Xpert Xpress CoV-2/Flu/RSV plus

K242071 · Cepheid · QOF · Jan 10, 2025 · Microbiology

Device Facts

• Record ID: K242071
• Device Name: Xpert Xpress CoV-2/Flu/RSV plus
• Applicant: Cepheid
• Product Code: QOF · Microbiology
• Decision Date: Jan 10, 2025
• Decision: SESE
• Submission Type: Dual Track
• Regulation: 21 CFR 866.3981
• Device Class: Class 2

Intended Use

The Xpert Xpress CoV-2/Flu/RSV plus test, performed on the GeneXpert Xpress System, is an automated multiplexed real-time reverse transcriptase polymerase chain reaction (RT-PCR) test intended for use in the simultaneous in vitro qualitative detection and differentiation of severe acute respiratory syndrome coronavirus (SARS-CoV-2), influenza A, influenza B, and/or respiratory syncytial virus (RSV) viral RNA in nasopharyngeal swab and anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2, influenza A, influenza B, and RSV can be similar. The Xpert Xpress CoV-2/Flu/RSV plus is intended for use in the differential detection of SARS-CoV-2, influenza A, influenza B, and/or RSV RNA and aids in the diagnosis of COVID-19, influenza, and/or RSV infections if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A, influenza B, and RSV viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection. Positive results are indicative of the presence of the identified virus, but do not rule out bacterial infection or co-infection with other pathogens not detected by the test. The agent(s) detected by the Xpert Xpress CoV-2/Flu/RSV plus test may not be the definite cause of the disease. Negative results do not preclude SARS-CoV-2, influenza A virus, influenza B virus, and/or RSV infection. The results of this test should not be used as the sole basis for treatment or other patient management decisions.

Device Story

Device is an automated, multiplexed, real-time RT-PCR assay for qualitative detection of SARS-CoV-2, influenza A, influenza B, and RSV viral RNA. Input: nasopharyngeal or anterior nasal swab specimens in VTM/UTM or eNAT media. Process: user transfers sample to single-use cartridge; GeneXpert Xpress System performs automated RNA extraction, reverse transcription, target amplification, and detection. Output: qualitative results displayed on system software. Used in clinical settings; operated by healthcare personnel. Provides rapid differential diagnosis to aid clinical decision-making for respiratory infections. Benefits include simultaneous multi-pathogen detection, reduced turnaround time, and automated processing to minimize cross-contamination.

Clinical Evidence

Prospective multi-site clinical study (23 US sites) evaluated 3,147 specimens for SARS-CoV-2 and 4,310 for Flu A/B/RSV. Performance compared to FDA-cleared molecular respiratory panels. SARS-CoV-2 PPA 98.7% (NPS), 98.4% (ANS); NPA 98.5% (NPS), 99.3% (ANS). Flu A PPA 99.1% (NPS), 97.6% (ANS); NPA 98.5% (NPS), 98.9% (ANS). RSV PPA 97.8% (NPS), 97.0% (ANS); NPA 100% (NPS), 99.9% (ANS).

Technological Characteristics

Real-time RT-PCR assay; targets SARS-CoV-2 (E, N2, RdRP), Flu A (MP, PB2, PA), Flu B (M, NS), and RSV (N). Automated sample prep, extraction, and amplification in single-use disposable cartridges. Integrated internal controls (SPC, PCC). Software-based result interpretation. Operates on GeneXpert Xpress System.

Indications for Use

Indicated for individuals with signs and symptoms of respiratory tract infection to detect and differentiate SARS-CoV-2, influenza A, influenza B, and RSV viral RNA in nasopharyngeal and anterior nasal swab specimens.

Regulatory Classification

Identification

A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.

