The ARIES® HSV 1&2 Assay is a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection and differentiation of Herpes Simplex Virus 1 and HSV 2) DNA in cutaneous or mucocutaneous lesion specimens from symptomatic patients. The test is indicated for use as an aid in diagnosis of HSV infection in symptomatic patients. The ARIES® HSV 1&2 Assay is indicated for use on the ARIES® System.

WARNING: The ARIES® HSV 1&2 Assay is not FDA cleared for use with cerebrospinal fluid (CSF). The assay is not intended to be used for prenatal screening.

Device Description

The Luminex ARIES® HSV 1 & 2 Kit is a polymerase chain reaction (PCR)-based qualitative in vitro diagnostic test for the direct detection and differentiation of herpes simplex virus (HSV) DNA using cutaneous and mucocutaneous lesion swab specimens. Patient lesion swab specimens are collected in Copan Universal Transport Medium, or identical Copan manufactured media formulations (Becton Dickinson Universal Viral Transport Media, Copan branded Universal Transport Medium for LabCorp, and the Quest Viral Culture Media) and transported to the laboratory. The specimen is pipetted into a cassette specific to the ARIES® HSV 1&2 Assay. In the cassette the specimen is lysed and nucleic acid is extracted using the ARIES® System and an extraction/ PCR cassette specific to the ARIES® HSV 1&2 Kit. An extractable sample processing control (SPC) target is present in the ARIES® HSV 1&2 assay cassette and is processed with the specimen. The Ct value of the SPC is designed to verify proper specimen lysis and nucleic acid extraction, to identify PCR inhibition, if any, and verify proper function of the extraction system and real-time instrument. The Tm value of the SPC is used as a reference for determining the target Tm.

The extracted nucleic acid is transferred via magnetic beads to the ARIES® HSV 1 & 2 Kit lyophilized PCR reagents in the cassette that contain a primer pair specific to HSV 1 and a primer pair specific to the SPC sequence. The specific primer pairs are labeled with distinct fluorophore labels. PCR amplification is performed and assay fluorescence is monitored on the Luminex ARIES® System. Incorporation of the quencher-labeled nucleotide causes a decrease in assay fluorescence. Following amplification, the reaction is slowly heated and fluorescence is monitored. The strands of the amplification products will separate at a specific melting temperature (Tm) that is determined by an increase in fluorescence as the strands are separated. The sequences between the PCR primer binding sites of the HSV 1 and HSV 2 amplicons have different base compositions that are distinguished by their different Tm. The instrument fluorescence output is analyzed and test results are determined using the ARIES® HSV 1 & 2 Kit assay protocol file. A printed results report is generated.

The Luminex ARIES® HSV 1&2 Assay chemistry is based on an expanded genetic alphabet technology, consisting of synthetic DNA base pair 2'-deoxy-5-methyl-isocytidine (iC): 2'deoxyisoguanosine (iG). The isobases ( iC and iG) pair specifically with each other and not with natural nucleotides. In addition isobases are efficiently incorporated during PCR. During PCR amplification, a quencher-modified iGTP is incorporated by the polymerase opposite an iC and a fluorophore reporter attached to a PCR primer. If the target is present and is amplified, assay fluorescence decreases with every cycle as amplification product accumulates. The decrease in assay fluorescence is monitored in real time using the Luminex ARIES® Instrument. Following PCR, the amplification products are thermally denatured and assay fluorescence is monitored. The strands of the amplification products are separated and assay fluorescence increases, thus enabling determination of the melting temperature (Tm) of the amplicon.

AI/ML Overview

Here's an analysis of the acceptance criteria and study details for the ARIES® HSV 1&2 Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a single, defined table. However, analytical and clinical performance metrics are provided and can be inferred as the criteria against which the device's performance was judged.

