collected within the United States" and tested at external labs suggests purpose-collected samples for the study.
3. Number of Experts and Qualifications for Ground Truth
- The document implies the use of "reference assay 1" for the ToRCH-mixed Zeptometrix panel and "results provided by the CDC" for the CDC panel, as well as a "Comparative Assay" and "validated Western Blot reference confirmatory test (University of Washington, Seattle)" for the clinical study and cross-reactivity assessment.
- Number of Experts: Not explicitly stated how many individual experts established the ground truth for these reference methods. The description refers to "characterized HSV samples" for panels and "validated Western Blot" from a university, which implies expert consensus or highly standardized laboratory procedures.
- Qualifications of Experts: Not explicitly stated (e.g., "radiologist with 10 years of experience" is not applicable here as it's an in vitro diagnostic test for antibodies). However, the use of "validated Western Blot" from a reputable institution (University of Washington, Seattle) and "CDC" as sources for ground truth implies the highest level of expertise and validated methodologies in serological testing.
4. Adjudication Method for the Test Set
- For the clinical study: Of the 864 specimens, 22 were equivocal with the Comparative Assay. These 22 samples were resolved by Western Blot testing. 20 were resolved to be negative, and 2 remained equivocal. This describes a form of adjudication where an equivocal result from one reference method is adjudicated by a more definitive reference method (Western Blot).
- No multi-reader consensus (e.g., 2+1, 3+1) is mentioned, as this is an in vitro diagnostic assay, not an image-reading task.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No MRMC comparative effectiveness study was done. This type of study is typically performed for AI/CAD systems that assist human readers in interpreting medical images, not for in vitro diagnostic assays like this one which provides a quantitative or qualitative result directly.
6. Standalone (Algorithm Only) Performance
- This device is an automated immunoassay (ADVIA Centaur HSV2 assay). Its performance is inherently "standalone" in the sense that it directly measures antibodies without human interpretation in the loop to generate the initial result. The reported sensitivity and specificity values are for the device (algorithm) itself against the established ground truth.
7. Type of Ground Truth Used
- Expert Consensus / Highly-validated Reference Methods:
- For panels: "characterized HSV samples," "reference assay 1," and "results provided by the CDC."
- For clinical and cross-reactivity studies: A Comparative Assay (likely another FDA-cleared or well-established commercial immunoassay) and a validated Western Blot reference confirmatory test (University of Washington, Seattle). Western Blot is generally considered a highly specific and confirmatory test for antibody presence in serology. The use of a confirmatory test like Western Blot for equivocal results strengthens the ground truth.
8. Sample Size for the Training Set
- The document describes a 510(k) submission for an in vitro diagnostic device (immunoassay). Immunoassays are based on biochemical reactions and established calibration curves, not typically on machine learning models requiring large "training sets" in the same sense as AI/ML software. Therefore, a "training set" for an algorithm, as understood in AI/ML, isn't applicable or mentioned for this device. The development process would involve characterization, optimization, and validation using various samples, but not "training data" for a learnable algorithm.
9. How the Ground Truth for the Training Set Was Established
- As explained in point 8, the concept of a "training set" with ground truth establishment in the AI/ML sense does not apply to this immunoassay. The device's performance is driven by its reagent chemistry and instrumentation, not by a trained algorithm.
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August 23, 2018
Biokit, S.A. Joan Guixe QA & RA Director Can Male. S/N Llica d'Amunt, 08186 Barcelona, Spain
Re: K181334
Trade/Device Name: ADVIA Centaur Herpes-2 IgG Regulation Number: 21 CFR 866.3305 Regulation Name: Herpes simplex virus serological assays Regulatory Class: Class II Product Code: MYF Dated: May 17, 2018 Received: May 25, 2018
Dear Joan Guixe:
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 (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 located 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.
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
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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 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html; 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 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely.
