K Number
K120959
Date Cleared
2012-06-22

(84 days)

Product Code
Regulation Number
866.3305
Reference & Predicate Devices
Predicate For
N/A
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit is a multiplex flow immunoassay intended for the qualitative detection and differentiation of IgG antibodies to herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) in human serum and EDTA or heparinized plasma. The test is indicated for sexually active individuals and expectant mothers as an aid for the presumptive diagnosis of HSV-1 or HSV-2 infection. The predictive value of positive or negative results depends on the population's prevalence and the pretest likelihood of HSV-1 and HSV-2. The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for use in a pediatric population, neonates and immunocompromised patients or for use at point of care facilities.

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit is intended for use with the Bio-Rad BioPlex® 2200 System.

The BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set is intended for the calibration of the BioPlex® 2200 HSV-1 & HSV-2 IgG Reagent Pack.

The BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex® 2200 Instrument and BioPlex® HSV-1 & HSV-2 IgG Reagent Pack in the clinical laboratory. The performance of the BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set has not been established with any other HSV-1 and HSV-2 antibody assays.

Device Description

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. Two (2) different populations of dyed beads are each coated with antigens associated with herpes simplex virus, types 1 and 2.

The BioPlex® 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel; the mixture is incubated at 37°C. After a wash cycle, antihuman IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads, and this mixture is incubated at 37℃. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data are calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex® 2200 System Operation Manual for more information.

The instrument is calibrated using a set of four (4) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. The four (4) vials representing four (4) different antibody concentrations are used for calibration. The result for each of these antibodies is expressed as an antibody index (AI).

The BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set includes a negative control as well as multi-analyte positive control. The Positive Control is manufactured to give positive results, with values above the cut-off for each specific analyte. The Negative Control is manufactured to give negative results, with values below the cut-off for each specific analyte.

AI/ML Overview

This document describes the BioPlex® 2200 HSV-1 & HSV-2 IgG kit for qualitative detection and differentiation of IgG antibodies to HSV-1 and HSV-2. The primary acceptance criteria provided relate to comparative testing against a predicate device and a CDC panel, as well as precision studies and interference testing.

Here's the breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state numerical "acceptance criteria" independently, but rather presents the performance of the modified device in comparison to a predicate device and a CDC panel. The comparisons effectively serve as the standard for acceptance, implying that the modified device should perform comparably or better.

Performance MetricBioPlex® 2200 HSV-1 IgGBioPlex® 2200 HSV-2 IgG
Comparative Testing vs. Predicate Device (Sexually Active Individuals)
HSV-1 (N=399)
% Positive Agreement (95% CI)100% (280/280) (98.6-100%)Not Applicable
% Negative Agreement (95% CI)98.3% (116/118) (94.0-99.5%)Not Applicable
% Total Agreement (95% CI)99.5% (396/398) (98.2-99.9%)Not Applicable
HSV-2 (N=399)
% Positive Agreement (95% CI)Not Applicable99.4% (166/167) (96.7-99.9%)
% Negative Agreement (95% CI)Not Applicable100% (232/232) (98.4-100%)
% Total Agreement (95% CI)Not Applicable99.7% (398/394) (98.6-100%)
Comparative Testing vs. CDC HSV Panel (N=80)
HSV-1 (N=80)
% Positive Agreement (95% CI)100.0% (42/42) (91.6-100%)Not Applicable
% Negative Agreement (95% CI)97.4% (37/38) (86.5-99.5%)Not Applicable
% Total Agreement (95% CI)98.8% (79/80) (93.3-99.8%)Not Applicable
HSV-2 (N=80)
% Positive Agreement (95% CI)Not Applicable100.0% (40/40) (91.2-100%)
% Negative Agreement (95% CI)Not Applicable100.0% (40/40) (91.2-100%)
% Total Agreement (95% CI)Not Applicable100.0% (80/80) (95.4-100%)
Linear Regression (Modified vs. Predicate Assays)
HSV-1 Slope0.9977Not Applicable
HSV-1 Intercept-0.002Not Applicable
HSV-1 Correlation (R2)0.9879Not Applicable
HSV-2 SlopeNot Applicable1.0352
HSV-2 InterceptNot Applicable-0.0514
HSV-2 Correlation (R2)Not Applicable0.9866
Precision – Total Precision %CV (Example: High Positive)
HSV-1 Predicate4.3% (for 3.2 AI)Not Applicable
HSV-1 Modified6.0% (for 3.1 AI)Not Applicable
HSV-2 Predicate6.1% (for 4.4 AI)Not Applicable
HSV-2 Modified6.4% (for 4.1 AI)Not Applicable
Interference (no significant interference observed for substances listed)AcceptableAcceptable
Matrix Comparison (Regression Correlation 'r')
HSV-1 EDTA vs Serum0.9902Not Applicable
HSV-1 Heparin vs Serum0.9946Not Applicable
HSV-2 EDTA vs SerumNot Applicable0.9945
HSV-2 Heparin vs SerumNot Applicable0.9946

