(85 days)
Not Found
No
The device description details a standard PCR-based diagnostic test with fluorescence monitoring and melting temperature analysis. There is no mention of AI or ML in the device description, intended use, or performance studies. The analysis of results is described as being determined by an "assay protocol file," which is typical for rule-based or algorithmic analysis in such systems, not AI/ML.
No.
This device is an in vitro diagnostic test designed to detect and differentiate Herpes Simplex Virus 1 and HSV 2 DNA, which aids in diagnosis rather than providing direct therapy or treatment.
Yes
The "Intended Use / Indications for Use" section explicitly states that the assay is "a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test" and is "indicated for use as an aid in diagnosis of HSV infection in symptomatic patients."
No
The device is an in vitro diagnostic test that involves physical specimen handling, nucleic acid extraction, PCR amplification, and fluorescence monitoring using a dedicated hardware system (ARIES® System). While software is used for analysis and reporting, it is an integral part of a larger hardware-based system, not a standalone software-only device.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The description explicitly states it is a "qualitative in vitro diagnostic test" and is intended for "aid in diagnosis of HSV infection in symptomatic patients."
- Device Description: The description details how the test is performed on patient specimens (cutaneous or mucocutaneous lesion specimens) outside of the body to detect and differentiate HSV DNA. This is the core definition of an in vitro diagnostic test.
- Performance Studies: The document includes summaries of both analytical and clinical performance studies, which are standard requirements for demonstrating the effectiveness and reliability of an IVD.
- Key Metrics: The inclusion of sensitivity, specificity, PPV, and NPV are key metrics used to evaluate the performance of diagnostic tests.
- Predicate Device: The mention of a predicate device (K151046; illumigene®HSV 1&2 DNA Amplification Assay) is common in regulatory submissions for IVDs, indicating a comparison to a previously cleared device.
All of these elements strongly indicate that this device is an In Vitro Diagnostic.
N/A
Intended Use / Indications for 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 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.
Product codes (comma separated list FDA assigned to the subject device)
PGI, OOI
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.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
cutaneous or mucocutaneous lesion specimens
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Analytical Performance:
- Limit of Detection (LoD):
- Study performed to evaluate analytical sensitivity using two HSV-1 strains (MacIntyre and F) and two HSV-2 strains (MS & G).
- Preliminary LoD determined by a six-point, five-fold dilution series in Copan Universal Transport Media.
- Confirmed with 24 replicates at preliminary LoD concentrations.
- Final LoD: HSV-1 at 7.11E+03 TCID50/mL, HSV-2 at 2.7 TCID50/mL.
- Co-infection Verification:
- Evaluated ability to detect HSV-1 and HSV-2 when both are present.
- Analytes tested at high (200X LoD) and low (5X LoD) concentrations with 12 replicates.
- Co-infections detected only when both analytes were at equal concentrations.
- HSV analyte at 5X LoD was not detected in the presence of a different HSV analyte at 200X LoD.
- Results: 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:
- Evaluated effect of 28 potential interfering substances on ARIES® HSV 1&2 Assay.
- Tested five replicates of HSV 1, HSV 2 near LoD, and negative samples spiked with substances.
- At tested concentrations, substances did not interfere; all HSV positive results were 100% positive, all HSV 1&2 negative results were 100% negative.
- Analytical Specificity (Cross-Reactivity and Microbial Interference Panel):
- Evaluated cross-reactivity and interference with 61 microorganisms found in cutaneous and mucocutaneous lesion specimens.
- Tested five replicates of HSV 1, HSV 2 near LoD, and Negative replicates spiked with organisms.
- Bacteria tested at 10^7 cfu/ml or higher, viruses at 10^5 pfu/ml or higher.
- At tested concentrations, organisms did not cross-react or interfere; all HSV positive results were 100% positive, all HSV 1&2 Negative results were 100% negative.
- Reproducibility:
- Evaluated across three sites, with two operators per site, on two ARIES® instruments, over five non-consecutive days.
- Panel included moderate positive (approx. 4X LoD), low positive (approx. 1X LoD), high negative (approx. 0.1X LoD for HSV 1 and 0.4X LoD for HSV 2), and negative samples.