Special Controls

*Classification.* Class II (special controls). The special controls for this device are:(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes and targets the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate. (2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device. (3) The labeling required under § 809.10(b) of this chapter must include: (i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens; (ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, precision, reproducibility, and clinical studies; (iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing; (iv) A warning statement that viral culture should not be attempted in cases of positive results for SARS-CoV-2 and/or any similar microbial agents unless a facility with an appropriate level of laboratory biosafety ( *e.g.,* BSL 3 and BSL 3+, etc.) is available to receive and culture specimens; and(v) A prominent statement that device performance has not been established for specimens collected from individuals not identified in the intended use population ( *e.g.,* when applicable, that device performance has not been established in individuals without signs or symptoms of respiratory infection).(vi) Limiting statements that indicate that: (A) A negative test result does not preclude the possibility of infection; (B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician; (C) There is a risk of incorrect results due to the presence of nucleic acid sequence variants in the targeted pathogens; (D) That positive and negative predictive values are highly dependent on prevalence; (E) Accurate results are dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and (F) When applicable ( *e.g.,* recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer-reviewed literature), that the clinical performance may be affected by testing a specific clinical subpopulation or for a specific claimed specimen type.(4) Design verification and validation must include: (i) Detailed documentation, including performance results, from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. The clinical study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator that FDA has determined is appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses. (ii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains ( *e.g.,* regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately.(iii) A detailed description of the identity, phylogenetic relationship, and other recognized characterization of the respiratory pathogen(s) that the device is designed to detect. In addition, detailed documentation describing how to interpret the device results and other measures that might be needed for a laboratory diagnosis of respiratory infection. (iv) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device ( *e.g.,* saturation level of hybridization and maximum amplification and detection cycle number, etc.), internal and external controls, and computational path from collected raw data to reported result (*e.g.,* how collected raw signals are converted into a reported signal and result), as applicable.(v) A detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review. (vi) For devices intended for the detection and identification of microbial agents for which an FDA recommended reference panel is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference panel of characterized samples. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses. (vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens, the design verification and validation must include a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. An evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses. (5) When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device's labeling under § 809.10(b) of this chapter. (6) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens in addition to detection of SARS-CoV-2 and similar microbial agents, the required labeling under § 809.10(b) of this chapter must include the following: (i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation. (ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to State or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens. (iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required followup actions or retesting in the case of an unusual or unexpected device result. (iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated ( *i.e.,* H1-2009 and H3), this result requires notification of appropriate local, State, or Federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.(7) If one of the actions listed at section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain: (i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those influenza viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. (ii) Within 60 days from the date that FDA notifies manufacturers that characterized influenza viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by: (A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or (B) In a section of the device's label or in other labeling that accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's website, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the website containing this information and must allow unrestricted viewing access.

Predicate Devices

• Xpert Xpress CoV-2/Flu/RSV plus (K231481)

Submission Summary (Full Text)

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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 this symbol, there is the FDA logo in blue, with the words "U.S. FOOD & DRUG" stacked on top of the word "ADMINISTRATION".

January 10, 2025

Cepheid Yen Nguven Director, Regulatory Affairs 904 East Caribbean Drive Sunnyvale, California 94089

Re: K242071

Trade/Device Name: Xpert Xpress CoV-2/Flu/RSV plus Regulation Number: 21 CFR 866.3981 Regulation Name: Device To Detect And Identify Nucleic Acid Targets In Respiratory Specimens From Microbial Agents That Cause The SARS-Cov-2 Respiratory Infection And Other Microbial Agents When In A Multi-Target Test Regulatory Class: Class II Product Code: QOF

Dated: July 15, 2024 Received: July 16, 2024

Dear Yen Nguyen:

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/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

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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" (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 (OS) 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 QS 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 (OS) 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.

All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-device-advicecomprehensive-regulatory-assistance/unique-device-identification-system-udi-system.

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 medical devices and radiation-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-regulatory

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assistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

# Anna M. Mielech -S

Anna Mielech, PhD. Deputy Branch Chief (Acting) Viral Respiratory and HPV Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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#### Indications for Use

510(k) Number (if known) K242071

Device Name Xpert Xpress CoV-2/Flu/RSV plus

#### Indications for Use (Describe)

The Xpert Xpress CoV-2/Flu/RSV plus test, performed on the GeneXpert Xpress System, is an automated multiplexed real-time reverse transcriptase polymerase chain reaction (RT-PCR) test intended for use in the simultaneous in vitro qualitative detection and differentiation of severe acute respiratory syndrome coronavirus (SARS-CoV-2), influenza A, influenza B, and/or respiratory syncytial virus (RSV) viral RNA in nasopharyngeal swab anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2, influenza B, and RSV can be similar.

The Xpert Xpress CoV-2/Flu/RSV plus is intended for use in the differential detection of SARS-CoV-2, influera A, influenza B, and/or RSV RNA and aids in the diagnosis of COVID-19, influenza, and/or RSV infections if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A. influenza B, and RSV viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection.