2. Sample size used for the test set and the data provenance

  • Comparative Testing (Predicate Device):
    • Test Set Size: 399 samples for HSV-1, 399 samples for HSV-2.
    • Data Provenance: Samples from sexually active individuals where an HSV-1 or HSV-2 test was ordered. The country of origin is not explicitly stated but is implied to be within the jurisdiction of the Bio-Rad Laboratories, Inc. (Benicia, CA). The data is retrospective, as it involves comparison to an already marketed predicate device and characterization of existing samples.
  • Comparative Testing (CDC HSV Panel):
    • Test Set Size: 80 samples.
    • Data Provenance: A "well characterized HSV serum panel from the CDC." This suggests existing, well-defined samples. The country of origin is the United States (CDC). This data is retrospective.
  • Precision Studies:
    • Test Set Size: 8 panel members for each analyte (HSV-1 and HSV-2), each tested 20 times (2 replicates x 2 runs x 5 days).
    • Data Provenance: Prepared by Bio-Rad Laboratories, tested at Bio-Rad Laboratories. Retrospective/internal data.
  • Interference Testing:
    • Test Set Size: Samples prepared by blending negative human serum with positive samples. Evaluated in replicates of ten. Specific number of donor samples not provided, but the interference substances are well-defined.
    • Data Provenance: Internal studies by Bio-Rad Laboratories. Retrospective.
  • Matrix Comparison:
    • Test Set Size: >40 matched serum and plasma (EDTA and heparin sodium) samples for each assay (47 for HSV-1, 44 for HSV-2).
    • Data Provenance: Matched serum and plasma drawn from the same donor, acquired from commercial sources. Retrospective.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The ground truth for the test sets (comparative testing with predicate and CDC panel) was established through existing reference methods.

  • Predicate Device Comparison: The "predicate method" served as the reference standard. The document does not specify the number or qualifications of experts involved in the initial determination by the predicate method.
  • CDC HSV Panel: The panel is described as "well characterized," implying its status as a reference standard. The document does not specify the number or qualifications of experts involved in characterizing the CDC panel.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

The document does not describe an adjudication method for disagreements. The comparisons rely on agreement with the predicate device results or the CDC panel's established status.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

A multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) kit that directly measures antibody levels, not an AI-assisted diagnostic tool that interprets images or other complex data requiring human reader interaction. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the performance studies presented are for the standalone device (BioPlex® 2200 HSV-1 & HSV-2 IgG kit on the BioPlex® 2200 Multi-Analyte Detection System) without human interpretation as part of the primary diagnostic output. The results (antibody index) are objectively measured by the automated system.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth used was based on:

  • Reference Method/Predicate Device: For the comparative testing against the predicate device, the results obtained from the legally marketed predicate device served as the reference standard.
  • Reference Panel: For the CDC HSV Panel, the "well-characterized" status of the panel served as the established ground truth. This type of panel typically undergoes extensive testing and validation, often using a combination of methods and expert consensus to establish the definitive status of each sample.

8. The sample size for the training set

The document does not explicitly mention a "training set" in the context of machine learning or AI. This is an IVD kit, and studies focus on analytical and clinical performance. The studies performed are validation studies, not training studies for an algorithm.

9. How the ground truth for the training set was established

As there is no "training set" in the context of an AI/ML algorithm for this IVD device, this question is not applicable. The development and validation of the device are based on laboratory testing and comparisons to established reference methods and panels.

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JUN 2 2 2012

BioPlex® 2200 HSV-1 & HSV-2 IgG 510(k) Summary

510(k) Number K120959

Date Prepared: June 22, 2012

Introduction

Bio-Rad Laboratories hereby submits this 510(k) in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. This summary of 510(k) safety and effectiveness information provides detail as a basis for a determination of substantial equivalence for the BioPlex® 2200 HSV-1 & HSV-2 IgG kit.