Parameter	Acceptance Criteria (Inferred)	Reported Device Performance
Analytical Sensitivity (LoD)	Lowest concentration with ≥ 95% positivity.	HSV-1 MacIntyre: 7.11E+03 TCID50/mL (100% positivity) HSV-1 F: 16.5 TCID50/mL (95.8% positivity) HSV-2 MS: 2.7 TCID50/mL (100% positivity) HSV-2 G: 2.8 TCID50/mL (100% positivity)
Co-infection Detection	All analytes detected when present at equal concentrations. Analytes at low concentration may not be detected in presence of high concentration of another analyte.	HSV-1 High / HSV-2 Low: HSV 1 Positive (100%) HSV-2 High / HSV-1 Low: HSV 2 Positive (100%) HSV-1 High/HSV-2 High: HSV 1&2 Positive (100%)
Interfering Substances	100% positive for HSV positive samples, 100% negative for HSV negative samples, no interference.	All HSV positive results were 100% positive, all HSV 1&2 negative results were 100% negative. (28 substances tested at specified concentrations).
Analytical Specificity (Cross-Reactivity)	100% positive for HSV positive samples, 100% negative for HSV negative samples, no cross-reactivity/interference.	All HSV positive results were 100% positive, all HSV 1&2 negative results were 100% negative. (61 microorganisms tested at specified concentrations).
Reproducibility	High agreement with expected results for moderate positive and low positive samples; expected agreement for high negative.	HSV-1 Moderate Positive: 100% HSV-1 Low Positive: 100% HSV-1 High Negative: 32.2% (expected 20-80%) HSV-2 Moderate Positive: 100% HSV-2 Low Positive: 97.8% HSV-2 High Negative: 92.2% (expected 20-80%) HSV1&2 Negative: 100%
Precision (Repeatability)	High agreement with expected results for moderate positive and low positive samples; expected agreement for high negative.	HSV-1 Moderate Positive: 100% HSV-1 Low Positive: 100% HSV-1 High Negative: 45.8% (expected 20-80%) HSV-2 Moderate Positive: 100% HSV-2 Low Positive: 100% HSV-2 High Negative: 97.4% (expected 20-80%) HSV1&2 Negative: 100%
Carryover/Cross-Contamination	0% carry-over/cross-contamination, 100% agreement for positive and negative samples.	0% carry-over and cross-contamination observed. Overall percent agreement was 100% for positive and negative samples.
Fresh Specimen Stability	Expected results for all concentrations across tested time points (up to 15 days at 2-8°C).	Data supports stability for up to 15 days at 2-8°C. Moderate positive 100% positive, low positive ~95% positive, high negative 20-80% positive, negative 0% positive.
Frozen Specimen Stability	Expected results for all concentrations across tested time points (up to 12 months at -65 to -95°C).	Data collected up to 3 months shows all targets yielding expected results. Moderate positive 100% positive, low positive ~95% positive, high negative 20-80% positive, negative 100% negative. Stable for up to 3 months.
Reagent Stability	Expected results for all targets, lots, and storage temperatures across tested time points (up to 19 months at 2-8°C and 25°C).	Data collected up to 3 months shows all targets for all lots and storage temperatures giving expected results. HSV-1 & HSV-2 replicates 100% positive, negative replicates 100% negative. Stable for 3 months.
Clinical Performance	High sensitivity and specificity for HSV-1 and HSV-2 detection in cutaneous and mucocutaneous lesions.	HSV-1 Cutaneous (N=347): Sensitivity 91.1% (95% CI: 80.4-97.0%), Specificity 94.2% (95% CI: 90.8-96.6%) HSV-1 Mucocutaneous (N=1190): Sensitivity 97.0% (95% CI: 94.2-98.7%), Specificity 95.4% (95% CI: 93.9-96.7%) HSV-2 Cutaneous (N=448): Sensitivity 95.0% (95% CI: 88.8-98.4%), Specificity 88.8% (95% CI: 85.0-91.9%) HSV-2 Mucocutaneous (N=1453): Sensitivity 98.5% (95% CI: 96.2-99.6%), Specificity 93.2% (95% CI: 91.6-94.6%)

2. Sample Sizes Used for the Test Set and Data Provenance

Clinical Test Set: A total of 1963 left-over clinical specimens were initially included.
- 1500 specimens were prospectively collected ("all comers").
- 463 specimens were pre-selected (also prospectively collected) to ensure representation of under-represented lesion types.
- 62 specimens were excluded from accuracy determinations (55 undeclared anatomical sites, 4 invalid upon re-testing, 3 unavailable for re-testing).
- Actual N values for clinical performance tables vary (e.g., N=347 for HSV-1 Cutaneous, N=1190 for HSV-1 Mucocutaneous, N=448 for HSV-2 Cutaneous, N=1453 for HSV-2 Mucocutaneous), reflecting subsets analyzed.
Data Provenance: The clinical study was conducted at three (3) geographically diverse clinical sites in the United States. The data were collected prospectively.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not specify the number or qualifications of experts used to establish the ground truth. The "reference/comparative method" used was the ELVIS HSV ID and D3 Typing Test System (a viral culture-based method). For discrepant results, bi-directional sequencing analysis using analytically validated primers was used as a supplemental reference. This implies that the ground truth was established by laboratory testing methods rather than by expert clinical consensus from a panel.

4. Adjudication Method for the Test Set

The primary reference method was the ELVIS viral culture. When the ARIES® HSV 1&2 Assay results differed from the ELVIS method, bi-directional sequencing analysis was performed as a confirmatory method for discrepancy resolution. This acts as a form of "adjudication" where a third, presumably more definitive, method is used to resolve conflicts between the index test and the primary reference.

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

No MRMC study was described. This device is a fully automated in vitro diagnostic test for direct detection of viral DNA, not an imaging or diagnostic aid that requires human interpretation. Therefore, the concept of "human readers improving with AI" is not applicable here.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) Was Done

Yes, the clinical performance study describes the standalone performance of the ARIES® HSV 1&2 Assay, comparing its results directly against the reference method (ELVIS viral culture, with sequencing for discrepancy resolution). The device itself is an automated system (ARIES® System) that performs nucleic acid extraction, amplification, and detection without human intervention in the result generation process.

7. The Type of Ground Truth Used

The ground truth for the clinical study was established using a reference laboratory method:

Primary Reference: ELVIS HSV ID and D3 Typing Test System (viral culture).
Discrepancy Resolution/Confirmatory: Bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assay. This can be considered a highly accurate laboratory-based ground truth.

8. The Sample Size for the Training Set

The document provided is a 510(k) summary for a diagnostic assay, which typically doesn't involve "training sets" in the same way machine learning algorithms do. The "assay" defines the biochemical and molecular components (primers, probes, reagents, protocol file) and the "system" (ARIES® System) is the instrument. These are developed and validated through analytical studies (LoD, specificity, reproducibility, etc.) and then clinically evaluated.

Therefore, there is no explicit "training set" sample size mentioned for a machine learning model, as this is a traditional in vitro diagnostic device, not an AI/ML-based one. The development of such assays involves extensive analytical testing of reagents and instrument parameters, which could be seen as an iterative "training" process for the assay design, but this is not reported in terms of "training set" sample sizes in the context of typical AI device submissions.