- Results: HSV-1 Moderate Positive (100% agreement), HSV-1 Low Positive (100% agreement), HSV-1 High Negative (32.2% agreement), HSV-2 Moderate Positive (100% agreement), HSV-2 Low Positive (97.8% agreement), HSV-2 High Negative (92.2% agreement), HSV1&2 Negative (100% agreement).
- Precision (Within Laboratory Repeatability):
- Evaluated by two operators across multiple ARIES® instruments, using one lot of cassettes, over 10 days (216 replicates).
- Panel similar to reproducibility study.
- Results: HSV 1 Moderate Positive (100%), HSV 1 Low Positive (100%), HSV 1 High Negative (45.80%), HSV 2 Moderate Positive (100%), HSV 2 Low Positive (100%), HSV 2 High Negative (97.40%), HSV 1&2 Negative (100%). Overall invalid rate of 0.8%.
- Carryover/Cross-Contamination:
- Assessed by testing 15 high positive HSV 1, 15 high positive HSV 2, and 30 HSV negative samples in an alternating pattern across 10 consecutive runs.
- No carry-over or cross-contamination observed. Overall percent agreement was 100% for positive and negative samples.
- Fresh and Frozen Specimen Stability:
- Fresh specimens: Evaluated stability at 2 – 8°C for up to 15 days using 6 replicates of various concentrations. Data supports 15-day stability.
- Frozen specimens: Evaluated stability at -65 to -95°C for up to 12 months using 6 replicates of various concentrations. Data up to 3 months collected supports stability.
- Reagent Stability:
- Real-time stability testing for ARIES® HSV 1&2 Assay Cassette to establish shelf life.
- Tested 4 replicates of HSV 1, HSV 2, and negative targets from three different lots at 2-8°C and 25°C at 10 time points up to 19 months.
- Data up to 3 months collected shows expected results. Supports 3 months stability at 4°C and Room Temperature (25°C).
Clinical Performance:
- Study Design:
- Performed at three geographically diverse clinical sites in the United States.
- Total of 1963 left-over clinical specimens from symptomatic male and female patients.
- 1500 specimens prospectively collected ("all comers").
- 463 specimens pre-selected for under-represented cutaneous and mucocutaneous lesion types (also prospectively collected).
- 55 specimens with undetermined anatomical sites, 4 invalid upon re-testing, 3 unavailable for re-testing were excluded (total 62 excluded from accuracy determinations).
- Reference Method: ELVIS HSV ID and D3 Typing Test System.
- Specimens positive for HSV-2 by ELVIS were excluded from HSV-1 clinical performance analysis as ELVIS provides no HSV-1 status information in such cases.
- Summary of Results (Compared to ELVIS viral culture):
- HSV 1 Cutaneous Lesions (N=347):
- Sensitivity: 91.1% (51/56)
- Specificity: 94.2% (274/291)
- Note: 13 HSV-1 ARIES® positive/reference negative specimens confirmed by bi-directional sequencing. 4 false positive specimens were HSV-2 negative by sequencing. 5 HSV-1 ARIES® negative/reference negative specimens confirmed negative by sequencing.
- HSV 1 Mucocutaneous Lesions (N=1190):
- Sensitivity: 97.0% (262/270)
- Specificity: 95.4% (878/920)
- Note: 19 HSV 1 ARIES® positive/reference negative specimens confirmed by bi-directional sequencing. 20 false positive specimens were HSV-2 negative by sequencing. 3 QNS for sequence analysis. 7 HSV 1 ARIES® negative/reference positive specimens confirmed negative by sequencing. 1 false negative confirmed positive by sequencing.
- HSV 2 Cutaneous Lesions (N=448):
- Sensitivity: 95.0% (96/101)
- Specificity: 88.8% (308/347)
- Note: 35 HSV 2 ARIES® positive/reference negative specimens confirmed by bi-directional sequencing. Unassessible specimens were HSV-1 and HSV-2 negative by sequencing. 5 HSV 2 ARIES® negative/reference negative specimens confirmed negative by sequencing.
