Predicate Devices

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The description details a real-time PCR assay with automated sample processing and detection based on fluorescence thresholds. There is no mention of AI or ML in the device description, intended use, or performance studies.

Therapeutic

No
The device is an in vitro diagnostic test intended to aid in the diagnosis of certain viral infections by detecting viral DNA. It does not provide treatment or therapy.

Diagnostic

Yes

The "Intended Use / Indications for Use" section explicitly states that the Savanna HSV 1+2/VZV Assay is an "in vitro diagnostic test" and "is intended to aid in the diagnosis of patients with signs or symptoms of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus infection."

SaMD (Software as a Medical Device)

No

The device description clearly states it consists of a "single, self-contained assay cartridge employing real-time PCR technology for use with the Savanna instrument" and details the physical processes involved (transferring sample, pumping liquids, sonication, PCR reactions). This indicates a significant hardware component (the cartridge and the Savanna instrument) is integral to the device's function, not just software running on general-purpose hardware.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use/Indications for Use: The document explicitly states, "This in vitro diagnostic test is intended to aid in the diagnosis of patients with signs or symptoms of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus infection." This directly identifies it as an in vitro diagnostic test.
Device Description: The description details how the device analyzes human biological samples (cutaneous or mucocutaneous lesion samples) to detect and differentiate specific viral DNA. This is a core function of an IVD.
Performance Studies: The document includes extensive performance studies (Limit of Detection, Inclusivity, Cross Reactivity, Repeatability, Reproducibility, Clinical Performance) which are standard requirements for demonstrating the analytical and clinical validity of an IVD.
Predicate Device: The mention of a "Predicate Device(s)" with a K number (K162451; Solana HSV 1+2/VZV Assay) indicates that this device is being compared to a previously cleared IVD, a common process in regulatory submissions for IVDs.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Savanna HSV 1+2/VZV Assay is an automated, rapid multianalyte real-time PCR test for the simultaneous qualitative detection and differentiation of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus DNA isolated from human cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This in vitro diagnostic test is intended to aid in the diagnosis of patients with signs or symptoms of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus infection.

The Savanna HSV 1+2/VZV Assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes simplex virus 2 and varicella-zoster virus active infections. The results of this test should not be used as the sole basis for diagnosis, treatment or other management decisions and must be combined with clinical observations, patient history and/or epidemiological information. Negative results do not preclude herpes simplex virus type 1, herpes simplex virus type 2, or varicella-zoster virus infection that is not detected by a cutaneous or mucocutaneous lesion swab specimen. Positive results do not rule out co-infection with other organisms. Additional laboratory testing (e.g., viral culture, immunoassay, serology) may be necessary for patient evaluation. Savanna HSV 1+2/VZV Assay is for professional use. The Savanna HSV 1+2/VZV Assay is intended for use only with the Savanna instrument.

Warning: The Savanna HSV 1+2/VZV Assay is not intended for use with the cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Savanna HSV 1+2/VZV Assay is not intended for use in prenatal screening.

Product codes (comma separated list FDA assigned to the subject device)

PGI

Device Description

The Savanna HSV 1+2/VZV Assay consists of a single, self-contained assay cartridge employing real-time PCR technology for use with the Savanna instrument to detect and differentiate DNA from herpes simplex virus type 1, herpes simplex virus type 2 and varicella-zoster virus. In approximately 24 minutes, this platform extracts, amplifies and detects DNA present in cutaneous or mucocutaneous lesion swab specimens obtained from symptomatic patients and placed in transport media.

To initiate the assay, a patient cutaneous or mucocutaneous lesion swab specimen in transport medium is transferred via the supplied transfer pipette to the Liguid Sample Port of the Test Cartridge. The user closes the Sample Port and inserts the Test Cartridge into the Savanna instrument, initiating sample processing. The sample containing human DNA is pushed out of the Sample Port by lysis buffer, which then rehydrates the Process Internal Control (IC), and together with the paramagnetic nucleic acid binding particles, are pumped into the extraction chamber. The solution is mixed, and virus and/ or bacteria are further lysed by sonication within the extraction chamber. Specimen and IC DNA are bound to, washed and then eluted off the paramagnetic particles. The purified specimen DNA and IC solution is used to rehydrate four individual lyophilized master mixes. Each master mix is pumped into a PCR chamber and Taq-man® multiplex real-time PCR reactions are carried out under optimized conditions, generating amplicons for the targeted pathogen (if present) and the Process Internal Control (IC).

Each master mix contains primers and dual-labeled probes unique for the pathogen targets and the IC. The probes are labeled with a fluorophore on one end and a quencher on the other end. Target DNA sequences are amplified by pathogen-specific primers and detected by correspondingly specific fluorescence probes. The IC targets are also amplified by specific primers and detected by an IC-specific fluorescence probe. A polymerase included in the master mix cleaves the probes bound to complementary DNA sequences, separating the fluorophore from the quencher. This step generates a signal and if it surpasses multiple defined thresholds, the sample is reported as positive for the detected target sequence.

The Savanna instrument will display the test results (Positive or Invalid) on the main bay screen.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

human cutaneous or mucocutaneous lesion samples

Indicated Patient Age Range

Not Found

Intended User / Care Setting

professional use

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)

Limit of Detection:

Study Type: Analytical study to determine the sensitivity of the assay.
Sample Size: Not explicitly stated as a single number but involved testing serial dilutions.
Key Results:
- HSV-1 (Isolate 2): LoD = 1.16E+02 TCID50/mL, 6.65E+02 cp/mL
- HSV-1 (Macintyre): LoD = 1.08E-03 TCID50/mL, 2.86E+02 cp/mL
- HSV-2 (Strain G): LoD = 2.50E+01 TCID50/mL, 1.27E+04 cp/mL
- HSV-2 (MS): LoD = 8.51E+00 TCID50/mL, 7.64E+01 cp/mL
- VZV (Ellen): LoD = N/A TCID50/mL, 3.32E+03 cp/mL
- VZV (Strain 82): LoD = N/A TCID50/mL, 2.76E+03 cp/mL

Co-spike Limit of Detection:

Study Type: Analytical study to demonstrate impact of multi-analyte preparation on LoD.
Sample Size: Not explicitly stated, but each test involved one strain of HSV-1, HSV-2, and VZV mixed at 1x LoD level and evaluated with three kit lots.
Key Results: Co-spiked multi-analyte sample mix showed >95% positivity for each target DNA, verifying that co-spike does not impact the LoD.

Inclusivity:

Study Type: Analytical reactivity study.
Sample Size: Tested four additional strains of HSV-1, four additional strains of HSV-2, and five additional strains of VZV.
Key Results: All tested pathogens were detected by the assay at specified concentrations.