Submitter name, address and contact

SubmitterContact Person
Bio-Rad Laboratories, IncJuang Wang
BioPlex DivisionRegulatory Affairs Representative
5500 E. Second StreetPhone: (510)741-4609
Benicia, CA 94510Fax: (510)741-3941

Device name

Product Trade Name: BioPlex® HSV-1 & HSV-2 IgG on the BioPlex® 2200 Multi-Analyte Detection System

Proprietary Name: BioPlex® 2200 HSV-1 & HSV-2 IgG

Classification Name:

enzyme linked immunosorbent assay, herpes simplex virus, hsv-1 enzyme linked immunosorbent assay, herpes simplex virus, hsv-2 calibrator, multi-analyte mixture multi-analyte controls, all kinds (assayed)

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Regulation Information

Product CodeClassificationRegulation SectionPanel
Enzyme linkedimmunosorbent assay,Herpes Simplex Virus,HSV-1(MXJ)Class II21 CFR § 866.3305,Herpes simplex virusserological assays.Microbiology
Enzyme linkedimmunosorbent assay,Herpes Simplex Virus,HSV-2(MYF)Class II21 CFR § 866.3305,Herpes simplex virusserological assays.Microbiology
Calibrator, multi-analytemixture(JIX)Class II21 CFR § 862.1150 -CalibratorClinical Chemistry
Multi-Analyte ControlsAll kinds(assayed)(JJY)Class I21 CFR § 862.1660 -Quality control Material(Assayed and Unassayed)Clinical Chemistry

Legally Marketed Predicate Device

BioPlex® 2200 HSV-1 & HSV-2 IgG Kit, K090409

INTENDED USE / INDICATIONS FOR USE

BioPlex® 2200 HSV-1 & HSV-2 IgG Kit

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit is a multiplex flow immunoassay intended for the qualitative detection and differentiation of IgG antibodies to herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) in human serum and EDTA or heparinized plasma. The test is indicated for sexually active individuals and expectant mothers as an aid for the presumptive diagnosis of HSV-1 or HSV-2 infection. The predictive value of positive or negative results depends on the population's prevalence and the pretest likelihood of HSV-1 and HSV-2. The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for use in a pediatric population, neonates and immunocompromised patients or for use at point of care facilities.

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit is intended for use with the Bio-Rad BioPlex® 2200 System.

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BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set

The BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set is intended for the calibration of the BioPlex® 2200 HSV-1 & HSV-2 IgG Reagent Pack.

11

BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set

The BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex® 2200 Instrument and BioPlex® HSV-1 & HSV-2 IgG Reagent Pack in the clinical laboratory. The performance of the BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set has not been established with any other HSV-1 and HSV-2 antibody assays.

Kit Components :

The BioPlex® 2200 HSV-1 & HSV-2 IgG Reagent Pack (665-3350). The reagent pack contains supplies sufficient for 100 tests. .

VialDescription
Bead SetOne (1) 10 mL vial, containing dyed beads coated withHSV-1 and HSV-2 antigen, an Internal Standard bead(ISB), a Serum Verification bead (SVB), and a ReagentBlank bead (RBB) in buffer with glycerol and proteinstabilizers (bovine). ProClin 300 (≤0.3%), sodiumbenzoate (≤0.1%) and sodium azide (<0.1%) aspreservatives.
ConjugateOne (1) 5 mL vial, containing phycoerythrin conjugatedmurine monoclonal anti-human IgG antibody andphycoerythrin conjugated murine monoclonal anti-humanFXIII antibody, in buffer with protein stabilizers (bovine).ProClin 300 (≤0.3%), sodium benzoate (≤0.1%) andsodium azide (<0.1%) as preservatives
Sample DiluentOne (1) 10 mL vial, containing buffer with proteinstabilizers (bovine and murine). ProClin 300 (≤0.3%),sodium benzoate (≤0.1%) and sodium azide (<0.1%) aspreservatives.

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Catalog #Description
663-3300BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set: Four(4) 0.5 mL vials, each containing human antibodies toHSV-1 and HSV-2 IgG derived from human disease stateplasma, in a human serum matrix made from defibrinatedplasma. All calibrators contain ProClin 300 (≤ 0.3%), .sodium benzoate (<0.1%) and sodium azide (< 0.1%) aspreservatives
663-3330BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set: Two (2)1.5 mL Positive Control serum vials, each containinghuman antibodies to HSV-1 and HSV-2 IgG derived fromhuman disease state plasma, in a human serum matrixmade from defibrinated plasma. Two (2) 1.5 mL NegativeControl serum vials, in a human serum matrix made fromdefibrinated plasma. All antibodies are derived fromhuman disease state plasma. All controls contain ProClin300 (≤ 0.3%), sodium benzoate (≤0.1%) and sodium azide(< 0.1%) as preservatives.
660-0817BioPlex® 2200 Sheath Fluid: Two 4 L bottles containingPhosphate Buffered Saline (PBS). ProClin® 300 (0.03%)and sodium azide (<0.1%) as preservatives.
660-0818BioPlex® 2200 Wash Solution: One 10 L bottlecontaining Phosphate Buffered Saline (PBS) and Tween20. ProClin® 300 (0.03%) and sodium azide (<0.1%) aspreservatives.
660-0000BioPlex®2200 Instrument and Software System.