Positive results are indicative of the identified virus, but do not rule out bacterial infection or co-infection with other pathogens not detected by the test. The agent (s) detected by the Xpert Xpress CoV-2/Flu/RSV plus test may not be the definite cause of the disease.

Negative results do not preclude SARS-CoV-2, influenza A virus, and/or RSV infection. The results of this test should not be used as the sole basis for treatment or other patient management decisions.

| Type of Use (Select one or both, as applicable) | |
|--------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| <span style="font-size: 12pt;"> ☒ Prescription Use (Part 21 CFR 801 Subpart D) </span> | <span style="font-size: 12pt;"> ☐ Over-The-Counter Use (21 CFR 801 Subpart C) </span> |

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Image /page/4/Picture/0 description: The image shows the Cepheid logo, which is a blue abstract shape. Below the logo is the text "Cepheid." in a serif font. Underneath that is the text "Xpert® Xpress CoV-2/Flu/RSV plus" in a serif font.

# 510(k) Summary for Xpert Xpress CoV-2/Flu/RSV plus

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Image /page/5/Picture/0 description: The image shows the Cepheid logo and the text "Xpert® Xpress CoV-2/Flu/RSV plus". The Cepheid logo is a blue graphic of three curved lines. The text is in a serif font, with "Xpert" in bold and the registered trademark symbol after it.

## TABLE OF CONTENTS

| 1. 510(k) SUMMARY | 3 |
|-------------------------------|----|
| 1.1. DEVICE DESCRIPTION | 4 |
| 1.2. DEVICE INTENDED USE | 5 |
| 1.3. SUBSTANTIAL EQUIVALENCE | 6 |
| 1.4. PERFORMANCE STUDIES | 8 |
| 1.4.1. ANALYTICAL PERFORMANCE | 8 |
| 1.4.2. CLINICAL PERFORMANCE | 26 |
| 1.5. CONCLUSIONS | 31 |

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#### 1. 510(k) Summary

As required by 21 CFR Section 807.92(c).

| Submitted by: | Cepheid<br>904 Caribbean Drive<br>Sunnyvale, CA 94089<br>Phone number: [phone] |
|----------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Yen H. Nguyen, Ph.D. |
| Date of Preparation: | January 7, 2025 |
| Device: | |
| Trade name: | Xpert® Xpress CoV-2/Flu/RSV plus |
| Common name: | Xpert Xpress CoV-2/Flu/RSV plus |
| Type of Test: | Qualitative real-time reverse transcription polymerase chain<br>reaction (RT-PCR) and detection test |
| Regulation number<br>Classification name<br>Product code | 21 CFR 866.3981, Multi-Target Respiratory Specimen<br>Nucleic Acid Test Including SARS-CoV-2 and Other<br>Microbial Agents, QOF.<br>21 CFR 862.2570, Real Time Nucleic Acid Amplification<br>System, OOI. |
| Classification<br>Advisory Panel | Microbiology (83) |
| Prescription Use | Yes |
| Predicate Device<br>Assay: | Xpert Xpress CoV-2/Flu/RSV plus (K231481) |

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#### 1.1. Device Description

The Xpert Xpress CoV-2/Flu/RSV plus test is an automated in vitro diagnostic test for the simultaneous qualitative detection and differentiation of SARS-CoV-2. Flu A. Flu B. and RSV viral RNA in nasopharyngeal swab (NPS) and anterior nasal swab (NS) specimens collected from individuals showing signs and symptoms of respiratory viral infection.

The Xpert Xpress CoV-2/Flu/RSV plus test is performed on GeneXpert Xpress System, which consist of a GeneXpert IV instrument that executes sample preparation, nucleic acid amplification and real-time fluorescent signal detection for the tests, and a GeneXpert Hub with preloaded GeneXpert Xpress software for running the tests and viewing the test results. The GeneXpert Hub accessory integrates the computer, touchscreen monitor and barcode scanner. Each of the GeneXpert modules in the GeneXpert IV instrument can perform independent sample preparation and testing. The GeneXpert Xpress System requires the use of single-use disposable cartridges that hold the RT-PCR reagents and host sample purification, nucleic acid amplification, and detection of the target sequences. Because the cartridges are self-contained, cross-contamination between samples is minimized.