9. How the Ground Truth for the Training Set Was Established

Since there is no "training set" in the AI/ML sense, this question is not directly applicable. The assay's performance characteristics (e.g., optimal primer design, reaction conditions, melting temperature thresholds) would have been established during the development and optimization phases before the formal validation studies, using internal R&D samples and controls. The specifics of how these internal "ground truths" were established for assay development are not detailed in this regulatory submission.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

October 5, 2015

LUMINEX CORPORATION RONALD DUNN SENIOR DIRECTOR GLOBAL REGULATORY AFFAIRS 12212 TECHNOLOGY BLVD. AUSTIN TX 78727

Re: K151906

Trade/Device Name: ARIES® HSV 1&2 Assay Regulation Number: 21 CFR 886.3309 Regulation Name: Herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel Regulatory Class: II Product Code: PGI, OOI

Dated: July 10, 2015 Received: July 13, 2015

Dear Mr. Dunn:

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. 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 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act): 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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 Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Stephen J. Lovell -S for

Uwe Scherf, M. Sc., 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) K151906

Device Name ARIES® HSV 1&2 Assay

Indications for Use (Describe)

WARNING: The ARIES® HSV 1&2 Assay is not FDA cleared for use with cerebrospinal fluid (CSF). The assay is not intended to be used for prenatal screening.

Type of Use (Select one or both, as applicable)
-------------------------------------------------

X 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 Executive Summary of 510(k) information is being submitted in accordance with the requirements of 21 CFR 807.92.

510(k) Number:

K151906

Submission Type: Traditional 510(k), New Device

Measurand:

Target DNA sequences from Herpes Simplex Virus type 1 (HSV-1) and Herpes Simplex Virus type 2 (HSV-2)

Type of Test: Qualitative nucleic acid multiplex test

Applicant:

Luminex Corporation 12212 Technology Blvd Suite 130 Austin, TX 78727

Proprietary and Established Names:

ARIES® HSV 1&2 Assay

Regulatory Information:

Regulatory Information

Product Code	Classification	Regulation Section	Review Panel
PGI	II	21 CFR 866.3309– Herpes simplex virusnucleic acid amplification assay	Microbiology (83)
OOI	II	21 CFR 862.2570 Multiplex Instrument System	Chemistry (75)

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Device Components:

Device Components

Product	Description
ARIES® HSV 1&2 Assay Cassette Kit	24 ARIES® HSV 1&2 Assay cassettes whichcontain the necessary reagents for sampleextraction, nucleic acid purification andamplification.
ARIES® HSV1&2 Assay Protocol File Kit	A USB thumb drive containing the ARIES® HSV 1&2Assay Protocol File, ARIES® HSV 1&2 Assay ProtocolFile package insert and ARIES® System Quick Guide.
ARIES® System	An in vitro diagnostic (IVD) platform that performsnucleic acid based tests in clinical laboratories. TheLuminex ARIES® System is capable of automatedextraction and purification of nucleic acids frommultiple sample types as well as the automatedamplification and detection of target nucleic acidsequences by fluorescence-based PCR.

Intended Use:

The ARIES® HSV 1&2 Assay is a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection and differentiation of Herpes Simplex Virus 1 and 2 (HSV 1 and HSV 2) DNA in cutaneous or mucocutaneous lesion specimens from symptomatic patients. The test is indicated for use as an aid in diagnosis of HSV infection in symptomatic patients. The ARIES® HSV 1&2 Assay is indicated for use on the ARIES® System

WARNING: The ARIES® HSV 1&2 Assay is not FDA cleared for use with cerebrospinal fluid (CSF). The assay is not intended to be used for prenatal screening.

Indication(s) for use: Same as intended use.

Special instrument requirements: ARIES® System

Device Description:

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collected in Copan Universal Transport Medium, or identical Copan manufactured media formulations (Becton Dickinson Universal Viral Transport Media, Copan branded Universal Transport Medium for LabCorp, and the Quest Viral Culture Media) and transported to the laboratory. The specimen is pipetted into a cassette specific to the ARIES® HSV 1&2 Assay. In the cassette the specimen is lysed and nucleic acid is extracted using the ARIES® System and an extraction/ PCR cassette specific to the ARIES® HSV 1&2 Kit. An extractable sample processing control (SPC) target is present in the ARIES® HSV 1&2 assay cassette and is processed with the specimen. The Ct value of the SPC is designed to verify proper specimen lysis and nucleic acid extraction, to identify PCR inhibition, if any, and verify proper function of the extraction system and real-time instrument. The Tm value of the SPC is used as a reference for determining the target Tm.

Substantial Equivalence Information:

a. Predicate device name(s):

illumigene®HSV 1&2 DNA Amplification Assay (Meridian Bioscience, Inc.)

b. Predicate 510(k) number(s): K151046

Confidential & Restricted

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c. Comparison to Predicate:

The following tables compare ARIES® HSV 1&2 Assay to illumigene® HSV 1&2 DNA Amplification Assay (K151046). The similarities and differences between the new device and the predicate are outlined in the tables below.