Additional Required Items, Available from Bio-Rad:

Device Description

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. Two (2) different populations of dyed beads are each coated with antigens associated with herpes simplex virus, types 1 and 2.

The BioPlex® 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel; the mixture is incubated at 37°C. After a wash cycle, antihuman IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads, and this mixture is incubated at 37℃. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data are calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of

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significant non-specific binding in serum or plasma. Refer to the BioPlex® 2200 System Operation Manual for more information.

The instrument is calibrated using a set of four (4) distinct calibrator vials, supplied separately by Bio-Rad Laboratories. The four (4) vials representing four (4) different antibody concentrations are used for calibration. The result for each of these antibodies is expressed as an antibody index (AI).

The BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set includes a negative control as well as multi-analyte positive control. The Positive Control is manufactured to give positive results, with values above the cut-off for each specific analyte. The Negative Control is manufactured to give negative results, with values below the cut-off for each specific analyte.

Technological Characteristics and Substantial Equivalence

The following tables summarize the similarities and differences between the modified BioPlex® 2200 HSV-1 & HSV-2 IgG kit and the predicate devices used in comparative studies.

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Similarities

ItemModified BioPlex® 2200HSV-1 & HSV-2 IgG KitPredicate
Intended UseThe BioPlex® 2200 HSV-1 & HSV-2 IgG kit is amultiplex flow immunoassay intended for thequalitative detection and differentiation of IgGantibodies to herpes simplex virus type 1 (HSV-1)and herpes simplex virus type 2 (HSV-2) inhuman serum and EDTA or heparinized plasma.The test is indicated for sexually activeindividuals and expectant mothers as an aid forthe presumptive diagnosis of HSV-1 or HSV-2infection. The predictive value of positive ornegative results depends on the population'sprevalence and the pretest likelihood of HSV-1and HSV-2.The test is not FDA cleared for screening blood orplasma donors. The performance of this assay hasnot been established for use in a pediatricpopulation, neonates and immunocompromisedpatients or for use at point of care facilities.The BioPlex® 2200 HSV-1 & HSV-2 IgG kit isintended for use with the Bio-Rad BioPlex® 2200System.Same
Capture Antigen1. gG1 glycoprotein (MW: 55 kD)2. gG2 glycoprotein (MW: 31kD)Same
Assay TypeSemi-Quantitative detectionSame
Specimen TypeSerum and plasmaSame
Cutoff1.0 AI for HSV-1 and HSV-2 IgG assaySame
ControlsNegative and Positive ControlsSame
Calibrator(s)Multiple CalibratorsSame
ItemModified BioPlex® 2200HSV-1 & HSV-2 IgG KitPredicate
QC procedureQC once per day and per new reagentpack lotQC once per packand per day
Bead Reagent2 mg/mL protein stabilizer (bovine)and protease inhibitor in particle(bead) diluent1 mg/mL proteinstabilizer (bovine)

:

.

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Differences

The differences are to modify QC testing procedure from each reagent pack to once per day as stated in the Instructions For Use (IFU) of the BioPlex® 2200 HSV-1 & HSV-2 IgG and to add an additional 1 mg/mL of protein stabilizer and protease stabilizer in particle (bead) reagent.

Other minor changes in the Instructions For Use are as follows.

  • Change BioPlex Trademark from TM to ® �
  • Use new Warning symbol and text for "Irritant"
  • Remove ProClin Trademark
  • Add " < " symbol for ProClin and sodium benzoate concentrations in Kit Components Section
  • � Revise the hazardous symbol in Precautions/Warning section in compliance with new EU regulation 2008/1272/EC and Global Harmonized System (GHS)

Summary of Design Control Activities

A Failure Mode and Effect Analysis (FMEA) was used to facilitate, capture, and quantify potential impacts of false positive or negative patient results. The Risk Priority Number (RPN) is a quantitative measure of the combined effects of severity, occurrence, and detection of potential risks. Specific mitigations are recommended that may include changes to the design or formulation if the RPN score exceeds a chosen threshold.