In silico Inclusivity Analysis:

Study Type: Bioinformatic analysis.
Data Source: NCBI databases for HSV-1, HSV-2, and VZV sequences.
Key Results: Primer and probe sets for HSV-1, HSV-2, and VZV have high homologies toward their respective target sequences (HSV-1: 93.3-100%, HSV-2: 93.33-100%, VZV: 100%).

Cross Reactivity/Microbial Interference:

Study Type: Analytical study.
Sample Size: Evaluated 22 viral isolates and 38 bacterial and fungal microorganisms.
Key Results: None of the tested viruses or microorganisms showed signs of cross-reactivity or microbial interference at the concentrations listed, in the presence or absence of the target analytes.

Interfering Substances:

Study Type: Analytical study.
Sample Size: Evaluated several endogenous substances, over-the-counter (OTC) products, and prescription medications.
Key Results: None of the substances interfered with the assay at the levels listed.

Competitive Interference:

Study Type: Analytical study.
Sample Size: Samples prepared with two target analytes at different combinations of high and low concentrations. Five replicates per sample were evaluated.
Key Results: When competitive interference was observed for HSV-1 with high HSV-2 (at 1000x LoD and 500x LoD), and for HSV-2 with high HSV-1 (at 1000x LoD), titration of the high-level analyte was performed. The report clarifies that negative results for analytes not present in the sample are true negatives and not due to competitive interference.

Repeatability/Within-Lab Precision:

Study Type: 20-day within-laboratory precision study.
Sample Size: Two testing events per day, two replicates of a three-member test panel (negative, co-spiked low positive, co-spiked moderate positive) on three product lots. (Total 240 tests for each analyte's negative/moderate samples, 239 for some of the low positive)
Key Results: High agreement with expected results.
- Negative sample: HSV-1 (99.6%), HSV-2 (99.6%), VZV (100.0%).
- Low positive sample: HSV-1 (99.2%), HSV-2 (100.0%), VZV (99.6%).
- Moderate positive sample: HSV-1 (99.6%), HSV-2 (100.0%), VZV (99.6%).
- Low %CV values for repeatability, between runs, between days, and between lots across all analytes.

Reproducibility:

Study Type: Five-day, multi-site reproducibility study.
Sample Size: Three healthcare facilities, two operators per site, two replicates of a three-member test panel (negative, co-spiked low positive, co-spiked moderate positive) each day. (Total 179/180 tests for each analyte)
Key Results: High agreement with expected results.
- Negative sample: 100% agreement across all sites for all three analytes.
- Low positive samples: HSV-1 (99.4%), HSV-2 (100%), VZV (100%).
- Moderate positive samples: HSV-1 (99.4%), HSV-2 (100%), VZV (99.4%).
- Low %CV values for repeatability, between day, between site, between lot, and between operator.

External Control Performance:

Study Type: Analytical study.
Sample Size: 30 replicates each of positive and negative controls on three device lots (total 180 tests).
Key Results:
- Positive control: 100% agreement to expected positive results on all three device lots.
- Negative control: 96.8% agreement on one device lot, 100% agreement on the other two.

Transport Media and Specimen Stability/Storage:

Study Type: Stability study.
Key Results: Specimens collected in transport medium are stable under specified conditions:
- Copan UTM: Up to 24 hours at Room Temperature (15-30°C), Up to 48 hours at Refrigerated (4°C).
- Remel M4RT: Up to 96 hours at Room Temperature (15-30°C), Up to 96 hours at Refrigerated (4°C).
- Remel M5: Up to 48 hours at Room Temperature (15-30°C), Up to 96 hours at Refrigerated (4°C).
- Remel M6: Up to 72 hours at Room Temperature (15-30°C), Up to 72 hours at Refrigerated (4°C).

Clinical Study #1 (Fresh Samples):

Study Type: Multi-site clinical study in the United States.
Sample Size: 590 residual specimens (cutaneous or mucocutaneous lesion samples) from symptomatic individuals.
Data Source: Specimens randomly selected from subjects tested for HSV-1, HSV-2 or VZV infection.
Annotation Protocol: Comparison to FDA-cleared nucleic acid amplification tests.
Key Results (PPA = Positive Percent Agreement, NPA = Negative Percent Agreement):
- HSV1 - Cutaneous (N=207): PPA=92.00% (23/25), NPA=99.45% (181/182)
- HSV1 - Mucocutaneous (N=383): PPA=100.00% (81/81), NPA=96.36% (291/302)
- HSV2 - Cutaneous (N=207): PPA=92.86% (13/14), NPA=100.00% (193/193)
- HSV2 - Mucocutaneous (N=383): PPA=94.34% (50/53), NPA=99.09% (327/330)
- VZV - Cutaneous (N=207): PPA=100.00% (37/37), NPA=99.41% (169/170)
- VZV - Mucocutaneous (N=383): PPA=100.00% (5/5), NPA=100.00% (377/377)

Clinical Study #2 (Frozen Residual Samples):

Study Type: Clinical study supplementing Clinical Study #1.
Sample Size: 154 evaluable residual frozen cutaneous and mucocutaneous swab samples.
Data Source: Residual specimens from patients with signs and symptoms of HSV-1, HSV-2 or VZV infection.
Annotation Protocol: Comparison to commercially available RT-PCR comparator method(s).
Key Results (PPA = Positive Percent Agreement, NPA = Negative Percent Agreement):
- HSV1 - Cutaneous (N=90): PPA=100.00% (27/27), NPA=96.83% (61/63)
- HSV1 - Mucocutaneous (N=64): PPA=100.00% (29/29), NPA=100.00% (35/35)
- HSV2 - Cutaneous (N=90): PPA=100.00% (30/30), NPA=100.00% (60/60)
- HSV2 - Mucocutaneous (N=64): PPA=100.00% (15/15), NPA=97.96% (48/49)
- VZV - Cutaneous (N=90): PPA=100.00% (17/17), NPA=100.00% (73/73)
- VZV - Mucocutaneous (N=64): PPA=100.01% (4/4), NPA=100.01% (60/60)

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Clinical Study #1: PPA (Positive Percent Agreement), NPA (Negative Percent Agreement)

HSV1 - Cutaneous (N=207)
- PPA: 92.00% (23/25)
- NPA: 99.45% (181/182)
HSV1 - Mucocutaneous (N=383)
- PPA: 100.00% (81/81)
- NPA: 96.36% (291/302)
HSV2 - Cutaneous (N=207)
- PPA: 92.86% (13/14)
- NPA: 100.00% (193/193)
HSV2 - Mucocutaneous (N=383)
- PPA: 94.34% (50/53)
- NPA: 99.09% (327/330)
VZV - Cutaneous (N=207)
- PPA: 100.00% (37/37)
- NPA: 99.41% (169/170)
VZV - Mucocutaneous (N=383)
- PPA: 100.00% (5/5)
- NPA: 100.00% (377/377)

Clinical Study #2 (Frozen Residual Specimens): PPA (Positive Percent Agreement), NPA (Negative Percent Agreement)

HSV1 - Cutaneous (N=90)
- PPA: 100.00% (27/27)
- NPA: 96.83% (61/63)
HSV1 - Mucocutaneous (N=64)
- PPA: 100.00% (29/29)
- NPA: 100.00% (35/35)
HSV2 - Cutaneous (N=90)
- PPA: 100.00% (30/30)
- NPA: 100.00% (60/60)
HSV2 - Mucocutaneous (N=64)
- PPA: 100.00% (15/15)
- NPA: 97.96% (48/49)
VZV - Cutaneous (N=90)
- PPA: 100.00% (17/17)
- NPA: 100.00% (73/73)
VZV - Mucocutaneous (N=64)
- PPA: 100.01% (4/4)
- NPA: 100.01% (60/60)

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.