- HSV 2 Mucocutaneous Lesions (N=1453):
- Sensitivity: 98.5% (250/263)
- Specificity: 93.2% (1109/1190)
- Note: 58 HSV 2 ARIES® positive/reference negative specimens confirmed by bi-directional sequencing. 21 false positive specimens were HSV-2 negative by sequencing. 2 QNS for sequence analysis. 4 HSV 2 ARIES® negative/reference positive specimens confirmed negative by sequencing.
- HSV 1 Cutaneous Lesions (N=347):
- Expected Values / Reference Range (Prevalence):
- HSV 1 and HSV 2 prevalence calculated for cutaneous and mucocutaneous specimens, summarized by age groups and specimen source.
- Cutaneous Prevalence by Age: Overall HSV-1 prevalence 15.2% (68/448), HSV-2 prevalence 30.1% (135/448).
- Cutaneous Prevalence by Lesion Source: Genital - Penis (HSV-1: 10.5%, HSV-2: 32.5%), Skin Lesion (HSV-1: 20.0%, HSV-2: 27.7%).
- Mucocutaneous Prevalence by Age: Overall HSV-1 prevalence 20.9% (304/1453), HSV-2 prevalence 23.4% (340/1453).
- Mucocutaneous Prevalence by Lesion Source: Anorectal/Perianal, Genital-Vaginal/Cervical, Genital-Labia/Vulva, Urethral, Nasal, Ocular, Oral.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
For HSV 1 Cutaneous Lesions (N=347):
Sensitivity: 91.1% (51/56) (95% CI: 80.4% - 97.0%)
Specificity: 94.2% (274/291) (95% CI: 90.8% - 96.6%)
For HSV 1 Mucocutaneous Lesions (N=1190):
Sensitivity: 97.0% (262/270) (95% CI: 94.2% - 98.7%)
Specificity: 95.4% (878/920) (95% CI: 93.9% - 96.7%)
For HSV 2 Cutaneous Lesions (N=448):
Sensitivity: 95.0% (96/101) (95% CI: 88.8% - 98.4%)
Specificity: 88.8% (308/347) (95% CI: 85.0% - 91.9%)
For HSV 2 Mucocutaneous Lesions (N=1453):
Sensitivity: 98.5% (250/263) (95% CI: 96.2% - 99.6%)
Specificity: 93.2% (1109/1190) (95% CI: 91.6% - 94.6%)
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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.
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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.
1
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)
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.
| 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:
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 virus | |
| nucleic 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 which |
| contain the necessary reagents for sample | |
| extraction, nucleic acid purification and | |
| amplification. | |
| ARIES® HSV1&2 Assay Protocol File Kit | A USB thumb drive containing the ARIES® HSV 1&2 |
| Assay Protocol File, ARIES® HSV 1&2 Assay Protocol | |
| File package insert and ARIES® System Quick Guide. | |
| ARIES® System | An in vitro diagnostic (IVD) platform that performs |
| nucleic acid based tests in clinical laboratories. The | |
| Luminex ARIES® System is capable of automated | |
| extraction and purification of nucleic acids from | |
| multiple sample types as well as the automated | |
| amplification and detection of target nucleic acid | |
| sequences 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:
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
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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.
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.