Based on the conclusion of the risk management report, the modified QC procedure fulfills the requirements of the specifications of the design control process. Therefore, the design control activities presented indicate that the modification of QC testing frequency provides an assay performance that is substantially equivalent to the current cleared kit

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Performance Summary

A. Expected Values

Prevalence

The observed prevalence and expected values for the modified BioPlex® 2200 HSV-1 & HSV-2 IgG kit are presented in the tables below by age and gender for serum samples from sexually active individuals where an HSV-1 (N=200) and HSV-2 (N=200) tests were ordered.

Age inYearsGenderPositiveEquivocalNegativeTotal
N%N%N%N
18-20F480.0%00.0%120.0%5
M660.0%00.0%440.0%10
21-30F1055.6%00.0%844.4%18
M1361.9%00.0%838.1%21
31-40F1794.4%00.0%15.6%18
M1575.0%00.0%525.0%20
41-50F1292.3%00.0%17.7%13
M2371.9%00.0%928.1%32
51-60F872.7%00.0%327.3%11
M1672.7%14.5%522.7%22
61-70F861.5%00.0%538.5%13
M975.0%00.0%325.0%12
71-80F00.0%00.0%1100.0%1
M2100.0%00.0%00.0%2
81-90F00.0%00.0%00.0%0
M00.0%00.0%00.0%0
UnknownUnknown150.0%00.0%150.0%2
Total14472.0%10.5%5527.5%200

Sexually Active Individuals with an HSV-1 Test Ordered (N=200): Modified BioPlex® 2200 HSV-1 IgG

Sexually Active Individuals with an HSV-2 Test Ordered (N=200): Modified BioPlex® 2200 HSV-2 IgG

BioPlex® 2200 HSV-2 IgG
Age inYearsGenderPositiveEquivocalNegativeTotal
N%N%N%
18-20F266.7%00.0%133.3%3
M116.7%00.0%583.3%6

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21-30F526.3%00.0%1473.7%19
M1338.2%00.0%2161.8%34
31-40F777.8%00.0%222.2%9
M929.0%00.0%2271.0%31
41-50F666.7%00.0%333.3%9
M1542.9%00.0%2057.1%35
51-60F666.7%00.0%333.3%9
M637.5%00.0%1062.5%16
61-70F450.0%00.0%450.0%8
M320.0%00.0%1280.0%15
71-80F00.0%00.0%00.0%0
M00.0%00.0%2100.0%2
81-90F00.0%00.0%1100.0%1
M00.0%00.0%00.0%0
UnknownUnknown133.3%00.0%266.7%3
Total7839.0%00.0%12261.0%200

B. Comparative Testing

Performance of the modified BioPlex® 2200 HSV-1 & HSV-2 IgG kit was tested against the predicate method for the populations from sexually active individuals where HSV-1 (N=200) and HSV-2 (N=200) test were ordered and a CDC HSV panel (N=80).

  • a. Sexually Active Individuals HSV-1 and HSV-2 Test Ordered
    Sexually Active Individuals With an HSV-1 Test Ordered: Modified BioPlex® 2200 HSV-1 IgG vs. Predicate (N=399)
PredicateSexually ActiveIndividualsTest Ordered(N=399)PositiveEquivocalNegativeTotal% PositiveAgreement(95% CI)% NegativeAgreement(95% CI)% TotalAgreement(95% CI)
BioPlex® 2200 HSV-1 IgG
Positive28000280100%(280/280)98.3%(116/118)99.5%(396/398)
Equivocal1102
Negative0111611798.6-100%94.0 –99.5%98.2%–99.9%
Total2812116399

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Sexually Active Individuals With an HSV-2 Test Ordered: · Modified BioPlex® 2200 HSV-2 IgG vs. Predicate (N=399)

BioPlex® 2200 HSV-2 IgG
Sexually Active. IndividualsTest Ordered(N=399)PositiveEquivocalNegativeTotal% PositiveAgreement(95% CI)% NegativeAgreement(95% CI)% TotalAgreement(95% CI)
Comparative MethodPositive1660016699.4%(166/167)100%(232/232)99.7%(398/394)
Equivocal0011
Negative0023223296.7-99.9%98.4-100%98.6-100%
Total1660233399

Comparison between modified and predicate devices

Linear regression analysis was performed using the results within the measuring range to compare the modified and predicate assays. Scatter plots along with regression statistics (slope, intercept, and correlation (Rt)) of are presented below.