Solana HSV 1+2/VZV Assay (K162451)

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

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.

Summary

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left, there is a symbol representing the Department of Health & Human Services - USA. To the right of the symbol, there is the FDA logo in blue, with the words "U.S. FOOD & DRUG" above the word "ADMINISTRATION".

Quidel Corporation % Selena Liu Senior Regulatory Affairs Specialist QuidelOrtho Corporation 9975 Summers Ridge Road San Diego. California 92121

Re: K232286

Trade/Device Name: Savanna HSV 1+2/VZV Assay, Savanna HSV 1+2/VZV Control Set, Savanna Instrument Regulation Number: 21 CFR 866.3309 Regulation Name: Herpes Virus Nucleic Acid-Based Cutaneous And Mucocutaneous Lesion Panel Regulatory Class: Class II Product Code: PGI Dated: November 21, 2023 Received: November 21, 2023

Dear Selena Liu:

We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrb/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"

1

(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE(@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely, Ryan C.
Karsner -S Digitally signed by Ryan Date: 2023.12.20
11:54:38 -05'00' Ryan Karsner, MD Deputy Assistant Director Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Ouality Center for Devices and Radiological Health

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Indications for Use

510(k) Number (if known) K232286

Device Name

Savanna HSV 1+2/VZV Assay Savanna HSV 1+2/VZV Assay Control Set, Savanna Instrument

Indications for Use (Describe)

The Savanna HSV 1+2/VZV Assay is an automated, rapid multianalyte real-time PCR test for the simultaneous qualitative detection and differentiation of herpes simplex virus type 1, and varicella-zoster virus DNA isolated from human cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This in vitro diagnostic test is intended to aid in the diagnosis of patients with signs or symptoms virus type 1, herpes simplex virus type 2, and varicella-zoster virus infection.

The Savanna HSV 1+2/VZV Assay is intended to aid in the diagnosis of herpes simplex virus 2 and varicella-zoster virus active infections. The results of this test should not be used as the sole basis for diagnosis, treatment or other management decisions and must be combined with clinical observations, patient history and/or epidemiological information. Negative results do not preclude herpes simplex virus type 2, or varicella-zoster virus infection that is not detected by a cutaneous lesion swab specimen. Positive results do not rule out co-infection with other organisms. Additional laboratory testing (e.g., viral culture, immunoassay, serology) may be necessary for patient evaluation. Savanna HSV 1+2/VZV Assay is for professional use. The Savanna HSV 1+2/VZV Assay is intended for use only with the Savanna instrument.

Warning: The Savanna HSV 1+2/VZV Assay is not intended for use with the cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Savanna HSV 1+2/VZV Assay is not intended for use in prenatal screening.

Type of Use (Select one or both, as applicable)
☑ Prescription Use (Part 21 CFR 801 Subpart D)	☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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510(K) SUMMARY

Submitter

Quidel Corporation 10165 McKellar Court San Diego, CA 92121 Telephone: (800) 874-1517

Submission Contact

Selena Liu Senior Regulatory Affairs Specialist (619) 818-6642

Date Prepared

July 31, 2023

Proprietary and Established Names

Savanna HSV 1+2/VZV Assay Savanna HSV 1+2/VZV Control Set Savanna Instrument

Classification

| Product Code | Classification
on | Regulatory
Section | Description |
|--------------|----------------------|-----------------------|----------------------------------------------------------------------------------------------------------|
| PGI | II | 866.3309 | Herpes Virus (Vzv, Hsv1, Hsv2), DNA
Detection Assay For Cutaneous And
Mucocutaneous Lesion Samples |

Panel

Microbiology

Predicate Device

Solana HSV 1+2/VZV Assay (K162451)

Intended Use

The Savanna HSV 1+2/VZV Assay is an automated, rapid multianalyte real-time PCR test for the simultaneous qualitative detection and differentiation of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus DNA isolated from human cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This in vitro diagnostic test is intended to aid in the diagnosis of patients with signs or symptoms of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus infection.

The Savanna HSV 1+2/VZV Assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes

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Image /page/4/Picture/0 description: The image shows the logo for QuidelOrtho Corporation. The logo features a square with rounded corners, divided into four sections, each filled with a different color of the rainbow. Below the square is the word "QUIDEL" in a simple, sans-serif font.

simplex virus 2 and varicella-zoster virus active infections. The results of this test should not be used as the sole basis for diagnosis, treatment or other management decisions and must be combined with clinical observations, patient history and/or epidemiological information. Negative results do not preclude herpes simplex virus type 1, herpes simplex virus type 2, or varicella-zoster virus infection that is not detected by a cutaneous or mucocutaneous lesion swab specimen. Positive results do not rule out co-infection with other organisms. Additional laboratory testing (e.g., viral culture, immunoassay, serology) may be necessary for patient evaluation. Savanna HSV 1+2/VZV Assay is for professional use. The Savanna HSV 1+2/VZV Assay is intended for use only with the Savanna instrument.

Warning: The Savanna HSV 1+2/VZV Assay is not intended for use with the cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Savanna HSV 1+2/VZV Assay is not intended for use in prenatal screening.

Device Description

The Savanna HSV 1+2/VZV Assay consists of a single, self-contained assay cartridge employing real-time PCR technology for use with the Savanna instrument to detect and differentiate DNA from herpes simplex virus type 1, herpes simplex virus type 2 and varicella-zoster virus. In approximately 24 minutes, this platform extracts, amplifies and detects DNA present in cutaneous or mucocutaneous lesion swab specimens obtained from symptomatic patients and placed in transport media.