The Xpert Xpress CoV-2/Flu/RSV plus test cartridge includes reagents for the detection of SARS-CoV-2, Flu A, Flu B and RSV viral RNA from NPS and NS specimens. The primers and probes in the Xpert Xpress CoV-2/Flu/RSV plus test are designed to amplify and detect unique sequences in the genes that encode the following proteins: SARS-CoV-2 nucleocapsid (N), SARS-CoV-2 envelope (E), SARS-CoV-2 RNA-dependent RNA polymerase (RdRP), influenza A matrix (M), influenza A basic polymerase (PB2), influenza A acidic protein (PA), influenza B matrix (M), influenza B non-structural protein (NS), and the RSV A and RSV B nucleocapsid. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert Xpress System. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the RT-PCR reaction. The SPC also ensures that the RT-PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the RT-PCR reagents are functional. The PCC verifies reagent rehydration, PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dye stability.

The Xpert Xpress CoV-2/Flu/RSV plus test is designed for use with NPS or NS specimens collected with nylon flocked swabs and placed into viral transport medium (VTM), Universal Transport Medium (UTM), or eNAT®. The ancillary specimen collection kits, swabs and transport media validated for use with the Xpert Xpress CoV-2/Flu/RSV plus test include:

- Nasopharyngeal Sample Collection Kit for Viruses
- Copan UTM® 3C057N (Flexible Minitip Flocked Swab with UTM® Medium O without Beads)
- Copan eNAT® Molecular Collection and Preservation Medium P/N 6U074S01 о (Flexible Minitip Flocked Swab with eNAT® Medium)

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- Becton Dickinson Universal Viral Transport Kit P/N 220531 (Flexible Minitip o Flocked Swab with UVT Medium)
- Nasal Sample Collection Kit for Viruses
- Copan UTM® 3C064N (Regular Flocked Swab with UTM® Medium without O Beads)
- Copan eNAT® Molecular Collection and Preservation Medium P/N 6U073S01 O (Regular Flocked Swab with eNAT® Medium)
- Alternatively, swabs and transport media can be obtained separately: ●
- Nylon flocked swab (Copan P/N 502CS01, 503CS01) o
- Viral transport medium, 3 mL (Copan P/N 330C, 3C047N, BD Universal O Transport Medium, Remel M4RT or Remel M5)

These ancillary reagents allow NPS and NS specimens from patients to be collected, preserved and transported to laboratory prior to analysis with the Xpert Xpress CoV-2/Flu/RSV plus test.

#### 1.2. Device Intended Use

The Xpert Xpress CoV-2/Flu/RSV plus test. performed on the GeneXpert Xpress System, is an automated multiplexed real-time reverse transcriptase polymerase chain reaction (RT-PCR) test intended for use in the simultaneous in vitro qualitative detection and differentiation of severe acute respiratory syndrome coronavirus (SARS-CoV-2), influenza A, influenza B, and/or respiratory syncytial virus (RSV) viral RNA in nasopharyngeal swab and anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2. influenza A, influenza B, and RSV can be similar.

The Xpert Xpress CoV-2/Flu/RSV plus is intended for use in the differential detection of SARS-CoV-2, influenza A, influenza B, and/or RSV RNA and aids in the diagnosis of COVID-19, influenza, and/or RSV infections if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A, influenza B, and RSV viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection.

Positive results are indicative of the presence of the identified virus, but do not rule out bacterial infection or co-infection with other pathogens not detected by the test. The agent (s) detected by the Xpert Xpress CoV-2/Flu/RSV plus test may not be the definite cause of the disease.

Negative results do not preclude SARS-CoV-2, influenza A virus, influenza B virus, and/or RSV infection. The results of this test should not be used as the sole basis for treatment or other patient management decisions.

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#### 1.3. Substantial Equivalence

Table 1 shows the similarities and differences between the subject device and the predicate device.

| | | | Table 1: Comparison of Similarities and Differences Between Subject and Predicate Device | | | |
|--|--|--|------------------------------------------------------------------------------------------|--|--|--|
|--|--|--|------------------------------------------------------------------------------------------|--|--|--|