Statistics of regression analysis

BioPlex AssaySlopeInterceptCorrelation (R2)
HSV-10.9977-0.0020.9879
HSV-21.0352-0.05140.9866

Image /page/9/Figure/7 description: This image contains two scatter plots comparing test vs control data. The left plot shows 'HSVG-1 (56) Prevalence Test vs. Control (n=126)' with a linear regression equation of y = 0.9977x - 0.002 and an R-squared value of 0.9879. The right plot shows 'HSVG-2 (75) Prevalence Test vs. Control (n=77)' with a linear regression equation of y = 1.0352x - 0.0514 and an R-squared value of 0.9866. Both plots have 'Control (108745) Al' on the x-axis and 'Test (108746) Al' on the y-axis, ranging from 0.0 to 8.0.

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  • b. CDC HSV Panel (N=80): The performance was assessed using a well characterized HSV serum panel from the CDC.
BioPlex® 2200 HSV-1 IgG
CDC HSV Panel(N=80)PositiveEquivocalNegativeTotal% PositiveAgreement(95% CI)% NegativeAgreement(95% CI)% TotalAgreement(95% CI)
CDC HSV-1ResultPositive420042100.0%(42/42)97.4%(37/38)98.8%(79/80)
Negative013738
Total421378091.6-100%86.5-99.5%93.3-99.8%

CDC HSV Panel: Modified BioPlex® 2200 HSV-1 IgG vs. CDC (N=80)

CDC HSV Panel: Modified BioPlex® 2200 HSV-2 IgG vs. CDC (N=80)

BioPlex® 2200 HSV-2 IgG
CDC HSV Panel(N=80)PositiveEquivocalNegativeTotal% Positive Agreement (95% CI)% Negative Agreement (95% CI)% Total Agreement (95% CI)
CDC HSV-2ResultPositive400040100.0%(40/40)100.0%(40/40)100.0%(80/80)
Negative004040
Total400408091.2-100%91.2-100%95.4-100%

C. Precision Studies

A precision panel, consisting of 8 panel members for each analyte, was prepared by Bio-Rad Laboratories. For each analyte, 2 had high positive, 2 had low positive, 2 had antibody levels near the cutoff, and 2 high negative panel members.

Precision testing was performed at Bio-Rad Laboratories on one lot of the modified BioPlex® 2200 HSV-1 & HSV-2 IgG kit. Each of the 8 panel members was tested in duplicate on 2 runs per days for 5 days for a total of 20 results per panel member (2 replicates x 2 runs x 5 days = 20 replicates per panel member). The data were analyzed for intra-assay and inter-

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assay precision in accordance to the CLSI EPS-A2 guideline. The standard deviation (SD) and percent coefficient of variation (%CV) were calculated. Results are shown in below.

HSV-1 IgGPanelMembersSampleMeanAIWithin RunBetweenRunBetween DayTotal
NSD%CVSD%CVSD%CVSD%CV
HighNegative200.50.024.5%0.000.0%0.000.0%0.024.5%
HighNegative200.70.045.5%0.045.5%0.000.0%0.057.8%
Near Cutoff201.00.065.9%0.065.9%0.000.0%0.088.4%
Near Cutoff201.00.055.0%0.000.0%0.000.0%0.055.0%
Low Positive201.30.064.9%0.053.8%0.000.0%0.086.2%
Low Positive201.60.138.0%0.053.1%0.095.6%0.1610.3%
HighPositive203.10.175.4%0.000.0%0.082.6%0.196.0%
HighPositive203.40.226.4%0.000.0%0.144.1%0.267.6%

Serum Precision- Modified BioPlex® 2200 HSV-1 IgG

Serum Precision- Modified BioPlex® 2200 HSV-2 IgG Serum

HSV-2 IgGBioPlex® 2200 HSV-2 IgG
PanelMembersSampleNMeanAIWithin RunBetween RunBetween DayTotal
SD%CVSD%CVSD%CVSD%CV
HighNegative200.60.046.5%0.000.0%0.000.0%0.046.5%
HighNegative200.80.045.6%0.044.8%0.000.0%0.067.4%
Near Cutoff201.10.065.4%0.032.9%0.021.6%0.076.3%
Near Cutoff201.10.055.0%0.000.0%0.000.0%0.055.0%
Low Positive201.30.064.6%0.032.4%0.010.6%0.075.2%
Low Positive202.30.135.8%0.083.4%0.000.0%0.156.7%
HighPositive204.10.215.2%0.071.7%0.143.3%0.266.4%
HighPositive204.70.173.5%0.081.7%0.051.1%0.194.1%

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Comparison of precision between modified and predicate devices is shown below.