Similarities between New Device and Predicate
Similarities
DeviceCharacteristic	ARIES® HSV 1 & 2 Assay(New Device)	illumigene® HSV 1&2 DNA AmplificationAssay(Predicate Device - K151046)
Intended use	The ARIES® HSV 1&2 Assay is a real-timepolymerase chain reaction (PCR) basedqualitative in vitro diagnostic test for thedirect detection and differentiation ofHerpes Simplex Virus 1 and 2 (HSV 1 andHSV 2) DNA in cutaneous ormucocutaneous lesion specimens fromsymptomatic patients. The test isindicated for use as an aid in diagnosis ofHSV infection in symptomatic patients.The ARIES® HSV 1&2 Assay is indicatedfor use on the ARIES® System.Warning: The ARIES® HSV 1&2 Assay isnot FDA cleared for use withcerebrospinal fluid (CSF). The assay is notintended to be used for prenatalscreening.	The illumigene® HSV 1&2 DNA amplificationassay, performed on the illumipro-10™, is aqualitative in vitro diagnostic test for thedirect detection and differentiation ofherpes simplex virus type 1 (HSV-1) andherpes simplex virus type 2 (HSV-2) DNA incutaneous and mucocutaneous lesionspecimens from male and female patientssuspected of Herpetic infections.illumigene® HSV 1&2 utilizes loop-mediatedisothermal DNA amplification (LAMP)technology to detect HSV-1 and HSV-2 bytargeting segments of the herpes simplexvirus 1 and herpes simplex virus 2 genomes.Results from illumigene® HSV 1&2 are usedas an aid in the diagnosis of HSV infection insymptomatic patients.The assay is intended for use in hospital,reference or state laboratory settings. Thisdevice is not intended for nonlaboratorypoint-of-care use.Warning: illumigene® HSV 1&2 is not FDAcleared for use with cerebrospinal fluid(CSF) or to aid in the diagnosis of HSVinfections of the central nervous system(CNS). The device is not intended forprenatal screening.
Specimen Types	Male and female cutaneous andmucocutaneous lesion swab specimens	Male and female cutaneous andmucocutaneous lesion swab specimens
Test Principle	DNA amplification	DNA amplification
Assay Results	Qualitative detection and differentiationof HSV-1 and HSV-2 DNA	Qualitative detection and differentiation ofHSV-1 and HSV-2 DNA
Differences
DeviceCharacteristic	ARIES® HSV 1 & 2 Assay(New Device)	illumigene® HSV 1&2 DNA AmplificationAssay(Predicate Device - K151046)
Sampleextraction andAmplificationInstrumentation	Automated sample extraction; Real-timePCR amplification/detection using theLuminex ARIES® System	Manual sample preparation; isothermalLoop Mediated Amplification (LAMP) usingthe illumipro-10 TM.
DetectionMethod	Pairs fluorescent-labeled primers withquencher labeled nucleotides. Measuresdecrease in assay fluorescence witheach PCR cycle.	Visible Light Transmission (Turbidity).

Similarities between New Device and Predicate

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Differences between New Device and Predicate

Analytical Performance:

Limit of Detection

A Limit of Detection (LoD) study was performed to evaluate the analytical sensitivity of the ARIES® HSV 1&2 Assay using two representative reference strains of HSV-1 (MacIntyre and F) and two representative strains of HSV-2 (MS & G). Preliminary LoD concentrations were determined by performing a six point, five-fold dilution series, in Copan Universal Transport Media, of each quantified (TCID50/mL) strain. The observed LoD of a HSV strain was determined as the lowest concentration that had a positivity rate of ≥ 95%.

The LoD concentrations determined in the preliminary study were confirmed with the same HSV-1 and HSV-2 reference strains diluted to the preliminary LoD concentrations and tested with twenty-four (24) replicates. The final LoD concentrations are presented in the table below.

HSV Type	Strain	LoD Concentration(TCID50/mL)	Positivity
HSV-1	MacIntyre	7.11E+03	24/24(100%)
	F	16.5	23/24(95.8%)
HSV-2	MS	2.7	24/24(100%)
	G	2.8	24/24(100%)

Limit of Detection of the ARIES® HSV 1&2 Assay

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Assay LoD: The final assay LoD claim is 7.11E+03 TCID50/mL for HSV-1 and 2.7 TCID50/mL for HSV-2.

Co-infection Verification

A study was designed to evaluate the ability of the ARIES® HSV 1&2 Assay to detect HSV-1 and HSV-2 analytes when both are present in one specimen. Analytes were tested at high (200X LoD) and low concentrations (5X LoD) using 12 replicates. The ARIES® HSV 1&2 Assay may not detect a co-infection of HSV-1 and HSV-2 in cases where the two virus types are not equally represented in clinical specimens Co-infections were only detected when both analytes were present at equal concentrations. An HSV analyte at 5X LoD was not detected in the presence of a different HSV analyte at 200X LoD. Results are presented in the table below.

Co-Infection Results

Condition	Result	Percent of Replicates
HSV-1 High / HSV-2 Low	HSV 1 Positive	100% (12/12)
HSV-2 High / HSV-1 Low	HSV 2 Positive	100% (12/12)
HSV-1 High/HSV-2 High	HSV 1&2 Positive	100% (12/12)

Interfering Substances

The effect of potential interfering substances on the ARIES® HSV 1&2 Assay was evaluated by testing five replicates of each HSV 1, HSV 2 near the device's Limit of Detection (LoD), and negative samples (Copan UTM) spiked with 28 potential interfering substances. At the tested concentrations of the substances do not interfere with the assay. All HSV positive results were 100% positive and all HSV 1&2 negative results were 100% negative. Results are presented below.

Interfering Substance Panel

Interfering Substance	Test Concentration
Abreva (Docosanol)	10%
Acyclovir (Acycloguanosine)	2.5 mg/mL
Buffy Coat	5%
Carmex Cold Sore Lip Balm	1%
Casein	7.0 mg/mL
Clotrimazole 3 Vaginal Cream	1%
Toothpaste	5%
Anti-itch cream (Benzalkonium Chloride)	5%
Cidofovir	2.5 mg/mL
Douche	10%
Foscarnet	2.5 mg/mL
Ganciclovir	2.5 mg/mL
Valganciclovir	2.5 mg/mL
Leukocytes	10%
Interfering Substance	Test Concentration