To initiate the assay, a patient cutaneous or mucocutaneous lesion swab specimen in transport medium is transferred via the supplied transfer pipette to the Liguid Sample Port of the Test Cartridge. The user closes the Sample Port and inserts the Test Cartridge into the Savanna instrument, initiating sample processing. The sample containing human DNA is pushed out of the Sample Port by lysis buffer, which then rehydrates the Process Internal Control (IC), and together with the paramagnetic nucleic acid binding particles, are pumped into the extraction chamber. The solution is mixed, and virus and/ or bacteria are further lysed by sonication within the extraction chamber. Specimen and IC DNA are bound to, washed and then eluted off the paramagnetic particles. The purified specimen DNA and IC solution is used to rehydrate four individual lyophilized master mixes. Each master mix is pumped into a PCR chamber and Taq-man® multiplex real-time PCR reactions are carried out under optimized conditions, generating amplicons for the targeted pathogen (if present) and the Process Internal Control (IC).

Each master mix contains primers and dual-labeled probes unique for the pathogen targets and the IC. The probes are labeled with a fluorophore on one end and a quencher on the other end. Target DNA sequences are amplified by pathogen-specific primers and detected by correspondingly specific fluorescence probes. The IC targets are also amplified by specific primers and detected by an IC-specific fluorescence probe. A polymerase included in the master mix cleaves the probes bound to complementary DNA sequences, separating the fluorophore from the quencher. This step generates a signal and if it surpasses multiple defined thresholds, the sample is reported as positive for the detected target sequence.

The Savanna instrument will display the test results (Positive or Invalid) on the main bay screen.

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Comparison with Predicate

Features	Predicate Device	New Device
	Solana HSV 1+2/VZV Assay (K162451)	Savanna HSV 1+2/VZV Assay (K232286)
Intended Use	The Solana HSV 1+2/VZV Assay is an in vitro
diagnostic test, using isothermal amplification
technology (helicase dependent amplification,
HDA), for the qualitative detection and
differentiation of herpes simplex virus type 1,
herpes simplex virus type 2, and varicella-zoster
virus DNA isolated and purified from cutaneous
or mucocutaneous lesion samples obtained from
symptomatic patients suspected of active herpes
simplex virus 1, herpes simplex virus 2 and/or
varicella-zoster infection. The Solana HSV
1+2/VZV Assay is intended to aid in the
diagnosis of herpes simplex virus 1, herpes
simplex virus 2 and varicella-zoster virus active
cutaneous or mucocutaneous infections.
Negative results do not preclude herpes simplex
virus 1, herpes simplex virus 2 and varicella-
zoster virus infections and should not be used as
the sole basis for diagnosis, treatment, or other
management decisions. The Solana HSV
1+2/VZV Assay is intended for use only with the
Solana instrument.
Warning: The Solana HSV 1 + 2/VZV Assay is
not intended for use with cerebrospinal fluid or
to aid in the diagnosis of HSV or VZV infections
of the central nervous system. The Solana HSV
1 + 2/VZV Assay is not intended for use in
prenatal screening.	The Savanna HSV 1+2/VZV Assay is an
automated, rapid, multianalyte real-time PCR
test for the simultaneous qualitative detection
and differentiation of herpes simplex virus type
1, herpes simplex virus type 2, and varicella-
zoster virus DNA isolated from human
cutaneous or mucocutaneous lesion samples
obtained from symptomatic patients suspected of
active herpes simplex virus 1, herpes simplex
virus 2 and/or varicella-zoster infection. This in
vitro diagnostic test is intended to aid in the
diagnosis of patients with signs or symptoms of
herpes simplex virus type 1, herpes simplex virus
type 2, and varicella-zoster virus infection.
The Savanna HSV 1+2/VZV Assay is intended
to aid in the diagnosis of herpes simplex virus 1,
herpes simplex virus 2 and varicella-zoster virus
active infections. The results of this test should
not be used as the sole basis for diagnosis,
treatment or other management decisions and
must be combined with clinical observations,
patient history and/or epidemiological
information. Negative results do not preclude
herpes simplex virus type 1, herpes simplex virus
type 2, or varicella-zoster virus infection that is
not detected by a cutaneous or mucocutaneous
lesion swab specimen. Positive results do not
rule out co-infection with other organisms.
Additional laboratory testing (e.g., viral culture,
immunoassay, serology) may be necessary for
patient evaluation. Savanna HSV 1+2/VZV
Assay is for professional use. The Savanna HSV
1+2/VZV Assay is intended for use only with the
Savanna instrument.
Warning: The Savanna HSV 1+2/VZV Assay is
not intended for use with the cerebrospinal fluid
(CSF) or to aid in the diagnosis of HSV or VZV
infections of the central nervous system (CNS).
The Savanna HSV 1+2/VZV Assay is not
intended for use in prenatal screening.

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| Features | Predicate Device
Solana HSV 1+2/VZV Assay (K162451) | New Device Savanna HSV 1+2/VZV
Assay (K232286) |
|--------------------------------|-----------------------------------------------------------------|-----------------------------------------------------------------|
| Instrument | Solana | Savanna |
| Qualitative | Yes | Yes |
| Analyte | Viral DNA from HSV-1, HSV-2 and VZV | Viral DNA from HSV-1, HSV-2 and VZV |
| Specimen
Types | Cutaneous or mucocutaneous lesion swabs
in transport medium | Cutaneous or mucocutaneous lesion swabs
in transport medium |
| Test Principle | Isothermal Helicase-Dependent
Amplification (HDA) | PCR |
| Automated
Analysis | Yes | Yes |
| Development
Time | 50 min | Within 24 min |
| Kit Storage | 2°C to 8°C | 2°C to 30°C |
| External
Controls | Positive and Negative Controls (Available
as a separate kit) | Positive and Negative Controls (Available
as a separate kit) |
| Quality
Control
Features | Competitive Process Control (PRC) | Process Internal Control (IC) |

Performance Data

Numerous studies were undertaken to document the performance characteristics and the substantial equivalence of the test to the predicate device. These studies included the following:

Limit of Detection

The limits of detection (LoD) for the Savanna HSV 1+2/VZV Assay were determined using two types/strains of HSV-1, two types/strains of HSV-2 and two types/strains of VZV, serially diluted in negative matrix. The LoD for each pathogen is listed below in Table 1.

Pathogen	Type/ Strain ID	LoD (TCID50/mL)	LoD (cp/mL)
HSV-1	Isolate 2	1.16E+02	6.65E+02
HSV-1	Macintyre	1.08E-03	2.86E+02
HSV-2	Strain G	2.50E+01	1.27E+04
	MS	8.51E+00	7.64E+01
VZV	Ellen	N/A	3.32E+03
	VZV	Strain 82	N/A

Table 1. Savanna HSV 1+2/VZV Limit of Detection

Co-spike Limit of Detection

Co-spike study demonstrated that multi-analyte preparation does not impact the LoD for the Savanna HSV 1+2/VZV Assay as established in Limit of Detection Study. DNA of one strain of each of HSV-1, HSV-2 and VZV were mixed at 1x LoD level and evaluated with three kit lots. The co-spiked multi-analyte sample mix showed >95% positivity for each target DNA, verifying that the co-spike does not impact the LoD.