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 | ||
| Device | ||
| Characteristic | ARIES® HSV 1 & 2 Assay | |
| (New Device) | illumigene® HSV 1&2 DNA Amplification | |
| Assay | ||
| (Predicate Device - K151046) | ||
| 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. | The illumigene® HSV 1&2 DNA amplification | |
| assay, performed on the illumipro-10™, is a | ||
| qualitative in vitro diagnostic test for the | ||
| direct detection and differentiation of | ||
| herpes simplex virus type 1 (HSV-1) and | ||
| herpes simplex virus type 2 (HSV-2) DNA in | ||
| cutaneous and mucocutaneous lesion | ||
| specimens from male and female patients | ||
| suspected of Herpetic infections. | ||
| illumigene® HSV 1&2 utilizes loop-mediated | ||
| isothermal DNA amplification (LAMP) | ||
| technology to detect HSV-1 and HSV-2 by | ||
| targeting segments of the herpes simplex | ||
| virus 1 and herpes simplex virus 2 genomes. | ||
| Results from illumigene® HSV 1&2 are used | ||
| as an aid in the diagnosis of HSV infection in | ||
| symptomatic patients. | ||
| The assay is intended for use in hospital, | ||
| reference or state laboratory settings. This | ||
| device is not intended for nonlaboratory | ||
| point-of-care use. | ||
| Warning: illumigene® HSV 1&2 is not FDA | ||
| cleared for use with cerebrospinal fluid | ||
| (CSF) or to aid in the diagnosis of HSV | ||
| infections of the central nervous system | ||
| (CNS). The device is not intended for | ||
| prenatal screening. | ||
| Specimen Types | Male and female cutaneous and | |
| mucocutaneous lesion swab specimens | Male and female cutaneous and | |
| mucocutaneous lesion swab specimens | ||
| Test Principle | DNA amplification | DNA amplification |
| Assay Results | Qualitative detection and differentiation | |
| of HSV-1 and HSV-2 DNA | Qualitative detection and differentiation of | |
| HSV-1 and HSV-2 DNA | ||
| Differences | ||
| Device | ||
| Characteristic | ARIES® HSV 1 & 2 Assay | |
| (New Device) | illumigene® HSV 1&2 DNA Amplification | |
| Assay | ||
| (Predicate Device - K151046) | ||
| Sample | ||
| extraction and | ||
| Amplification | ||
| Instrumentation | Automated sample extraction; Real-time | |
| PCR amplification/detection using the | ||
| Luminex ARIES® System | Manual sample preparation; isothermal | |
| Loop Mediated Amplification (LAMP) using | ||
| the illumipro-10 TM. | ||
| Detection | ||
| Method | Pairs fluorescent-labeled primers with | |
| quencher labeled nucleotides. Measures | ||
| decrease in assay fluorescence with | ||
| each 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 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Agreeme | ||||||||||||||
| nt with | ||||||||||||||
| expected | ||||||||||||||
| resultsa | AvgTm | % CV | ||||||||||||
| Tm | Avg Tm | |||||||||||||
| Deflectionb | Agreement | |||||||||||||
| with | ||||||||||||||
| expected | ||||||||||||||
| resultsa | AvgTm | % CV | ||||||||||||
| Tm | Avg Tm | |||||||||||||
| Deflectionb | Agreement | |||||||||||||
| with | ||||||||||||||
| expected | ||||||||||||||
| resultsa | AvgTm | % CV | ||||||||||||
| Tm | Avg Tm | |||||||||||||
| Deflectionb | Total | |||||||||||||
| Agreement | ||||||||||||||
| with | ||||||||||||||
| expected | ||||||||||||||
| results | 95% | |||||||||||||
| Confidence | ||||||||||||||
| Interval | ||||||||||||||
| HSV-1 | ||||||||||||||
| Moderate | ||||||||||||||
| Positive | 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-1 | ||||||||||||||
| Low | ||||||||||||||
| Positive | 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-1 | ||||||||||||||
| High | ||||||||||||||
| Negative | 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-2 | ||||||||||||||
| Moderate | ||||||||||||||
| Positive | 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-2 | ||||||||||||||
| Low | ||||||||||||||
| Positive | 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-2 | ||||||||||||||
| High | ||||||||||||||
| Negative | 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&2 | ||||||||||||||
| Negative | 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
14
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&2
| Assay | 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&2
| Assay | 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&2
| Assay | 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&2
| Assay | 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 # | Total | |||||
| Positive | Expected | |||||
| Value | Total # | Total | ||||
| Positive | Expected | |||||
| Value | ||||||
| 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 # | Total | |||||
| Positive | Expected | |||||
| Value | Total # | Total | ||||
| Positive | Expected | |||||
| Value | ||||||
| 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 # | Total | |||||
| Positive | Expected | |||||
| Value | Total # | Total | ||||
| Positive | Expected | |||||
| Value | ||||||
| 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 # | Total | |||||
| Positive | Expected | |||||
| Value | Total # | Total | ||||
| Positive | Expected | |||||
| Value | ||||||
| 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.