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Lip Clear Lysine+	1%
Listerine	10%
Male Urine	10%
Female Urine	10%
Whole Blood	10%
Monistat 1	5%
Monistat 3	5%
Albumin	10 mg/mL
Releev Cold Sore Treatment	1%
K-Y Brand Jelly	5%
Spermicide	5%
Tioconazole	5%
Vagisil Cream	1%
YeastGard	1%

Analytical Specificity

A study was performed to evaluate cross reactivity and interference of the ARIES® HSV 1&2 Assay with 61 microorganisms that might be found in cutaneous and mucocutaneous lesion specimens. The effect of potential cross reactivity or interference was evaluated by testing five replicates of each HSV 1, HSV 2 near the device's Limit of Detection (LoD), and Negative replicates (Copan UTM) spiked with 61 potential cross reacting organisms. Bacteria were tested at 10° cfu/ml or higher for bacteria and 105 pfu/ml or higher for viruses. At the tested concentrations of the organisms, the organisms do not cross react or interfere with the assay: all HSV positive results were 100% positive and all HSV 1&2 Negative results were 100%. Results are presented below.

Cross-Reacting and Microbial Interference Panel

Microorganism	Test Concentration
Acinetobacter calcoaceticus	$9.27 x 10^7$ cfu/mL
Bacteroides fragilis	$4.2 x 10^8$ cfu/mL
Candida albicans	$1.74 x 10^7$ cfu/mL
Candida glabrata	$7.87 x 10^6$ cfu/mL
Chlamydia trachomatis	$1.8 x 10^4$ TCID50/mL
Clostridium sordellii	$4.9 x 10^6$ cfu/mL
Cytomegalovirus (AD169 Strain)	$1.15 x 10^6$ TCID50/mL
Enterobacter cloacae	$7.43 x 10^8$ cfu/mL
Enterococcus faecalis	$4.57 x 10^8$ cfu/mL
Enterovirus (Type 71)	$4.17 x 10^4$ TCID50/mL
Epstein-Barr virus (B95-8 Strain)	$9.27 x 10^7$ copy/mL
Microorganism	Test Concentration
Escherichia coli	5.13 x 108 cfu/mL
Gardnerella vaginalis	5.43 x 106 cfu/mL
Hepatitis A Virus	8.47 x 102 IU/mL
Hepatitis B Virus	5.62 x 108 IU/mL
HIV-1	1.05 x 105 TCID50/mL
Human Herpes 6 virus (Z29 Strain)	4.17 x 104 TCID50/mL
Human Herpes 7 virus (SB Strain)	1.15 x 106 TCID50/mL
Human Papilloma virus	1.68 x 109 copy/mL
Lactobacillus acidophilus	2.00 x 107 cfu/mL
Legionella micdadei	2.70 x 108 cfu/mL
Mobiluncus mulieris	3.18 x 108 cfu/mL
Moraxella cartarrhalis	9.90 x 105 cfu/mL
Mycoplasma hominis	3.6 x 106 cfu/mL
Mycoplasma orale	1.4 x 108 cfu/mL
Mycoplasma salivarium	4.7 x 106 cfu/mL
Neisseria gonorrhoeae	5.73 x 107 cfu/mL
Propionibacterium acnes	3.7 x 108 cfu/mL
Proteus mirabilis	2.10 x 108 cfu /mL
Rubella virus	1.26 x 105 TCID50/mL
Salmonella enteritidis	2.08 x 107 cfu/mL
Serratia marcescens	4.07 x 108 cfu/mL
Staphylococcus aureus	1.42 x 109 cfu/mL
Staphylococcus epidermidis	3.47 x 108 cfu/mL
Streptococcus pyoqenes	2.60 x 108 cfu/mL
Staphylococcus saprophyticus	6.60 x 106 cfu/mL
Streptococcus aqalactiae	8.67 x 107 cfu/mL
Toxoplasma qondii	6.6 x 10岁 tachyzoites/mL
Treponema pallidum	9.8 x 106 genome copy/mL
Trichomonas vaqinalis	4.21 x 105 trophozoites/mL
Microorganism	Test Concentration
Varicella Zoster virus	2.45 x 104 TCID50/mL
Acinetobacter Iwoffi	8.27 x 107 cfu/mL
Haemophilus influenza type B	5.33 x 107 cfu/mL
Klebsiella pneumoniae	6.28 x 108 cfu/mL
Neisseria meningitides Serogroup A	7.07 x 108 cfu/mL
Prevotella melaninogenica	4.10 x 106 cfu/mL
Streptococcus mitis	5.73 x 107 cfu/mL
Streptococcus mutans	4.37 x 108 cfu/mL
Streptococcus pneumoniae	9.2 x 107 cfu/mL
Streptococcus salivarius	7.47 x 107 cfu/mL
Candida parapsilosis	2.87 x 106 cfu/mL
Candida tropicalis	2.15 x 106 cfu/mL
Human genomic DNA	10 µg/mL
Adenovirus 2	5.01 x 105 U/mL
Candida guilliermondii Z008	1.78 x 107 cfu/mL
Candida krusei Z009	6.3 x 106 cfu/mL
Candida lusitaniae Z010	1.42 x 108 cfu/mL
Fusobacterium nucleatum	N/Aa
Haemophilus ducreyi	2.05 x 106 cfu/mL
Mobiluncus curtisii V125 [DSM 2711] ATCC 43063	>103 cfu/mL
Simian Virus type 40 Pa-57 ATCC strain VR-239	2.8 x 106 TCID50/mL

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a Concentration information not available.