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Inclusivity

Inclusivity, or analytical reactivity, for Savanna HSV 1+2/VZV Assay was demonstrated using four additional strains of HSV-1 (Isolate 3, Isolate 11, Isolate 20), four additional strains of HSV-2 (Isolate 6, Isolate 9, Isolate 20) and five additional strains of VZV (AV923L, 9939, Isolate B, 275, Isolate D). All pathogens tested were detected by the assay at the following concentrations (Table 2).

| Virus | Type/Strain | Concentration in UTM
(TCID50/mL) | Concentration in
UTM (cp/mL) | Inclusive (Yes/No) |
|-------|-------------|-------------------------------------|---------------------------------|--------------------|
| HSV-1 | Isolate 3 | 4.00E+00 | 8.56E+02 | Yes |
| | Isolate 7 | 1.72E+01 | Not Available | Yes |
| | Isolate 11 | 2.53E+01 | Not Available | Yes |
| | Isolate 20 | 5.45E+01 | 1.40E+02 | Yes |
| HSV-2 | Isolate 6 | 2.94E+00 | 2.54E+03 | Yes |
| | Isolate 9 | 2.94E+00 | 3.26E+02 | Yes |
| | Isolate 10 | 2.94E+00 | 1.34E+02 | Yes |
| | Isolate 20 | 2.94E+00 | Not Available | Yes |
| VZV | AV923L | Not Available | 4.00E+02 | Yes |
| | 9939 | 1.05E+01 | 1.09E+03 | Yes |
| | Isolate B | Not Available | 8.20E+02 | Yes |
| | 275 | Not Available | 2.88E+02 | Yes |
| | Isolate D | Not Available | 1.65E+03 | Yes |

In silico Inclusivity Analysis

Specific nucleic acid sequences used in the Savanna HSV 1+2/VZV Assay target the highly conserved regions of each pathogen. The inclusivity of the assay was established through in silico analyses of available HSV-1. HSV-2 and VZV sequences in NCBI databases. The analyses determined that the primer and probe sets for HSV-1, HSV-2 and VZV have high homologies toward their respective target sequences as summarized in Table 3.

Table 3. Summary of Savanna HSV 1+2/VZV Assay Oligo Homologies
----------------------------------------------------------------	--	--	--

| Analyte | Total # Aligned Sequences
(%) | Homology Range |
|---------|----------------------------------|----------------|
| HSV-1 | 136 (100%) | 93.3-100% |
| HSV-2 | 284 (100%) | 93.33-100% |
| VZV | 181 (100%) | 100% |

Cross Reactivity/Microbial Interference

The potential cross reactivity and microbial interference of 22 viral isolates and 38 bacterial and fungal microorganisms were evaluated in the Savanna HSV 1+2/VZV Assay. None of the viruses or microorganisms listed below in Table 4 showed signs of cross reactivity or microbial interference at the concentrations listed, in the presence or absence of the target analytes.

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| Condition Description Concentration | Condition Description Concentration |
|------------------------- | Acholeplasma laidlawi Type B | 1.00E+06 CFU/mL | Acinetobacter
calcoaceticus | 1.00E+06 CFU/mL | Acinetobacter lwoffii | Adenovirus 7 | Bacteroides fragilis | Bordetella
bronchiseptica HHV6 | ≥ 1.01E+05 TCID50/mL | Bordetella pertussis HHV7 | 2.34E+04 TCID50/mL | Candida albicans HHV8 | 1.01E+05 TCID50/mL | Candida glabrata Metapneumovirus A1 | Candida krusei HPV-16 | 2.85E+05 cp/mL | Candida parapsilosis HPV-18 | 2.60E+05 cp/mL | Candida tropicalis | Chlamydia trachomatis acidophilus | 1.04E+06 CFU/mL | Chlamydophila
pneumoniae | 1.13E+06 CFU/mL | Clostridium perfringens | Coronavirus OC43 | Coxsackievirus B1 | Cutibacterium acnes pneumoniae | Cytomegalovirus | Cytomegalovirus Towne | Echovirus 11 melaninogenica | Enterobacter cloacae | Enterococcus faecalis RA 27/3 | 1.00E+05 TCID50/mL | Enterovirus 70 | Epstein Barr (EBV) (MRSA) | 1.03E+06 CFU/mL | Escherichia coli saprophyticus | 1.15E+06 CFU/mL | Fusobacterium
nucleatum | 1.07E+06 CFU/mL agalactiae | 1.13E+06 CFU/mL | Gardnerella vaginalis pneumoniae | 1.20E+06 CFU/mL | Haemophilus ducreyi | Haemophilus influenzae
(Type A) | 1.00E+06 CFU/mL salivarius | 1.00E+06 CFU/mL | Virus/Bacteria/Fungus
| Virus/Bacteria/Fungus
-----------|----------------------------------------|-----------------------------------|----------------------------------------|
| 1.00E+06 CFU/mL | Haemophilus influenzae
|
| Hepatitis A virus | 2.70E+05 cp/mL |
| 1.01E+06 CFU/mL | Hepatitis B virus | 2.45E+05 cp/mL |
| 1.04E+05 TCID50/mL | Hepatitis C virus | 4.15E+05 cp/mL |
| 1.00E+06 CFU/mL | HIV-1 Type 1 | 1.95E+05 cp/mL |
| 1.06E+06 CFU/mL | Human Herpes virus
|
| 1.01E+06 CFU/mL | Human Herpes virus
|
| 1.00E+06 CFU/mL | Human Herpes virus
|
| 1.03E+06 CFU/mL | Human
| 1.90E+05 TCID50/mL |
| 1.14E+06 CFU/mL | Human papillomavirus
|
| 1.20E+06 CFU/mL | Human papillomavirus
|
| 1.04E+06 CFU/mL | Klebsiella pneumoniae | 1.00E+06 CFU/mL |
| 1.06E+06 CFU/mL | Lactobacillus
|
| Measles virus | 1.04E+05 TCID50/mL |
| 1.00E+06 CFU/mL | Mobiluncus mulieris | 1.00E+06 CFU/mL |
| 1.00E+05 TCID50/mL | Moraxella catarrhalis | 1.34E+06 CFU/mL |
| 1.00E+05 TCID50/mL | Mycoplasma orale | 1.00E+06 CFU/mL |
| 1.00E+06 CFU/mL | Mycoplasma
| 1.00E+06 CFU/mL |
| 1.00E+05 TCID50/mL | Neisseria gonorrhoeae | 1.00E+06 CFU/mL |
| 8.00E+04 TCID50/mL | Neisseria meningitidis | 1.09E+06 CFU/mL |
| 1.40E+05 TCID50/mL | Prevotella
| 1.20E+06 CFU/mL |
| 1.04E+06 CFU/mL | Proteus mirabilis | 1.04E+06 CFU/mL |
| 1.04E+06 CFU/mL | Rubella virus; Strain:
|
| 1.00E+05 TCID50/mL | Staphylococcus aureus | 1.15E+06 CFU/mL |
| 6.05E+06 cp/mL | Staphylococcus aureus
|
| 1.00E+06 CFU/mL | Staphylococcus
|
| Streptococcus
|
| 1.03E+06 CFU/mL | Streptococcus
|
| 1.00E+06 CFU/mL | Streptococcus pyogenes | 3.17E+06 CFU/mL |
| Streptococcus
|