| | Subject Device | Predicate Device |
|--------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Attribute | Xpert® Xpress CoV-2/Flu/RSV plus<br>on the GeneXpert Xpress System | Xpert® Xpress CoV-2/Flu/RSV plus<br>on the GeneXpert Instrument Systems<br>[K231481] |
| Regulation | Same | 21 CFR 866.3981<br>Devices to detect and identify nucleic acid<br>targets in respiratory samples from<br>microbial agents that cause the SARS-CoV-<br>2 respiratory infection and other microbial<br>agents when in a multi-analyte test |
| Product Code | Same | QOF<br>Multi-target respiratory specimen nucleic<br>acid test including SARS-CoV-2 and other<br>microbial agents |
| Device Class | Same | II (Special Controls) |
| Technology/<br>Detection | Same | Real-time reverse transcription polymerase<br>chain reaction (RT-qPCR) |
| Intended Use | The Xpert® Xpress CoV-2/Flu/RSV plus<br>test, performed on the GeneXpert® Xpress<br>System, is an automated multiplexed real-<br>time reverse transcriptase polymerase<br>chain reaction (RT-PCR) test intended for<br>use in the simultaneous <i>in vitro</i> qualitative<br>detection and differentiation of severe<br>acute respiratory syndrome coronavirus<br>(SARS-CoV-2), influenza A, influenza B,<br>and/or respiratory syncytial virus (RSV)<br>viral RNA in nasopharyngeal swab and<br>anterior nasal swab specimens collected<br>from individuals with signs and symptoms<br>of respiratory tract infection. Clinical signs<br>and symptoms of respiratory tract<br>infection due to SARS-CoV-2, influenza<br>A, influenza B, and RSV can be similar.<br><br>The Xpert Xpress CoV-2/Flu/RSV plus is<br>intended for use in the differential<br>detection of SARS-CoV-2, influenza A,<br>influenza B and/or RSV RNA and aids in<br>the diagnosis of COVID-19, influenza<br>and/or RSV infections if used in<br>conjunction with other clinical and<br>epidemiological information, and<br>laboratory findings. SARS-CoV-2,<br>influenza A, influenza B, and RSV | The Xpert® Xpress CoV-2/Flu/RSV plus<br>test, performed on the GeneXpert® Dx and<br>GeneXpert® Infinity Systems, is an<br>automated multiplexed real-time reverse<br>transcriptase polymerase chain reaction<br>(RT-PCR) test intended for use in the<br>simultaneous <i>in vitro</i> qualitative detection<br>and differentiation of severe acute<br>respiratory syndrome coronavirus (SARS-<br>CoV-2), influenza A, influenza B, and/or<br>respiratory syncytial virus (RSV) viral RNA<br>in nasopharyngeal swab and anterior nasal<br>swab specimens collected from individuals<br>with signs and symptoms of respiratory tract<br>infection. Clinical signs and symptoms of<br>respiratory tract infection due to SARS-<br>CoV-2, influenza A, influenza B, and RSV<br>can be similar.<br><br>The Xpert Xpress CoV-2/Flu/RSV plus is<br>intended for use in the differential detection<br>of SARS-CoV-2, influenza A, influenza B<br>and/or RSV RNA and aids in the diagnosis<br>of COVID-19, influenza and/or RSV<br>infections if used in conjunction with other<br>clinical and epidemiological information,<br>and laboratory findings. SARS-CoV-2,<br>influenza A, influenza B, and RSV |
| | Subject Device | Predicate Device |
| Attribute | Xpert® Xpress CoV-2/Flu/RSV plus<br>on the GeneXpert Xpress System | Xpert® Xpress CoV-2/Flu/RSV plus<br>on the GeneXpert Instrument Systems<br>[K231481] |
| | RNA are generally detectable in<br>nasopharyngeal swab and anterior nasal<br>swab specimens during the acute phase of<br>infection. | RNA are generally detectable in<br>nasopharyngeal swab and anterior nasal<br>swab specimens during the acute phase of<br>infection. |
| | Positive results are indicative of the<br>presence of the identified virus, but do not<br>rule out bacterial infection or co-infection<br>with other pathogens not detected by the<br>test. The agent(s) detected by the Xpert<br>Xpress CoV-2/Flu/RSV plus test may not<br>be the definite cause of disease. | Positive results are indicative of the<br>presence of the identified virus, but do not<br>rule out bacterial infection or co-infection<br>with other pathogens not detected by the<br>test. The agent(s) detected by the Xpert<br>Xpress CoV-2/Flu/RSV plus test may not be<br>the definite cause of disease. |
| | Negative results do not preclude SARS-<br>CoV-2, influenza A, influenza B and/or<br>RSV infection. The results of this test<br>should not be used as the sole basis for<br>diagnosis, treatment, or other patient<br>management decisions. | Negative results do not preclude SARS-<br>CoV-2, influenza A, influenza B and/or<br>RSV infection. The results of this test<br>should not be used as the sole basis for<br>diagnosis, treatment, or other patient<br>management decisions. |
| Assay Targets | Same | SARS-CoV-2, Influenza A, Influenza B,<br>RSV viral RNA |
| Specimen Type | Same | Nasopharyngeal swab (NPS) Anterior nasal swab (NS) |
| Transport<br>Media | Same | Universal Transport Medium (UTM) /<br>Viral Transport Medium (VTM) eNAT |
| Test Format | Same | Single Use |
| Automation | Same | Automated Nucleic Acid Extraction,<br>Detection and Results Interpretation |
| Assay Results | Same | Qualitative |
| Internal<br>Control | Same | Sample Processing Control (SPC)<br>Probe Check Control (PCC) |
| Instrument<br>Systems | Cepheid GeneXpert® Xpress System | Cepheid GeneXpert® Instrument Systems |
| Time to Result | Same | 36 min or less for sample preparation and<br>RT-PCR |