Steven R. Gitterman -S for
Uwe Scherf, Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K183334
Device Name ADVIA Centaur Herpes-2 IgG
Indications for Use (Describe)
The ADVIA Centaur® Herpes-2 IgG (HSV2) assay is for in vitro diagnostic use in the qualitative determination of IgG antibodies to herpes simplex virus type 2 (HSV-2) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur systems. The test is indicated for testing sexually active adults or expectant mothers for aiding in the presumptive diagnosis of HSV infection. The predictive or negative result depends on the prevalence of HSV-2 infection in the population and the pre-test likelihood of HSV-2 infection.
The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for immunocompromised patients, pediatic patients or matrices other than human serum and plasma (EDTA and lithium heparin).
| 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 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.Can Malé S/NLliçà d'Amunt 08186Barcelona (Spain) |
|---|---|
| ---------------------------- | -------------------------------------------------------------------------- |
| 2. Contact Person | Joan Guixer, QA & RA Director |
|---|---|
| Phone: +34 93 860 90 00 / +34 657 88 33 47 | |
| Email: jguixer@biokit.com |
| 3. Preparation Date | May 17th, 2018 |
|---|---|
| --------------------- | ---------------- |
| 4. Device Trade Name | ADVIA Centaur Herpes-2 IgG |
|---|---|
| ---------------------- | ---------------------------- |
| 5. Regulatory Information | Regulation Number | 21 CFR 866.3305 |
|---|---|---|
| Regulation Description | Herpes simplex virusserological assays | |
| Classification | Class II Special Controls | |
| Product Code | MYF | |
| Classification Panel | Microbiology |
| 6. Predicate Device | K000238 (Focus HerpeSelect 1 and 2 Immunoblot IgG) |
|---|---|
| --------------------- | ---------------------------------------------------- |
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| 7. Indications for Use /Intended Use | The ADVIA Centaur® Herpes-2 IgG (HSV2) assay is for invitro diagnostic use in the qualitative determination ofIgG antibodies to herpes simplex virus type 2 (HSV-2) inhuman serum and plasma (EDTA and lithium heparin)using the ADVIA Centaur systems. The test is indicatedfor testing sexually active adults or expectant mothersfor aiding in the presumptive diagnosis of HSVinfection. The predictive value of a positive or negativeresult depends on the prevalence of HSV-2 infection inthe population and the pre-test likelihood of HSV-2infection. |
|---|---|
| The test is not FDA cleared for screening blood orplasma donors. The performance of this assay has notbeen established for immunocompromised patients,pediatric patients or matrices other than human serumand plasma (EDTA and lithium heparin). |
| 8. Device Description | The ADVIA Centaur Herpes-2 IgG (HSV2) assay is a fullyautomated two-step sandwich immunoassay usingindirect chemiluminometric technology. The specimenis incubated with the Solid Phase, which contains HSV-2-specific recombinant-gG2 antigen. Antigen-antibodycomplexes will form if anti-HSV-2 antibody is present inthe specimen. The Lite Reagent contains monoclonalanti-human IgG labeled with acridinium ester, and isused to detect HSV-2 IgG in the specimen. |
|---|---|
| ----------------------- | --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
| COMPARISON PREDICATE | Manufacturer | Focus DiagnosticsCypress, CA 90630 -USA | Siemens HeathcareDiagnostics Inc.511 Benedict Avenue,Tarrytown, NY 10591- USA | ||
|---|---|---|---|---|---|
| Item | Predicate | New Device | Similarities | ||