Table 4. Potential-Cross-Reacting and Interfering Viruses and Microorganisms evaluated

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Interfering Substances

The performance of Savanna HSV 1+2/VZV Assay was evaluated with potentially interfering substances that may be present in lesion specimens. Several endogenous substances, over the counter (OTC) products, and prescription medications were evaluated with the Savanna HSV 1+2/VZV Assay. None of the substances in Table 5 interfered with the assay at the levels listed below.

Substance	Active Ingredient	Test Concentration
Blood/EDTA	N/A	0.63%
Casein	Casein Bovine Milk	7 mg/mL
Feces	N/A	2.5 mg/mL
Female Urine	Urea	7%
Leukocytes	N/A	2.5x105 cells/mL
Male Urine	Urea	3.5%
Mucus (Mucin, bovine submaxillary gland, type I-S)	Mucin	5% (w/v)
Seminal fluid	Semen	2%
Abreva Docosanol	Docosanol	3.5% (w/v)
Acetaminophen	Acetaminophen	1.75% (w/v)
Anti-itch cream	Benzalkonium chloride	3.5% (w/v)
Balneol Hygienic Cleansing Lotion	N/A	3.5% (w/v)
Carmex Cold Sore Lip Balm	Benzocaine, White Petrolatum	3.5% (w/v)
Chlor-Trimeton	Chlorpheniramine maleate	1.25 mg/mL
Clotrimazole 3 Vaginal Cream	Clotrimazole	3.5% (w/v)
Cornstarch	N/A	1.25 mg/mL
Dextromethorphan hydrobromide (i.e. Mucinex)	Dextromethorphan, Guaifenesin, Phenylephrine	5 mg/mL
Douche	Decyl Glucoside; Octoxynol-9	7% (w/v)
K-Y Brand Jelly	Glycerol	7% (w/v)
Lanacane	3% w/w Benzocaine	3.5% (w/v)
Lip Clear Lysine+	Menthol	3.5% (w/v)
Listerine	Thymol	7% (w/v)
Miconazole 1	N/A	7% (w/v)
Miconazole 3	N/A	7% (w/v)
Monistat 1	N/A	7% (w/v)
Monistat 3	N/A	7% (w/v)
Preparation H	Witch Hazel	3.5% (w/v)
Releev	Benzalkonium chloride	3.5% (w/v)
Toothpaste	Sodium Fluoride	7% (w/v)
Triconazole 1	Tioconazole	7% (w/v)

Table 5. Potential Interfering Substances evaluated

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Substance	Active Ingredient	Test Concentration
Vagisil Cream	Benzocaine, Resorcinol	7% (w/v)
YeastGard	Sodium Borate	7% (w/v)
Acyclovir	Acyclogauanosine	7 mg/mL
Cidofovir	Cidofovir Hydrate	2.5 mg/mL
Foscarnet	Foscarnet Sodium	1.25 mg/mL
Ganciclovir	Ganciclovir	2.5 mg/mL

Competitive Interference

A competitive interference study was conducted to evaluate the performance of the Savanna HSV 1+2/VZV Assay using samples containing 2 target analytes at different combination of high and low analyte concentrations. Each sample was prepared with one of the analytes at 3X LoD and the other analytes at 10X, 500X or 1000X LoD in negative buccal matrix. Five replicates per sample were evaluated. When competitive interference was observed (shaded in Table 6), titration of the high-level analyte was done and tested. Results are listed in Table 6.

| | Low Analyte | High Analyte | HSV-1
Positivity | HSV-2
Positivity | VZV Positivity |
|----|----------------|-------------------|---------------------|---------------------|----------------|
| 1 | HSV-1 (3x LoD) | HSV-2 (1000x LoD) | 0.0% (0/5) | 100.0% (5/5) | 0% (0/5)* |
| 2 | HSV-1 (3x LoD) | HSV-2 (500x LoD) | 0.0% (0/5) | 100.0% (5/5) | 0% (0/5)* |
| 3 | HSV-1 (3x LoD) | HSV-2 (250x LoD) | 20.0% (1/5) | 100.0% (5/5) | 0% (0/5)* |
| 4 | HSV-1 (3x LoD) | HSV-2 (100x LoD) | 60.0% (3/5) | 100.0% (5/5) | 0% (0/5)* |
| 5 | HSV-1 (3x LoD) | HSV-2 (10x LoD) | 100.0% (5/5) | 100.0% (5/5) | 0% (0/5)* |
| 6 | HSV-1 (3x LoD) | VZV (500x LoD) | 100.0% (5/5) | 0% (0/5)* | 100.0% (5/5) |
| 7 | HSV-2 (3x LoD) | HSV-1 (1000x LoD) | 100.0% (5/5) | 60.0% (3/5) | 0% (0/5)* |
| 8 | HSV-2 (3x LoD) | HSV-1 (500x LoD) | 100.0% (5/5) | 100.0% (5/5) | 0% (0/5)* |
| 9 | HSV-2 (3x LoD) | HSV-1 (250x LoD) | 100.0% (5/5) | 100.0% (5/5) | 0% (0/5)* |
| 10 | HSV-2 (3x LoD) | HSV-1 (100x LoD) | 100.0% (5/5) | 100.0% (5/5) | 0% (0/5)* |
| 11 | HSV-2 (3x LoD) | HSV-1 (10x LoD) | 100.0% (5/5) | 100.0% (5/5) | 0% (0/5)* |
| 12 | HSV-2 (3x LoD) | VZV (500x LoD) | 0% (0/5)* | 100.0% (5/5) | 100.0% (5/5) |
| 13 | VZV (3x LoD) | HSV-1 (1000x LoD) | 100.0% (5/5) | 0% (0/5)* | 100.0% (5/5) |
| 14 | VZV (3x LoD) | HSV-2 (1000x LoD) | 0% (0/5)* | 100.0% (5/5) | 100.0% (5/5) |

Analyte not present in the sample, the negative results are not due to competitive interference. The negative results are true negative.