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The following performance data (analytical and clinical) were provided in support of the substantial equivalence determination.

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#### 1.4. Performance Studies

#### 1.4.1. Analytical Performance

#### Analytical Sensitivity (Limit of Detection) - Clinical Nasopharyngeal Swab (NPS) Matrix

The analytical sensitivity of the Xpert Xpress CoV-2/Flu/RSV plus test was first estimated by using 2 reagent lots and testing limiting dilutions of viruses (NATtrol SARS-CoV-2, 1st World Health Organization (WHO) International Standard for SARS-CoV-2, Flu A H1, Flu A H3 . Flu B Victoria linage, Flu B Yamagata lineage, RSV A and RSV B) in pooled negative clinical NPS-UTM/VTM matrix, following the guidance in Clinical and Laboratory Standards Institute (CLSI) document EP17-A2. The LoD is defined as the lowest concentration for each strain at which 95% (19/20) of replicates yield a positive result. The estimated LoD values as determined by Probit regression analysis were verified using 2 lots of Xpert Xpress CoV-2/Flu/RSV plus reagents, by testing 20 replicates per virus/lot combination. The highest (least sensitive) LoD value for the two lots was reported as the final, verified LoD. The verified LoD values for the viruses tested are summarized in Table 2.

| Virus/Strain | LoD Concentration |
|--------------------------------|-------------------|
| USA-WA1/2020 (NATtrol) | 138 copies/mL |
| 1st WHO International Standard | 94 IU/mL |
| Flu A/Idaho/07/2018 | 0.007 TCID50/mL |
| Flu A/California/07/2009 | 0.0022 TCID50/mL |
| Flu A/Hong Kong/45/2019 | 0.44 FFU/mL |
| Flu A/Victoria/361/2011 | 0.05 TCID50/mL |
| Flu B/Washington/2/2019 | 12.9 CEID50/mL |
| Flu B/Wisconsin/10/2016 | 2.4 TCID50/mL |
| RSV A/2/Australia/61 | 0.33 TCID50/mL |
| RSV A/Long/MD/56 | 0.17 TCID50/mL |
| RSV B/9320/MA/77 | 0.37 TCID50/mL |
| RSV B/Wash/18537/62 | 0.2 TCID50/mL |

Table 2. Xpert Xpress CoV-2/Flu/RSV plus Limit of Detection in Clinical NPS-UTM/VTM Matrix

#### Analytical Sensitivity - Clinical Anterior Nasal Swab (NS) Matrix

The analytical sensitivity of the Xpert Xpress CoV-2/Flu/RSV plus test in clinical anterior nasal swab (NS) matrix was first estimated by using 2 lots and testing limiting dilutions of viruses (NATtrol SARS-CoV-2, 1st World Health Organization (WHO) International Standard for SARS-CoV-2, Flu A H1, Flu A H3, Flu B Victoria linage, Flu B Yamagata lineage, RSV A and RSV B) in pooled negative clinical NS UTM/VTM matrix, following the guidance in Clinical and Laboratory Standards Institute (CLSI) document EP17-A2. The LoD is defined as the lowest concentration for each strain at which 95% (19/20) of replicates yield a positive result. The estimated LoD values as determined by Probit regression analysis were verified using 2 lots of Xpert Xpress CoV-2/Flu/RSV plus reagents, by testing 20 replicates per

