XPERT FLU, GENEXPERT DX SYSTEMS, GENEXPERT INFINITY SYSTEM, GENEXPERT SYSTEM SOFTWARE VERISIONS 2.1 AND 4.0

K103766 · Cepheid · OQW · Apr 21, 2011 · Microbiology

Device Facts

• Record ID: K103766
• Device Name: XPERT FLU, GENEXPERT DX SYSTEMS, GENEXPERT INFINITY SYSTEM, GENEXPERT SYSTEM SOFTWARE VERISIONS 2.1 AND 4.0
• Applicant: Cepheid
• Product Code: OQW · Microbiology
• Decision Date: Apr 21, 2011
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.3332
• Device Class: Class 2

Intended Use

The Cepheid® Xpert Flu Assay is an automated, multiplex real-time RT-PCR assay intended for the in vitro qualitative detection and differentiation of influenza A, influenza B and 2009 H1N1 influenza viral RNA. The Xpert Flu Assay uses nasal aspirates/washes and nasopharyngeal swab specimens collected from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The Xpert Flu Assay is intended as an aid in the diagnosis of influenza. Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions. Performance characteristics for influenza A were established during the 2009-2010 influenza season when 2009 H1N1 influenza was the predominant influenza A virus in circulation. When other influenza A viruses are emerging, performance characteristics may vary. 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 department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

Device Story

Xpert Flu Assay is an automated, multiplex real-time RT-PCR diagnostic test for qualitative detection/differentiation of Influenza A, Influenza B, and 2009 H1N1 viral RNA. Input: nasal aspirates/washes or nasopharyngeal swabs collected in Universal Transport Medium. Process: cartridge-based system (GeneXpert Dx or Infinity) automates sample preparation (lysis, nucleic acid capture on cellulose column, washing, elution) and rRT-PCR amplification. Output: qualitative results (detected/not detected) displayed in tabular/graphic formats within 75 minutes. Used in clinical settings; operated by laboratory personnel. Provides rapid diagnostic aid for influenza; negative results do not rule out infection. Benefits include automated workflow, reduced contamination risk, and integrated sample processing control (SPC) to monitor inhibition and reagent functionality.

Clinical Evidence

Clinical performance evaluated using 649 prospective and 602 archived specimens. Prospective NA/W sensitivity/specificity for Flu A: 85.7%/99.1%; 2009 H1N1: 100%/98.8%; Flu B: 100%/99.4%. Prospective NP swab sensitivity/specificity for Flu A: 100%/98.3%; 2009 H1N1: 100%/99.0%; Flu B: 87.5%/99.7%. Comparator methods included viral culture/DFA and FDA-cleared molecular assays. Sequencing used for confirmation of Flu A positive specimens.

Technological Characteristics

Multiplex real-time RT-PCR assay. Uses single-use, multi-chambered fluidic cartridges with integrated sample preparation (ultrasonic lysis) and I-CORE thermocycler. Analyte detection via real-time fluorescence. System is networked/standalone (GeneXpert Dx or Infinity). Includes Sample Processing Control (SPC) and Probe Check Control (PCC).

Indications for Use

Indicated for symptomatic patients with signs/symptoms of respiratory infection requiring influenza A, influenza B, and 2009 H1N1 viral RNA detection from nasal aspirates/washes or nasopharyngeal swabs. Not for use as sole diagnostic basis.

Regulatory Classification

Identification

Reagents for detection of specific novel influenza A viruses are devices that are intended for use in a nucleic acid amplification test to directly detect specific virus RNA in human respiratory specimens or viral cultures. Detection of specific virus RNA aids in the diagnosis of influenza caused by specific novel influenza A viruses in patients with clinical risk of infection with these viruses, and also aids in the presumptive laboratory identification of specific novel influenza A viruses to provide epidemiological information on influenza. These reagents include primers, probes, and specific influenza A virus controls.

Special Controls

The device is classified as Class II under regulation 21 CFR 866.3332 with special controls. The special control guidance document "Reagents for Detection of Specific Novel Influenza A viruses" will be available shortly.

*Classification.* Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Reagents for Detection of Specific Novel Influenza A Viruses.” See § 866.1(e) for information on obtaining this document. (2) The distribution of these devices is limited to laboratories with experienced personnel who have training in standardized molecular testing procedures and expertise in viral diagnosis, and appropriate biosafety equipment and containment.