| Trade Names | Focus HerpeSelect 1 and 2Immunoblot IgG | ADVIA Centaur Herpes-2 IgG | Intended use | Focus Diagnostics HerpeSelect 1and 2 Immunoblot IgG test isintended for qualitatively detectingthe presence or absence of humanIgG class antibodies to HSV-1 andHSV-2 in human sera. The test isindicated for testing sexually activeadults or expectant mothers foraiding in the presumptive diagnosisof HSV-1 and HSV-2 infection. Thepredictive value of a positive ornegative result depends on thepopulation's prevalence and thepretest likelihood of HSV- 1 andHSV-2 infection. The performanceof this assay has not beenestablished for use in a pediatricpopulation, for neonatal screening,for testing ofimmunocompromised patients, foruse by a point of care facility or foruse with automated equipment | The ADVIA Centaur® Herpes-2 IgG (HSV2) assay is for invitro diagnostic use in thequalitative determination oflgG antibodies to herpessimplex virus type 2 (HSV-2)in human serum and plasma(EDTA and lithium heparin)using the ADVIA Centaursystems. The test is indicatedfor testing sexually activeadults or expectant mothersfor aiding in the presumptivediagnosis of HSV infection.The predictive value of apositive or negative resultdepends on the prevalence ofHSV-2 infection in thepopulation and the pre-testlikelihood of HSV-2 infection.The test is not FDA clearedfor screening blood or plasmadonors. The performance ofthis assay has not beenestablished forimmunocompromisedpatients, pediatric patients ormatrices other than humanserum and plasma (EDTA andlithium heparin). |
| 510K nº | K000238 | K183334 | Measurand | To detect the presence or absenceof human IgG class antibodies toHSV-1 and HSV-2 | To detect IgG antibodies toherpes simplex virus type 2(HSV-2). |
| Regulation Section | 21 CFR 866.3305 | Same |
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| Product Code | LGC | MYF |
|---|---|---|
| Classification | Class II Special Controls | Same |
| Assay Type | Qualitative | Same |
| Differences | ||
| Technology | Nitrocellulose immunoblot | Chemiluminescentimmunoassay |
| Sample type | Human serum | Human serum andplasma (EDTA and lithiumheparin) |
9. Performance Summary
Precision
A precision study was performed according to CLSI EP05-A3 , using the Negative and Positive Controls as well as 6 samples prepared at different levels in the assay range. Each material was tested in duplicate, twice a day for 20 days, for a total of 80 replicates per level.
The ADVIA Centaur HSV2 assay is designed to have the following repeatability and withinlab precision requirements:
| Design Requirement | ||
|---|---|---|
| ADVIA Centaur HSV2 Level (Index) | Repeatability% CV | Within-Lab% CV |
| < 0.5 | NAa | NA |
| 0.51-0.79 | ≤ 10.0% | ≤ 15.0% |
| 0.80–1.20 | ≤ 6.0% | ≤ 8.0% |
| 1.21-3.00 | ≤ 5.0% | ≤ 8.0% |
| 3.01-6.00 | ≤ 5.0% | ≤ 7.0% |
| > 6.00 | ≤ 5.0% | ≤ 7.0% |
೩ NA = not applicable
The results for this study are presented below.
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| Specimen Type | N | Mean(Index) | Repeatability | Within-Lab | ||
|---|---|---|---|---|---|---|
| SD | CV(%) | SD | CV(%) | |||
| Negative Control(Plasma) | 80 | 0.29 | 0.01 | NAa | 0.02 | NAa |
| Positive Control(Plasma) | 80 | 3.09 | 0.07 | 2.3 | 0.20 | 6.5 |
| Serum 1 | 80 | 0.36 | 0.01 | NAa | 0.02 | NAa |
| Plasma 2 | 80 | 0.63 | 0.02 | 2.4 | 0.04 | 5.9 |
| Serum 3 | 80 | 1.08 | 0.05 | 4.3 | 0.08 | 7.2 |
| Serum 4 | 80 | 2.58 | 0.09 | 3.6 | 0.20 | 7.6 |
| Serum 5 | 80 | 5.29 | 0.09 | 1.7 | 0.34 | 6.4 |
| Serum 6 | 80 | 7.62 | 0.17 | 2.2 | 0.47 | 6.1 |
Precision results for the HSV-2 Assay
NAª= Not applicable
Sample matrix
This study was performed on one ADVIA Centaur XP instrument, using 68 sets of matched samples of different matrixes (serum, serum separator tube (SST), EDTA plasma and lithium heparin plasma) from commercial sources.
The samples were analyzed in duplicate in randomized order using one reagent lot.
- . Comparing Serum Separator Tube (y) vs Serum (x): (Deming regression) y = 0.00 + 0.99x, r=0.999, sample range for both matrixes 0.02-9.59 Index Value and 0.02-9.49 Index Value respectively. Note - correlation coefficient is calculated using linear regression.