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Image /page/12/Picture/0 description: The image shows the Cepheid logo and the text "Xpert® Xpress CoV-2/Flu/RSV plus". The Cepheid logo is a stylized blue image. The text is in black font and appears to be the name of a product.

virus/lot combination. The highest (least sensitive) LoD value for the two lots was reported as the final, verified LoD. The verified LoD values for the viruses tested are summarized in Table 3.

| Virus/Strain | LoD Concentration |
|--------------------------------|-------------------|
| USA-WA1/2020 (NATtrol) | 64 copies/mL |
| 1st WHO International Standard | 143 IU/mL |
| Flu A/Idaho/07/2018 | 0.012 TCID50/mL |
| Flu A/California/07/2009 | 0.0028 TCID50/mL |
| Flu A/Hong Kong/45/2019 | 0.49 FFU/mL |
| Flu A/Victoria/361/2011 | 0.065 TCID50/mL |
| Flu B/Washington/2/2019 | 26.3 CEID50/mL |
| Flu B/Wisconsin/10/2016 | 2.41 TCID50/mL |
| RSV A/2/Australia/61 | 0.28 TCID50/mL |
| RSV A/Long/MD/56 | 0.22 TCID50/mL |
| RSV B/9320/MA/77 | 0.27 TCID50/mL |
| RSV B/Wash/18537/62 | 0.4 TCID50/mL |

Table 3. Xpert Xpress CoV-2/Flu/RSV plus Limit of Detection in Clinical NS-UTM/VTM Matrix

#### Analytical Reactivity (Inclusivity)

#### SARS-CoV-2 in silico Analyses

The inclusivity of Xpert Xpress CoV-2/Flu/RSV plus was evaluated using in silico analysis of the assay amplicons in relation to SARS-CoV-2 sequences available in the GISAID gene database as of June 15, 2022. The sequences were separated into the lineages of interest based on the Pango Lineage assigned to each genome by GISAID, and those with ambiguous nucleotides were removed. Thus, the following inclusivity analyses focus on the combined, non-ambiguous sequences from the variants of interest and variants of concern as of June 15, 2022. These constituted 10,310,839 sequences for the E target, 10,428,014 sequences for the N2 target, and 10,178,602 sequences for the RdRP target. Table 4 summarizes the effective predicted inclusivity for E, N2 and RdRP amplicons for the variants of interests and concern.

Table 4. Predicted Inclusivity for E, N2 and RdRP Amplicons for SARS-CoV-2 Variants of Interests and Concern

| Amplicon | Exact Match | 1 Mismatcha | 2 or More<br>Mismatches | % Total <2<br>Mismatches |
|----------------|----------------------------------|----------------|-------------------------|--------------------------|
| CEP-COV-E-PLUS | 10,262,080 of 10,310,839 (99.5%) | 47,959 (0.5%) | 800 (0.01%) | 100% |
| CEP-COV-N2 | 10,228,739 of 10,428,014 (98.1%) | 194,319 (1.9%) | 4,956 (0.05%) | 99.9% |
| CEP-COV-RDRP | 10,092,873 of 10,178,602 (99.2%) | 84,595 (0.8%) | 1,134 (0.01%) | 100% |

a. Single-nucleotide mismatches are predicted to not impact the performance of the test.

Based on the built-in redundancy of the Xpert Xpress CoV-2/Flu/RSV plus test's SARS-CoV-2 amplification system (i.e., 3 independent targets, only 1 of 3 must be detected to assign a

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positive result), it is not anticipated that any of the evaluated SARS-CoV-2 sequences would be missed by the Xpert Xpress CoV-2/Flu/RSV plus test.

#### SARS-CoV-2, Flu A, Flu B, and RSV Inclusivity Wet-Testing

In addition to the in silico analysis of the SARS-CoV-2 primers and probes for inclusivity, the inclusivity of the Xpert Xpress CoV-2/Flu/RSV plus test was evaluated by bench testing against multiple strains of SARS-CoV-2, influenza A H1N1 (seasonal pre-2009), influenza A H1N1 (pandemic 2009), influenza A H3N2 (seasonal), avian influenza A (H5N1, H5N2, H6N2, H7N2, H7N3, H2N2, H7N9, and H9N2), influenza B (representing strains from both Victoria and Yamagata lineages), and respiratory syncytial virus subgroups A and B (RSV A and RSV B) at concentrations of ~3x LoD in simulated matrix. A total of 102 respiratory viral strains comprised of 18 SARS-CoV-2 strains, 69 inf…