Predicate Devices

• ProFLU+™ Assay (K073029)
• Simplexa™ Influenza A H1N1(2009) (K100148)

Submission Summary (Full Text)

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K103766

#### 510(k) Summary

As required by 21 CFR Section 807.92(c).

APR 2 1 2011

| Submitted by: | Cepheid®<br>904 Caribbean Drive<br>Sunnyvale, CA 90489<br>Phone number: [phone].<br>Fax number: [phone] |
|--------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Russel K. Enns, Ph.D. |
| Date of Preparation: | April 22, 2011 |
| Device: | |
| Trade name: | Xpert® Flu |
| Common name: | Xpert Flu Assay |
| Type of Test: | Automated, multiplex real-time reverse transcription-<br>polymerase chain reaction (rRT-PCR) assay intended for the<br><i>in vitro</i> qualitative detection and differentiation of influenza<br>A, influenza B and 2009 H1N1 influenza viral RNA. |
| Regulation number/<br>Classification name: | 866.3980/Respiratory viral panel multiplex nucleic acid assay |
| Product code: | OQW, OCC, OOI |
| Classification<br>Advisory Panel | Microbiology (83) |
| Predicate Devices: | K073029: ProFLU+™ Assay,<br>Gen-Probe Prodesse, Inc.<br>K100148: Simplexa™ Influenza A H1N1(2009),<br>Focus Diagnostics, Inc. |

#### Device Description:

The Xpert Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A, influenza B and influenza A, subtype 2009 HINI. The assay is performed on the Cepheid GeneXpert Instrument Systems. The GeneXpert Instrument Systems automate and integrate sample purification, nucleic acid amplification, and detection of the target sequence in simple or complex samples using real-time PCR and RT-PCR assays. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is eliminated.

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The Xpert Flu Assay includes reagents for the detection and differentiation of influenza A, influenza B and influenza A, subtype 2009 H1N1 directly from nasal aspirates/washes (NA/W) and nasopharyngeal (NP) swab specimens from patients with signs and symptoms of respiratory infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included. The SPC is present to control for adequate processing of the target viruses and to monitor the presence of inhibitors in the PCR reaction. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity and dye stability.

The liquid specimen (NA/W) or swab specimen (NP) is collected according to the institution's standard procedures and placed into Universal Transport Medium (3mL UTM tubes). Following a brief mixing by inverting the UTM tube five times, the eluted material and one single-use reagent (Reagent 1), that is provided with the assay, are transferred to different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert Flu cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off reverse transcription and real-time, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fully-automated and completely integrated.

The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time RT-PCR for detection and differentiation of influenza A, influenza B and influenza A, subtype 2009 H1N1 in 75 minutes. The GeneXpert Instrument Systems have 1 to 48 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.

#### Device Intended Use:

The Cepheid® Xpert Flu Assay is an automated, multiplex real-time RT-PCR assay intended for the in vitro qualitative detection and differentiation of influenza B and 2009 H1N1 influenza viral RNA. The Xpert Flu Assay uses nasal aspirates/washes and nasopharyngeal swab specimens collected from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The Xpert Flu Assay is intended as an aid in the diagnosis of influenza.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions.

Performance characteristics for influenza A were established during the 2009-2010 influenza season when 2009 H1N1 influenza was the predominant influenza A virus in circulation. When other influenza A viruses are emerging, performance characteristics may vary.

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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 department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

## Substantial Equivalence:

The Xpert Flu Assay is substantially equivalent to the following predicate assays:

- K073029: ProFLU+TM Assay, Gen-Probe Prodesse, Inc. .
- K100148: Simplexa™ Influenza A H1N1(2009), Focus Diagnostics, Inc. .

Similarities and differences between the Cepheid Xpert Flu Assay and the predicate devices are shown in Table 5.1.