Reproducibility

Reproducibility of the ARIES® HSV 1&2 Assay was evaluated by testing one lot of ARIES® HSV 1&2 Assay Cassettes on two ARIES® instruments by two operators at each of three sites on five nonconsecutive days. A reproducibility panel was prepared containing a moderate positive (approximately 4X LoD for both HSV 2), low positive (approximately 1X LoD for both HSV 1 and HSV 2) and high negative (approximately 0.1X LoD for HSV 1 and 0.4X LoD for HSV 2) independently for HSV 1 and HSV 2 as well as a negative. The reproducibility panels were created by an independent operator and blinded. The results of the reproducibility study are presented in the table below.

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Reproducibility Panel Results

	Site 1					Site 2			Site 3
	Agreement withexpectedresultsa	AvgTm	% CVTm	Avg TmDeflectionb	Agreementwithexpectedresultsa	AvgTm	% CVTm	Avg TmDeflectionb	Agreementwithexpectedresultsa	AvgTm	% CVTm	Avg TmDeflectionb	TotalAgreementwithexpectedresults	95%ConfidenceInterval
HSV-1ModeratePositive	30/30	85.5	0.16%	2.25E+06	30/30	85.5	0.12%	2.56E+06	30/30	85.6	0.18%	2.72E+06	90/90(100%)	96.0-100%
HSV-1LowPositive	30/30	85.5	0.16%	2.04E+06	30/30	85.6	0.16%	2.24E+06	30/30	85.5	0.16%	2.45E+06	90/90(100%)	96.0-100%
HSV-1HighNegative	11/30	85.4	0.17%	1.39E+06	9/30	85.5	0.20%	2.33E+06	9/30	85.5	0.17%	2.06E+06	29/90(32.2%)	22.8-42.9%
HSV-2ModeratePositive	30/30	87.9	0.17%	2.17E+06	30/30	87.8	0.16%	2.52E+06	30/30	87.8	0.15%	2.43E+06	90/90(100%)	96.0-100%
HSV-2LowPositive	30/30	87.8	0.11%	1.95E+06	29/30	87.7	0.17%	2.23E+06	30/31	87.7	0.16%	2.04E+06	89/91(97.8%)	92.3-99.7%
HSV-2HighNegative	30/30	87.7	0.19%	1.75E+06	30/30	87.7	0.14%	1.98E+06	23/30	87.7	0.15%	1.94E+06	83/90(92.2%)	84.6-96.8%
HSV1&2Negative	30/30	76.4	0.30%	2.76E+05	30/30	76.3	0.24%	3.11E+05	30/30	76.3	0.68%	3.34E+05	90/90(100%)	96.0-100%

3 kgreenent with expected results for the HSV 1 cr HSV 2 was detected. Expected Expected tor HSV 1 Moderate Positive target was 100% HSV Postive, HSV 1 Low Positive was approximately 95% KSV 1 High Negative was 20% to 80% HSV 1 Postive target was 10% HSV 2 Positive, HSV 2 low Positive ws approxi- mately 95% HSV 2 Positive, HSV 2 High Negative was 20% to 80% HSV 2 Negative was 100% HSV 1&2 Negative.

ී Neerage Typ defection (RFU) was calculated using all of the target type. Average The defection for the HSV 182 Negative reflection ince no HSV 1 or HSV 2 was detected.

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Precision

Within Laboratory Precision/Repeatability of the ARIES® HSV 1&2 Assay was evaluated by two operators performing testing across multiple ARIES® instruments using one lot of ARIES® HSV 1&2 Assay Cassettes. Testing was performed in 10 days and included a total of 216 replicates used in assessing repeatability. A reproducibility panel was prepared containing moderate positive (approximately 4X LoD for both HSV 2), low positive (approximately 1X LoD for both HSV 1 and HSV 2) and high negative (approximately 0.1X LoD for HSV 1 and 0.4X LoD for HSV 2) samples independently for HSV 1 and HSV 2 as well as a negative sample. The results of the repeatability study are shown in the table below.

Target Type	Agreement with Expected Resultsb	95% Confidence Interval	Average Tm	% Coefficient of Variation - Tm	Average Tm Deflectionc
HSV 1 Moderate Positive	100%(72/72)	95.0 – 100%	85.6	0.17%	3.28E+06
HSV 1 Low Positive	100%(72/72)	95.0 – 100%	85.6	0.13%	2.88E+06
HSV 1 High Negative	45.80%(33/72)	34.0 – 58.0%	85.4	0.12%	2.18E+06
HSV 2 Moderate Positive	100%(72/72)	95.0 – 100%	87.9	0.16%	3.16E+06
HSV 2 Low Positive	100%(72/72)	95.0 – 100%	87.8	0.15%	2.75E+06
HSV 2 High Negative	97.40%(76/78)	91.0 – 99.7%	87.8	0.17%	2.39E+06
HSV 1&2 Negative	100%(72/72)	95.0 – 100%	76.5	0.66%	4.41E+05

Repeatability Panel Results a

a An overall invalid rate of 0.8% (4/514) was observed.

b Expected result for HSV 1 Moderate Positive target was 100% HSV 1 Low Positive was approximately 95% HSV 1 Positive, HSV 1 High Negative was 20% to 80% HSV 1 Positive, HSV 2 Moderate Positive target was 100% HSV 2 Positive, HSV 2 Low Positive was approximately 95% HSV 1 Positive was 20% to 80% Positive, and HSV 1&2 Negative was 100% HSV 1&2 Negative.

6 Average Tm deflection (RFU) was calculated using all of the positive replicates for that target type. Average Tm deflection for the HSV 1&2 Negative reflects SPC Tm deflection since no HSV 1 or HSV 2 was detected.