- Comparing EDTA Plasma(y) vs Serum (x): (Deming regression) y= 0.00 + 0.98 x, ● r=0.998, sample range for both matrixes 0.02-9.59 Index Value and 0.02-9.34 Index Value respectively. Note - correlation coefficient is calculated using linear regression.
- . Comparing Lithium Heparin Plasma(y) vs Serum (x): (Deming regression) y= -0.01 + 0.98 x, r=0.997, sample range for both matrixes 0.02-9.59 Index Value and 0.01-9.23 Index Value respectively. Note - correlation coefficient is calculated using linear regression.
The results supports that Serum Separator Tube is equivalent matrix to Serum, EDTA Plasma is equivalent matrix to Serum and Lithium Heparin Plasma is an equivalent matrix to Serum.
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Panels
The commercial sample panels ToRCH-mixed Zeptometrix and CDC panel were analysed.
The ToRCH-mixed Zeptometrix panel included 24 characterized HSV samples. All of the samples were evaluated with the ADVIA Centaur Herpes-2 IgG assay on ADVIA Centaur XP instrument and 100% total agreement was observed with reference assay 1.
The CDC panel included 100 blind characterized HSV samples. All of the samples were evaluated with the ADVIA Centaur Herpe-2 IgG assay on ADVIA Centaur XP instrument and 100% total agreement was observed in concordance with the results provided by the CDC.
Interferences
Potential interference in the ADVIA Centaur HSV2 assay from the compounds listed below is designed to be ≤ 10%. Interfering substances at the levels indicated were tested as described in CLSI Document EP7-A2. The testing was done in three levels of samples in the assay range (high negative, low positive and positive samples) with at least one reagent lot on ADVIA Centaur XP instrument.
Testing confirmed no interference (Demonstrate ≤ 10% change in results) for the ADVIA Centaur Herpes-2 IgG up to the following concentrations:
| Serum specimens that are... | Demonstrate ≤10% change in results up to... |
|---|---|
| Biotin | 3500 ng/mL |
| Hemoglobin | 500 mg/dL |
| Bilirubin complex | 40 mg/dL |
| Bilirubin free | 40 mg/dL |
| Hypoproteinemia | 3 g/dL |
| Hyperproteinemia | 12 g/dL |
| Lipemia | 1000 mg/dL |
| Cholesterol | 400 mg/dL |
Cross-reactivity
The ADVIA Centaur HSV2 assay was evaluated for potential cross-reactivity other viral antibodies, disease-state specimens, and other populations. The HSV-2 IgG status of each specimen was verified using the Comparative Assay. Repeat equivocal specimens on the Comparative Assay were sent to a reference laboratory for Western Blot testing. Total
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percent agreement for the following clinical categories was 96.9% (506/522). The following results were obtained:
| Clinical Category | Numbertested | ADVIA CentaurHSV2Reactive | ReferenceMethodPositive | |
|---|---|---|---|---|
| Antibody to hepatitis B surface antigen (Anti-HBs) | 10 | 5 | 6 | |
| Anti-gliadin | 10 | 1 | 1 | |
| Anti-nuclear antibodies (ANA) | 10 | 0 | 1 | |
| Candida albicans | 10 | 3 | 3 | |
| Chlamydia trachomatis | 10 | 4 | 4 | |
| Cytomegalovirus (CMV; HHV-5) | 25 | 9 | 11 | |
| Elevated IgG levels | 10 | 8 | 8 | |
| Elevated IgM levels | 10 | 3 | 3 | |
| Epstein-Barr Virus (EBV IgG) | 10 | 3 | 3 | |
| Escherichia coli | 10 | 5 | 5 | |
| Flu vaccine | 10 | 1 | 1 | |
| Gardenerella vaginalis | 10 | 5 | 5 | |
| Hepatitis B surface antigen (HBsAg) | 10 | 4 | 4 | |
| Hepatitis C Virus (HCV) | 10 | 7 | 7 | |
| Herpes simplex virus type 1 (HSV-1) | 117 | 29 | 31 | |
| Heterophile antibodies (EBV) | 10 | 0 | 0 | |
| Human Anti-mouse antibodies (HAMA) | 10 | 4 | 4 | |