Repeatability/ Within-Lab Precision

A 20-day within laboratory precision study was performed with two testing events per day, each testing had two replicates of a three- member test panel on three product lots. The test panel was prepared in negative buccal cell matrix comprised of a negative sample, a co-spiked low positive sample (at LoD for each pathogen), and a co- spiked moderate positive sample (at 4 times the LoD for each pathogen). The negative sample had an overall 99.6% (239/240) expected agreement for HSV-1, 99.6% (239/240) expected agreement for HSV-2 and 100.0% (242/242) expected agreement for VZV across all lots. The

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low positive sample had an overall 99.2% (237/239) expected agreement for HSV-1, 100.0% (239/239) expected agreement for HSV- 2 and 99.6% (238/239) expected agreement for VZV across all lots. The moderate positive sample had an overall 99.6% (239/240) expected agreement for HSV-1, 100.0% (240/240) expected agreement for HSV- 2 and 99.6% (240/241) expected agreement for VZV across all lots. Results are presented in Table 7.

| Analyte | Sample | Agreement with
Expected Results | Detected
Mean
Ct | Repeatability | | Between
Runs | | Between
Days | | Between Lot | | Total | |
|---------|----------------------|------------------------------------|------------------------|---------------|------|-----------------|------|-----------------|------|-------------|------|-------|------|
| | | | | SD | % CV | SD | % CV | SD | % CV | SD | % CV | SD | % CV |
| | Negative | 239/240
(99.6%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| HSV-1 | Low
Positive | 237/239
(99.2%) | 36.4 | 1.50 | 4.1 | 0.07 | 0.2 | 0.19 | 0.5 | 0.50 | 1.4 | 1.60 | 4.4 |
| | Moderate
Positive | 239/240
(99.6%) | 34.3 | 1.06 | 3.1 | 0.70 | 2.0 | 0.00 | 0.0 | 0.41 | 1.2 | 1.33 | 3.9 |
| | Negative | 239/240
(99.6%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| | Low
Positive | 239/239
(100%) | 33.9 | 0.95 | 2.8 | 0.49 | 1.5 | 0.05 | 0.2 | 0.42 | 1.3 | 1.16 | 3.4 |
| HSV-2 | Moderate
Positive | 240/240
(100%) | 31.9 | 0.98 | 3.1 | 0.46 | 1.5 | 0.00 | 0.0 | 0.00 | 0.0 | 1.09 | 3.4 |
| | Negative | 242/242
(100%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| | Low
Positive | 238/239
(99.6%) | 35.7 | 0.77 | 2.2 | 0.11 | 0.3 | 0.20 | 0.6 | 0.19 | 0.5 | 0.83 | 2.3 |
| VZV | Moderate
Positive | 240/241
(99.6%) | 34.1 | 0.54 | 1.6 | 0.00 | 0.0 | 0.11 | 0.3 | 0.18 | 0.5 | 0.58 | 1.7 |

	Table 7. Repeatabilitv/Within-Laboratory Precision

Reproducibility

A five-day, multi-site reproducibility study was conducted at three healthcare facilities. Each day, two operators at each site ran two replicates of a three-member test panel prepared in negative buccal cell matrix comprised of a negative sample, a co-spiked low positive sample (at LoD for each pathogen), and a co-spiked moderate positive sample (at 4 times the LoD for each pathogen). The negative sample had an 100% (179/179) expected agreement across all sites for all three analytes. The low positive samples were called positive 99.4% (179/180) of the time for HSV-1, 100% (180/180) of the time for HSV-2 and 100% (180/180) of the time for VZV. The moderate positive samples were called positive 99.4% (179/180) of the time for HSV-1, 100% (180/180) HSV-2 and 99.4% (179/180) for VZV. Results are in Table 8.

| Analyte | Sample | Agreement with
Expected
Results | Detected
Mean
Ct | Repeatability | | Between
Day | | Between
Site | | Between
Lot | | Between
Operator | | Reproducibility | |
|---------|----------------------|---------------------------------------|------------------------|---------------|---------|----------------|---------|-----------------|------|----------------|---------|---------------------|---------|-----------------|---------|
| | | | | SD | %
CV | SD | %
CV | SD | %CV | SD | %
CV | SD | %
CV | SD | %
CV |
| | Negative | 179/179
(100%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| HSV-1 | Low
Positive | 179/180
(99.4%) | 36.22 | 1.31 | 3.6 | 0.35 | 1.0 | 0.06 | 1.36 | 1.36 | 0.4 | 0.00 | 0.0 | 1.36 | 3.8 |
| | Moderate
Positive | 179/180
(99.4%) | 34.38 | 1.05 | 3.1 | 0.00 | 0.0 | 0.27 | 1.23 | 1.23 | 1.6 | 0.14 | 0.4 | 1.23 | 3.6 |

Table 8. Reproducibility Study Results (3 Sites)

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| Analyte | Sample | Agreement with
Expected | Detected
Mean | Repeatability | Between
Day | Between
Site | Between
Lot | Between
Operator | Reproducibility |
|---------|----------------------|----------------------------|------------------|---------------|----------------|-----------------|----------------|---------------------|-----------------|
| | Negative | 179/179
(100%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| HSV-2 | Low
Positive | 180/180
(100%) | 33.73 | 1.19 | 0.25 | 0.00 | 1.23 | 0.00 | 1.23 |
| | Moderate
Positive | 180/180
(100%) | 31.86 | 0.96 | 0.00 | 0.19 | 1.10 | 0.5 | 0.14 |
| | Negative | 179/179
(100%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| VZV | Low
Positive | 180/180
(100%) | 35.79 | 1.29 | 0.00 | 0.34 | 1.34 | 0.00 | 1.34 |
| | Moderate
Positive | 179/180
(99.4%) | 33.99 | 0.52 | 1.5 | 0.00 | 0.25 | 0.6 | 0.17 |

External Control Performance

The Savanna HSV 1+2/VZV External Control Set, comprised of a pouched positive control swab and a negative control, was evaluated with the Savanna HSV 1+2/VZV Assay at 30 replicates each on three device lots for a total of 180 tests. The positive control produced 100% agreement to the expected positive results on all three device lots. The negative control produced 96.8% agreement to the expected results on one device lot and 100% agreement on the other two device lots.

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Transport Media and Specimen Stability/Storage

Specimen stability in various Transport Media (Copan UTM, Remel M4RT, Remel M6) was evaluated. The following Co-spike samples were used in the test: Negative, Low Positive (2x LoD), and High Positive (4x LoD). Specimens collected in transport medium are stable when stored according to the conditions specified in Table 9.