Carryover/Cross-Contamination

Carry-over and cross contamination for the ARIES® HSV 1&2 Assay was assessed by testing fifteen (15) high positive HSV 1 samples, 15 high positive HSV 2 samples and thirty (30) HSV negative

Confidential & Restricted

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samples (Copan UTM). Samples were tested in an alternating pattern with high positive samples run adjacent to negative samples across ten (10) consecutive runs. No carry-over and cross contamination was observed. The overall percent agreement was 100% for positive and negative samples.

Fresh and Frozen Specimen Stability

The objective of fresh specimen stability testing was to evaluate the stability of specimens when stored at 2 – 8°C. This was assessed by testing 6 replicates of each contrived target concentration across 6 different time points. The concentrations tested were a moderate positive, low positive and high negative for HSV 1 and HSV 2 as well as a negative concentration. Moderate positive specimens gave the expected result of 100% positive specimens gave the expected result of approximately 95% positivity and high negative specimens gave the expected result of 20 – 80% positivity. Finally negative specimens gave the expected result of 0% positivity. The data from this stability study support the claim in the package insert that fresh specimens for the ARIES® HSV 1&2 Assay can be held at 2 – 8°C for up to 15 days.

The objective of frozen specimen stability was to evaluate the stability of specimens when stored at -65 to -95°C. This was assessed by testing 6 replicates of each of contrived target concentrations in Copan across 7 different time points extending out to 12 months. The concentrations used for testing are a moderate positive and high negative concentration for HSV 1 and HSV 2 as well as a negative concentration. Data up to 3 months has been collected with all targets yielding the expected result. Moderate positive specimens are 100% positive, low positive specimens are positive approximately 95% of the time, high negative specimens are positive 20 - 80% of the time and negative specimens are negative 100% of the time. HSV 1&2 specimens are stable for up to 3 months when stored at -65 to -95°C.

Reagent Stability

The objective of ARIES® HSV 1&2 Assay Cassette real time stability testing was to evaluate the stability of ARIES® HSV 1&2 Assay Cassette in order to establish a shelf life. This was assessed by testing 4 replicates of HSV 1, 4 replicates of HSV 2 and 4 replicates of negative (Copan UTM) targets on three different lots of ARIES® HSV 1&2 Assay Cassettes stored at 2 different temperatures (2 – 8°C and 25°C) at 10 different time points extending out to 19 months. Data up to 3 months has been collected and to date all targets for all lots and all storage temperatures have given the expected result. HSV 1 replicates are 100% HSV 1 Positive, HSV 2 replicates are 100% HSV 2 Positive and negative replicates are 100% HSV 1&2 Negative. Therefore, ARIES® HSV 1&2 Assay Cassettes are stable for 3 months when stored at both 4°C and Room Temperature (25°C).

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Clinical Performance:

The performance of ARIES® HSV 1&2 Assay was assessed at three (3) geographically diverse clinical sites in the United States. A total of 1963 left-over clinical specimens from symptomatic male and female patients were included in the clinical study. Of these, 1500 specimens were prospectively collected (all comers). The remaining 463 were pre-selected for cutaneous and mucocutaneous lesion types that were under-represented in the initial prospective sample set. All of the pre-selected specimens were also prospectively collected. Of the 1963 specimens tested, fifty five (55) specimens were lesion sources from anatomical sites that could not be determined, four (4) specimens remained invalid upon re-testing by ARIES® HSV 1&2 Assay and three (3) were unavailable for re-testing. All of these 62 specimens were excluded from accuracy determinations.

The reference/comparative method used to evaluate the clinical performance of ARIES® HSV 1&2 Assay was the ELVIS HSV ID and D3 Typing Test System. Because the ELVIS method provides no information on HSV-1 patient infected status (positive or negative) in specimens that test positive for HSV-2, all specimens that were positive for HSV-2 by the ELVIS " HSV-ID and Dr Typing System were excluded from the analysis of HSV-1 clinical performance.

The performance of ARIES® HSV 1&2 assay when compared to ELVIS viral culture is summarized for cutaneous and mucocutaneous lesions in the tables below:

ARIES® HSV 1&2Assay	Reference Method
	Positive	Negative	Total
Positive	51	171	68
Negative	52	274	279
TOTAL	56	291	347
	95% CI
Sensitivity	91.1%(51/56)	80.4% - 97.0%
Specificity	94.2%(274/291)	90.8% - 96.6%

Summary of HSV 1 Results for Cutaneous Lesions (N=347)

1 Thirteen (13) HSV-1 ARIES® positive specimens that were negative by the reference method were positive by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assay. The remaining four (4) false positive specimens were negative for both HSV 2 by bi- directional sequencing.

7 All five (5) HSV-1 ARE® negative specimens that were negative by the reference method were negative by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assay. One of these specimens was positive for HSV-2 by both ARIES® and sequencing

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ARIES® HSV 1&2Assay	Reference Method
	Positive	Negative	Total
Positive	262	421	304
Negative	82	878	886
TOTAL	270	920	1190
	95% CI
Sensitivity	97.0%(262/270)	94.2% - 98.7%
Specificity	95.4%(878/920)	93.9% - 96.7%

Summary of HSV 1 Results for Mucocutaneous Lesions (N=1190)

1 Nineteen (19) HSV 1 ARIES® positive speciment that were nethod were positive by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assay. Twenty (20) false positive specimens were negative for both HSV-2 by bi-directional sequencing. The remaining three (3) specimens were unavailable (QNS) for sequence analysis.

Seven (7) HSV 1 ARIES® negative specimens that were positive by the reference method were negative by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARES® HSV 1&2 Assay. One of the for HSV 2 by both ARIES® and sequencing. One (1) false negative specimen was confirmed as positive for HSV-1 by bi-directional sequencing.