HSV-1 IgG Precision Comparison Summary: Modified vs. Predicate devices

HSV-1 IgGMean, AlWithin Run %CVTotal Precision %CVBetween Run %CVBetween Day %CV
Panel MembersPredicateModifiedPredicateModifiedPredicateModifiedPredicateModifiedPredicateModified
High Negative0.50.56.3%4.5%6.3%4.5%0.0%0.0%0.0%0.0%
High Negative0.70.76.4%5.5%7.6%7.8%0.0%5.5%4.1%0.0%
Near Cutoff1.01.07.1%5.9%7.7%8.4%3.2%5.9%0.0%0.0%
Near Cutoff1.01.05.0%5.0%6.9%5.0%3.2%0.0%3.5%0.0%
Low Positive1.31.36.9%4.9%8.6%6.2%3.0%3.8%4.3%0.0%
Low Positive1.71.68.0%8.0%10.1%10.3%6.0%3.1%1.0%5.6%
High Positive3.23.14.1%5.4%4.3%6.0%1.2%0.0%0.0%2.6%
High Positive3.63.46.0%6.4%6.4%7.6%2.2%0.0%0.0%4.1%

HSV-2 IgG Precision Comparison Summary: Modified vs. Predicate devices

HSV-2 IgGMean, AlWithin Run %CVTotal Precision %CVBetween Run %CVBetween Day %CV
Panel MembersPredicateModifiedPredicateModifiedPredicateModifiedPredicateModifiedPredicateModified
High Negative0.70.66.4%6.5%7.8%6.5%4.5%0.0%0.0%0.0%
High Negative0.80.86.3%5.6%7.4%7.4%4.0%4.8%0.0%0.0%
Near Cutoff1.11.14.1%5.4%5.2%6.3%2.0%2.9%2.6%1.6%
Near Cutoff1.21.14.9%5.0%4.9%5.0%0.0%0.0%0.0%0.0%
Low Positive1.31.37.7%4.6%9.8%5.2%2.4%2.4%5.6%0.6%
Low Positive2.42.36.3%5.8%6.8%6.7%2.6%3.4%0.0%0.0%
High Positive4.44.16.1%5.2%6.1%6.4%0.0%1.7%0.0%3.3%
High Negative4.84.73.7%3.5%3.7%4.1%0.0%1.7%0.0%1.1%

D. Interference

Testing for interfering substances was conducted according to CLSI EP7-A2. Samples were prepared by blending a pool of negative human serum with samples positive for HSV-1 and HSV-2 IgG to achieve values of 2.0 to 3.0 AI and interferent or solvent (negative control) was added exogenously at levels indicated below. Test and control samples were evaluated in replicates of ten using the modified BioPlex® 2200 HSV-1 & HSV-2 IgG Kits.

Interference Substances

SubstanceConcentration
Hemoglobin500 mg/dL
Bilirubin(unconjugated)20 mg/dL
Bilirubin (conjugated)30 mg/dL
Cholesterol500 mg/dL
Red Blood Cells0.4% (v/v)

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SubstanceConcentration
Gamma-Globulin6 g/dL
Triglycerides3300 mg/dL
Total Protein(albumin)12 g/dL
Beta-Carotene0.6 mg/dL
Ascorbic Acid3 mg/dL
Lithium Heparin8000 units/dL
Sodium Heparin8000 units/dL
EDTA800 mg/dL
Sodium Citrate1000 mg/dL

E. Matrix Comparison

Matched serum and plasma (EDTA and heparin sodium) samples drawn from the same donor were acquired from commercial sources. For each assay in the panel more than 40 samples were collected within the measurement range of the assay. Samples were assayed in replicates of two using the modified BioPlex® 2200 HSV-1 & HSV-2 IgG kits. Mean plasma AI values were compared to matched mean serum AI values. The regression correlation parameters for the slopes, intercepts and correlation coefficient (r) are shown below

BioPlexAssayMatrixNSlopeInterceptCorrelation (r)
HSV-1EDTA vs.Serum471.0023-0.03580.9902
HSV-1Heparin vs.Serum470.9988-0.00690.9946
HSV-2EDTA vs.Serum440.9945-0.07370.9945
HSV-2Heparin vs.Serum440.95230.06490.9946

Matrix Comparison Regression Statistics

Scatter plots comparing the performance of EDTA and heparin plasma samples against serum samples are shown below.

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HSV-1: EDTA Plasma vs. Serum (N=47)

Image /page/14/Figure/2 description: This image is a scatter plot comparing two methods, titled "Method Comparison Mean Test vs Mean Comp." The x-axis represents serum, and the y-axis represents EDTA Plasma. The plot shows a strong positive correlation between the two methods, with the equation of the line of best fit being y = 1.0023x - 0.0358 and a correlation coefficient of r = 0.9902.