Transport Medium	Room Temperature (15-30°C)	Refrigerated (4°C)
Copan UTM	Up to 24 hours	Up to 48 hours
Remel M4RT	Up to 96 hours	Up to 96 hours
Remel M5	Up to 48 hours	Up to 96 hours
Remel M6	Up to 72 hours	Up to 72 hours

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Clinical Performance

Performance characteristics of the Savanna HSV 1+2/VZV Assay were established through 2 multi-site clinical studies, testing cutaneous and mucocutaneous lesions from symptomatic individuals, as described below. Clinical Study 1 evaluated assay performance from fresh samples while clinical study 2 evaluated performance after residual samples were stored frozen.

Clinical Study #1

A multi-site study was conducted in the United States to evaluate the Savanna HSV 1+2/VZV Assay using cutaneous or mucocutaneous lesion samples in transport media. Five hundred and ninety (590) residual specimens were randomly selected from subjects with signs and symptoms of HSV-1, HSV-2 or VZV infection that were tested and for whom samples were collected in an all-comers fashion. A single replicate of each specimen was tested with both the candidate assay, Savanna HSV 1+2/VZV Assay and the comparator assay. Testing was split across three clinical sites and 44 Savanna instruments. Savanna HSV 1+2/VZV Control Sets were tested each day by the clinical sites during sample testing. The clinical performance of the Savanna HSV 1+2/VZV Assay was established by comparing to FDA-cleared nucleic acid amplification tests.

The specimens have been categorized as cutaneous (skin lesion, genital), or mucocutaneous (anorectal, genital, nares, ocular, oral and urethral). The gender and age demographics for each category are listed below.

Specimen	Age	Female	Male	Total
Cutaneous Lesion	= 60 years	50	23	73
	Total	125	82	207
Mucocutaneous Lesion	= 60 years	43	14	57
	Total	286	97	383
Total	= 60 years	93	37	130
	Total	411	179	590

Table 10. Subject Demographics - Clinical Study #1

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The clinical performance results commercially available RT-PCR comparator method are shown in Tables 11 to 13, for cutaneous and mucocutaneous lesions separately.

		HSV1 Results
		Cutaneous (N=207)		Mucocutaneous (N=383)
		Comparator		Comparator
		Positive	Negative	Positive	Negative
Savanna HSV
1+2/VZV Assay
Results	Positive	23	1	81	11
	Negative	2	181	0	291
	Total	25	182	81	302
		PPA= 92.00%
(23/25)
(75.04% -
97.78%)	NPA= 99.45%
(181/182)
(96.95% - 99.90%)	PPA= 100.00%
(81/81)
(95.47% - 100.00%)	NPA= 96.36%
(291/302)
(93.60% - 97.95%)

Table 11: HSV1 Clinical performance for the Savanna HSV 1+2/VZV Assay in cutaneous fresh specimens

Table 12: HSV2 Clinical performance for the Savanna HSV 1+2/VZV Assay in cutaneous fresh specimens

	HSV2 Results
	Cutaneous (N=207)		Mucocutaneous (N=383)
	Comparator	Comparator
	Positive	Negative	Positive	Negative
Savanna HSV
1+2/VZV Assay
Results	Positive	13	0	50	3
	Negative	1	193	3	327
	Total	14	193	53	330
		PPA= 92.86%
(13/14)
(68.53% -
98.73%)	NPA= 100.00%
(193/193)
(98.05% - 100.00%)	PPA= 94.34%
(50/53)
(84.63% - 98.06%)	NPA= 99.09%
(327/330)
(97.36% - 99.69%)

Table 13: VZV Clinical performance for the Savanna HSV 1+2/VZV Assay in cutaneous and mucocutaneous fresh specimens

		VZV Results
		Cutaneous (N=207)		Mucocutaneous (N=383)
		Comparator	Comparator	Comparator	Comparator
		Positive	Negative	Positive	Negative
Savanna HSV
1+2/VZV Assay
Results	Positive	37	1	5	0
	Negative	0	169	0	377
	Total	37	170	5	377
		PPA= 100.00%
(37/37)
(90.60% - 100.00%)	NPA= 99.41%
(169/170)
(96.74% - 99.90%)	PPA= 100.00%
(5/5)
(56.56% - 100.00%)	NPA= 100.00%
(377/377)
(98.99% - 100.00%)

Clinical Study #2

Analysis of frozen residual cutaneous and mucocutaneous swab samples in transport medium was performed in July 2023 to supplement Clinical Study #1. The samples were residual specimens left over

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from patients with signs and symptoms of HSV-1, HSV-2 or VZV infection. The total number of evaluable samples was one hundred fifty-four (154). The clinical study #2 performance results compared to commercially available RT- PCR comparator method(s) are shown in Tables 14 to 16.

Table 14: HSV1 Clinical performance for the Savanna HSV 1+2V Assay in cutaneous and mucocutaneous residual frozen specimens

		HSV1 Results
		Cutaneous (N=90)		Mucocutaneous (N=64)
		Comparator		Comparator
		Positive	Negative	Positive	Negative
Savanna HSV
1+2/VZV Assay
Results	Positive	27	2	29	0
	Negative	0	61	0	35
	Total	27	63	29	35
		PPA= 100.00%
(27/27)
(87.55% -
100.00%)	NPA= 96.83%
(61/63)
(89.14% -
99.13%)	PPA= 100.00%
(29/29)
(88.31% - 100.00%)	NPA= 100.00%
(35/35)
(90.11% - 100.00%)

Table 15: HSV2 Clinical performance for the Savanna HSV 1+2/VZV Assay in cutaneous and mucocutaneous residual frozen specimens

			HSV2 Results
			Cutaneous (N=90)		Mucocutaneous (N=64)
			Comparator		Comparator
		Positive	Negative	Positive	Negative
Savanna HSV
1+2/VZV Assay
Results	Positive	30	0	15	1
	Negative	0	60	0	48
	Total	30	60	15	49
		PPA= 100.00%
(30/30)
(88.65% -
100.00%)	NPA= 100.00%
(60/60)
(93.98% -
100.00%)	PPA= 100.00%
(15/15)
(79.62% - 100.00%)	NPA= 97.96%
(48/49)
(89.31% - 99.64%)

Table 16: VZV Clinical performance for the Savanna HSV 1+2/VZV Assay in cutaneous residual frozen specimens

		VZV Results
		Cutaneous (N=90)		Mucocutaneous (N=64)
		Comparator		Comparator
		Positive	Negative	Positive	Negative
Savanna HSV
1+2/VZV Assay
Results	Positive	17	0	4	0
	Negative	0	73	0	60
	Total	17	73	4	60
		PPA= 100.00%
(17/17)
(81.57% -
100.00%)	NPA= 100.00%
(73/73)
(95.00% - 100.00%)	PPA= 100.01%
(4/4)
(51.02% - 100.01%)	NPA= 100.01%
(60/60)
(93.98% - 100.00%)

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Conclusion

These studies demonstrated equivalent performance of the Savanna HSV 1+2/VZV Assay to the predicate product, the Solana HSV 1+2/VZV Assay.