ARIES® HSV 1&2Assay	Reference Method
	Positive	Negative	Total
Positive	96	391	135
Negative	52	308	313
TOTAL	101	347	448
	95% CI
Sensitivity	95.0%(96/101)	88.8% - 98.4%
Specificity	88.8%(308/347)	85.0% - 91.9%

Summary of HSV 2 Results for Cutaneous Lesions (N=448)

් Thirty five (35) HSV 2 ARIES® positive specive by the reference method were positive by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARES® HSV 1&2 Assessible specimens were negative for both HSV-1 and HSV-2 by bi-directional sequencing.

´All five (5) HSV 2 ARIES® negative speciment by the reference method were negative by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARES® HSV 1&2 Assay. Two of these specifie for HSV 1 by both ARIES® and sequencing.

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ARIES® HSV 1&2Assay	Reference Method
	Positive	Negative	Total
Positive	259	811	340
Negative	42	1109	1113
TOTAL	263	1190	1453
	95% CI
Sensitivity	98.5%(250/263)	96.2% - 99.6%
Specificity	93.2%(1109/1190)	91.6% - 94.6%

Summary of HSV 2 Results for Mucocutaneous Lesions (N=1453)

් Fifty eight (58) HSV 2 ARIES® positive specive by the reference method were positive by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assey.Twenty-one (21) false positive specimens were negative for both HSV-2 by bi-direc- tional sequencing. The remaining two (2) specimens were unavailable (QNS) for sequence analysis.

² All four (4) HSV 2 ARES® negative specimens that were positive by the reference method were negative by bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assay. Three (3) of these specimens were positive for HSV 1 by both ARIES® and sequencing.

Expected Values / Reference Range:

The prevalence of HSV 1 and HSV 2 with the ARIES® HSV 1&2 Assay is calculated for cutaneous and mucocutaneous specimens and is summarized for the combined sample set per age groups and by specimen source in the tables below.

Age (years)	HSV-1			HSV-2
	Total #	TotalPositive	ExpectedValue	Total #	TotalPositive	ExpectedValue
0 - 10	10	4	40.0%	10	0	0.0%
11 - 20	53	16	30.2%	53	9	17.0%
21 - 30	125	19	15.2%	125	39	31.2%
31 - 40	85	17	20.0%	85	26	30.6%
41 - 50	63	5	7.9%	63	18	28.6%
51 - 60	50	4	8.0%	50	16	32.0%
>60	62	3	4.8%	62	27	43.5%
Not Determined	0	0	0.0%	0	0	0.0%
Overall	448	68	15.2%	448	135	30.1%

Cutaneous Prevalence by Age

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Source	HSV-1			HSV-2
	Total #	TotalPositive	ExpectedValue	Total #	TotalPositive	ExpectedValue
Genital - Penis	228	24	10.5%	228	74	32.5%
Skin Lesion	220	44	20.0%	220	61	27.7%
Overall	448	68	15.2%	448	135	30.1%

Cutaneous Prevalence by Lesion Source

Mucocutaneous Prevalence by Age

Age (years)	HSV-1			HSV-2
	Total #	TotalPositive	ExpectedValue	Total #	TotalPositive	ExpectedValue
0 - 10	103	14	13.6%	103	3	2.9%
11 - 20	233	78	33.5%	233	47	20.2%
21 - 30	463	114	24.6%	463	127	27.4%
31 - 40	262	54	20.6%	262	62	23.7%
41 - 50	177	23	13.0%	177	48	27.1%
51 - 60	112	12	10.7%	112	26	23.2%
>60	95	8	8.4%	95	27	28.4%
Not Determined	8	1	0.0%	8	0	0.0%
Overall	1453	304	20.9%	1453	340	23.4%

Mucocutaneous Prevalence by Lesion Source

Source	HSV-1			HSV-2
	Total #	TotalPositive	ExpectedValue	Total #	TotalPositive	ExpectedValue
Anorectal /Perianal	37	3	8.1%	37	14	37.8%
Genital -Vaginal /Cervical	688	142	20.6%	688	187	27.2%
Genital -Labia / Vulva	377	71	18.8%	377	121	32.1%
Urethral	25	4	16.0%	25	4	16.0%
Nasal	45	5	11.1%	45	5	11.1%
Ocular	43	5	11.6%	43	3	7.0%
Oral	238	74	31.1%	238	6	2.5%
Overall	1453	304	20.9%	1453	340	23.4%

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Conclusion:

The information submitted in this premarket notification supports the intended use of the device and demonstrates that the device is substantially equivalent to the predicate device.

Regulation Number and Section

§ 866.3309 Herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel.

(a)
Identification. A herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel is a qualitative in vitro diagnostic device intended for the simultaneous detection and differentiation of different herpes viruses in cutaneous and mucocutaneous lesion samples from symptomatic patients suspected of Herpetic infections. Negative results do not preclude infection and should not be used as the sole basis for treatment or other patient management decisions. The assay is not intended for use in cerebrospinal fluid samples.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed documentation for the device description, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology including primer design and selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (Limit of Detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, and cross contamination.
(3) Premarket notification submissions must include detailed documentation of a clinical study using lesion samples in which Herpes Simplex Virus 1, Herpes Simplex Virus 2, or Varicella Zoster Virus DNA detection was requested. The study must compare the device performance to an appropriate well established reference method.
(4) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(5) The device labeling must include a limitation statement that reads: “The device is not intended for use with cerebrospinal fluid or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS).”
(6) Premarket notification submissions must include quality assurance protocols and a detailed documentation for device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.
(7) The risk management activities performed as part of the manufacturer's 21 CFR 820.30 design controls must document an appropriate end user device training program that will be offered as part of efforts to mitigate the risk of failure to correctly operate the instrument.