HSV-1: Heparin Plasma vs. Serum (N=47)

Image /page/14/Figure/4 description: This image is a scatter plot comparing two methods, mean test versus mean comp. The x-axis represents serum, and the y-axis represents heparin plasma. The data points are tightly clustered around a regression line, which is described by the equation y = 0.9988x - 0.0069, with a correlation coefficient of r = 0.9946.

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HSV-2: EDTA Plasma vs. Serum (N=44)

Image /page/15/Figure/2 description: This image is a scatter plot comparing two methods, titled "Method Comparison Mean Test vs Mean Comp.". The x-axis represents serum, and the y-axis represents EDTA Plasma. The plot shows a strong positive correlation between the two methods, with the equation of the line of best fit being y = 0.9945x - 0.0737 and a correlation coefficient of r = 0.9945.

HSV-2: Heparin Plasma vs. Serum (N=44)

Image /page/15/Figure/4 description: This image is a scatter plot comparing two methods, labeled as 'Mean Test' versus 'Mean Comp'. The x-axis represents 'Serum' and the y-axis represents 'Heparin Plasma'. The plot shows a strong positive correlation between the two methods, with data points closely clustered around a linear trendline. The equation of the trendline is given as y = 0.9523x + 0.0649, and the correlation coefficient (r) is 0.9946, indicating a very strong linear relationship.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/16/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS) of the United States. The seal features the department's name encircling a symbol. The symbol is a stylized representation of an eagle with its wings spread, conveying a sense of protection and care.

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993

JUN 2 2 2012

Bio-Rad Laboratories, Inc. c/o Mr. Juang Wang BioPlex Division 5500 E. Second Street Benicia, CA 94510

Re: K120959

Trade/Device Name: BioPlex 2200 HSV-1 & HSV-2 IgG Kit on the BioPlex 2200 Multi-analyte Detection System BioPlex 2200 HSV-1 & HSV-2 IgG Calibrator Set BioPlex 2200 HSV-1 & HSV-2 IgG Control Set

Regulation Number: 21 CFR 866.3305

Regulation Name: Herpes Simplex Virus Serological Reagents Regulatory Class: Class II Product Code: MXJ, MYF, JIX, JJY Dated: March 28, 2012 Received: March 30, 2012

Dear Mr. Wang:

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. 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.

If your device is classified (see above) into class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, additional controls. Enting may 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 touse of actived that I Drivination that your device complies with other requirements of the Act that I Dr has Intacted and regulations administered by other Federal agencies. You must

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Page 2 - Mr. Juang Wang

comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. 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 the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Uve Saif for

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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Indication(s) For Use Statement

510(k) Number (if known): K120959

Device Name: BioPlex® 2200 HSV-1 & HSV-2 IgG Kit BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set

Indications for Use:

BioPlex® 2200 HSV-1 & HSV-2 IgG Kit

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit is a multiplex flow immunoassay intended for the qualitative detection and differentiation of IgG antibodies to herpes simplex virus type 1 (HSV-1) and hernes simplex virus type 2 (HSV-2) in human serum and EDTA or heparinized plasma. The test is indicated for sexually active individuals and expectant mothers as an aid for the presumptive diagnosis of HSV-1 or HSV-2 infection. The predictive value of positive or negative results depends on the population's prevalence and the pretest likelihood of HSV-1 and HSV-2.

The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for use in a pediatric population, neonates and immunocompromised patients or for use at point of care facilities.

The BioPlex® 2200 HSV-1 & HSV-2 IgG kit is intended for use with the Bio-Rad BioPlex® 2200 System.

BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set

The BioPlex® 2200 HSV-1 & HSV-2 IgG Calibrator Set is intended for the calibration of the BioPlex® 2200 HSV-1 & HSV-2 IgG Reagent Pack.

BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set

The BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex® 2200 Instrument and BioPlex® 2200 HSV-1 & HSV-2 IgG Reagent Pack in the clinical laboratory. The performance of the BioPlex® 2200 HSV-1 & HSV-2 IgG Control Set has not been established with any other HSV-1 and HSV-2 antibody assays.

Over-the-Counter Use AND/OR Prescription Use X (21 CFR 801 Subpart C) (Part 21 CFR 801 Subpart D)

(Please do not write below this line-Continue on another page if needed)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Tamara Feldhuh

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K120959

Page 1 of 1

§ 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).