| Human herpes virus 6 (HHV-6) | 10 | 2 | 3 | |
| Human herpes virus 8 (HHV-8) | 10 | 5 | 5 | |
| Human immunodeficiency virus (HIV) | 10 | 9 | 9 | |
| Human Papillomavirus (HPV) | 25 | 3 | 5 | |
| Numbertested | ADVIA CentaurHSV2 | ReferenceMethod | ||
| Clinical Category | Reactive | Positive | ||
| Multiple myeloma | 10 | 3 | 3 | |
| Neisseria gonorrhoeae | 10 | 4 | 4 | |
| Parvovirus B19 | 10 | 0 | 0 | |
| Rheumatoid factor (RF) | 10 | 5 | 5 | |
| Rubella IgG | 10 | 2 | 2 | |
| Syphilis | 10 | 7 | 7 | |
| Systemic lupus erythematosus (SLE) | 10 | 1 | 0 | |
| Toxoplasma IgG | 95 | 26 | 30 | |
| Varicella Zoster virus (HHV-3) | 10 | 1 | 1 | |
| Total Samples | 522 | 159 | 171 |
Cross Reactivity Study Performance Results
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Biokit
A Werfen Company
Multisite reproducibility
Reproducibility was evaluated according to the CLSI protocol EP5-A3.25. The ADVIA Centaur HSV2 assay is designed to have reproducibility precision requirements of ≤ 15% for specimens with ≥ 0.80 Index.
A reproducibility study was conducted using 1 reagent lot at 3 external sites on the ADVIA Centaur XP instrument, using a sample panel blinded and randomized that was composed by the Controls (Negative and Positive) and 6 samples prepared at different levels in the assay range.
The protocol was run over 5 days, 2 runs per day, and 3 replicates per run for the sample pools, and for the negative and positive control materials. The data in the following table represents pooled results from the 3 sites.
The results are presented in the table below.
| Specimentype | N | Mean(Index) | Repeatability | Between-Run | Between-Day | Between-Site | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Negativecontrol | 90 | 0.31 | 0.01 | 4.5% | 0.00 | 1.1% | 0.01 | 1.8% | 0.02 | 6.2% | 0.02 | 7.9% |
Multisite Precision Study Repeatability
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A Werfen Company
| Specimentype | N | Mean(Index) | Repeatability | Between-Run | Between-Day | Between-Site | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Positive control | 90 | 3.27 | 0.06 | 1.9% | 0.04 | 1.2% | 0.04 | 1.4% | 0.06 | 1.8% | 0.10 | 3.2% |
| Serum 1 | 90 | 0.36 | 0.01 | 2.3% | 0.01 | 3.6% | 0.01 | 3.1% | 0.02 | 4.8% | 0.03 | 7.1% |
| Plasma 2 | 90 | 0.64 | 0.01 | 1.8% | 0.01 | 1.1% | 0.02 | 2.7% | 0.00 | 0.0% | 0.02 | 3.4% |
| Serum 3 | 90 | 1.07 | 0.02 | 1.8% | 0.03 | 2.8% | 0.03 | 2.9% | 0.03 | 2.8% | 0.06 | 5.2% |
| Serum 4 | 90 | 2.47 | 0.08 | 3.1% | 0.06 | 2.5% | 0.05 | 1.8% | 0.13 | 5.4% | 0.17 | 7.0% |
| Serum 5 | 90 | 5.24 | 0.34 | 6.4% | 0.12 | 2.3% | 0.11 | 2.2% | 0.21 | 4.0% | 0.43 | 8.2% |
| Serum 6 | 90 | 7.87 | 0.14 | 1.8% | 0.18 | 2.2% | 0.20 | 2.5% | 0.20 | 2.5% | 0.36 | 4.6% |
Clinical study
A multicenter clinical study to compare the reference device with ADVIA Centaur Herpes-2 IgG was performed. Sensitivity and specificity were determined by comparing the performance of the ADVIA Centaur HSV2 assay to a commercially available anti-HSV-2 IgG immunoblot method (Comparative Assay) and a validated Western Blot reference confirmatory test (University of Washington, Seattle). A total of 864 specimens (≥ 18 years of age), including specimens from 274 pregnant women, were collected within the United States and tested at 3 independent external laboratories. Of these specimens, 254 were reactive, and 610 were nonreactive with the ADVIA Centaur HSV2 assay. The overall agreement was 97.6% (843/864) with a 95% confidence interval (CI) of 96.3%-98.4%. Samples were analyzed in singlicate.
Of the 864 specimens tested by the Comparative Assay, 22 were equivocal and were further tested by the Western Blot test. After Western Blot testing, 20 of the 22 specimens were resolved to be negative and 2 remained equivocal.
| Intended use population | Comparative AssayEquivocal results have been resolved by Western Blot (WB) | Positive | Negative | Equivocal | Total | |
|---|---|---|---|---|---|---|
| ADVIA Centaur HSV2 | Reactive | 245 | 9 | 0 | 254 | |
| Nonreactive | 10 | 598 | 2 | 610 | ||
| Total | 255 | 607 | 2 | 864 |
The results obtained for the intended use population are presented below
The sensitivity of the ADVIA Centaur HSV2 assay was 95.3% (245/257), with a 95% confidence interval (CI) of 92.0%-97.3%.
The specificity of the ADVIA Centaur HSV2 assay was 98.5% (598/607), with a 95% confidence interval (CI) of 97.2%-99.2%.
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Sensitivity and specificity were determined for the pregnant population by comparing the performance of the ADVIA Centaur HSV2 assay to the Comparative Assay and Western Blot confirmatory method. The results of pregnant women samples are presented below:
| Pregnant women | Comparative assayEquivocal results have been resolved by Western Blot (WB) | ||||
|---|---|---|---|---|---|
| Positive | Negative | Equivocal | Total | ||
| ADVIA Centaur HSV2 | Reactive | 34 | 4 | 0 | 38 |
| Nonreactive | 0 | 236 | 0 | 236 | |
| Total | 34 | 240 | 0 | 274 |
Pregnant women Study Contingency (WB resolution) table
The sensitivity of the ADVIA Centaur HSV2 assay was 100.0% (34/34) with a 95% confidence interval of 89.9%—100.0%.
The specificity of the ADVIA Centaur HSV2 assay was 98.3% (236/240) with a 95% confidence interval of 95.8%–99.4%.
10. Stability
The onboard stability of the ADVIA Centaur Herpes-2 IgG reagents is 60 days with a calibration interval of 28 days. The onboard stability of the ADVIA Centaur Herpes-2 IgG Calibrators is 8 hours. The opened vial stability of the ADVIA Centaur Herpes-2 IgG Calibrators is 65 days. Unopened reagents and calibrators are stable until the 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 Herpes-2 IgG are substantially equivalent to the predicate device, Focus HerpeSelect 1 and 2 Immunoblot IgG (FDA cleared under K000238), and that the assay is safe and effective for its labeled intended use.
§ 866.3305 Herpes simplex virus serological assays.
(a)
Identification. Herpes simplex virus serological assays are devices that consist of antigens and antisera used in various serological tests to identify antibodies to herpes simplex virus in serum. Additionally, some of the assays consist of herpes simplex virus antisera conjugated with a fluorescent dye (immunofluorescent assays) used to identify herpes simplex virus directly from clinical specimens or tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by herpes simplex viruses and provides epidemiological information on these diseases. Herpes simplex viral infections range from common and mild lesions of the skin and mucous membranes to a severe form of encephalitis (inflammation of the brain). Neonatal herpes virus infections range from a mild infection to a severe generalized disease with a fatal outcome.(b)
Classification. Class II (special controls). The device is classified as class II (special controls). The special control for the device is FDA's revised guidance document entitled “Class II Special Controls Guidance Document: Herpes Simplex Virus Types 1 and 2 Serological Assays.” For availability of the guidance revised document, see § 866.1(e).