A clinical study at six sites was conducted to compare Xpert Flu Assay performance to the standard of care, viral culture followed by direct fluorescent assay (DFA). Sequencing for all influenza A positive specimens. For archived specimens, where viral culture was not performed prior to freezing, a FDA cleared molecular assay was performed as the comparator assay followed by sequencing of all influenza A positive specimens.

| Table 5.1: Comparison of Similarities and Differences of the Xpert Flu Assay with | |
|-----------------------------------------------------------------------------------|--|
| the Predicate Devices | |

| Item | Device<br>Cepheid Xpert Flu | Gen-Probe Prodesse,<br>Inc. ProFLU+ | Predicates<br>Focus Simplexa<br>Influenza A H1N1 |
|-----------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 510(k) No. | K103766 | K073029 | K100148 |
| Regulation | 866.3332 and 866.3980 | 866.3980 | 866.3332 |
| Product Code | OQW, OCC, OOI | OCC | OQW |
| Device Class | II | II | II |
| Technology/<br>Detection | Multiplex real time RT/PCR | Multiplex real time<br>RT/PCR | Multiplex real time<br>RT/PCR |
| Intended Use | An automated, multiplex<br>real-time RT-PCR assay<br>intended for the in vitro<br>qualitative detection and<br>differentiation of influenza<br>A, influenza B and 2009<br>H1N1 influenza viral RNA.<br>The Xpert Flu Assay uses<br>nasal aspirates/washes and<br>nasopharyngeal swab | A multiplex Real Time<br>RT-PCR in vitro<br>diagnostic test for the<br>rapid and qualitative<br>detection and<br>discrimination of<br>Influenza A Virus,<br>Influenza B Virus, and<br>Respiratory Syncytial<br>Virus (RSV) nucleic | For use on the 3M<br>Integrated Cycler as part of<br>the Microfluidic Molecular<br>System for the in vitro<br>qualitative detection and<br>differentiation of influenza<br>A and 2009 H1N1<br>influenza viral RNA in<br>nasopharyngeal swabs<br>(NPS), nasal swabs (NS), |
| | Device | | Predicates |
| Item | Cepheid Xpert Flu | Gen-Probe Prodesse,<br>Inc. ProFLU+\ | Focus Simplexa<br>Influenza A H1N1 |
| | specimens collected from<br>patients with signs and<br>symptoms of respiratory<br>infection in conjunction<br>with clinical and<br>epidemiological risk factors.<br>The Xpert Flu Assay is<br>intended as an aid in the<br>diagnosis of influenza.<br>Negative results do not<br>preclude influenza virus<br>infection and should not be<br>used as the sole basis for<br>treatment or other patient<br>management decisions.<br>Performance characteristics<br>for influenza A were<br>established during the 2009-<br>2010 influenza season when<br>2009 H1N1 influenza was<br>the predominant influenza<br>A virus in circulation. When<br>other influenza A viruses<br>are emerging, performance<br>characteristics may vary.<br>If infection with a novel<br>influenza A virus is<br>suspected based on current<br>clinical and epidemiological<br>screening criteria<br>recommended by public<br>health authorities,<br>specimens should be<br>collected with appropriate<br>infection control<br>precautions for novel<br>virulent influenza viruses<br>and sent to state or local<br>health department for<br>testing. Viral culture should<br>not be attempted in these<br>cases unless a BSL 3+<br>facility is available to<br>receive and culture<br>specimens. | acids isolated and<br>purified from<br>nasopharyngeal (NP)<br>swab specimens<br>obtained from<br>symptomatic patients.<br>This test is intended for<br>use to aid in the<br>differential diagnosis of<br>Influenza A, Influenza<br>B and RSV2 viral<br>infections in humans<br>and is not intended to<br>detect Influenza C.<br>A negative test is<br>presumptive and it is<br>recommended these<br>results be confirmed by<br>cell culture. Negative<br>results do not preclude<br>influenza or RSV virus<br>infection and should<br>not be used as the sole<br>basis for treatment or<br>other management<br>decisions. | and nasopharyngeal<br>aspirates (NPA) from<br>human patients with signs<br>and symptoms of<br>respiratory infection in<br>conjunction with clinical<br>and epidemiological risk<br>factors.<br>Negative results do not<br>preclude influenza virus<br>infection and should not be<br>used as the sole basis for<br>treatment or other patient<br>management decisions.<br>Performance characteristics<br>for influenza A were<br>established during the<br>2009-2010 influenza season<br>when 2009 H1N1 influenza<br>was the predominant<br>influenza A virus in<br>circulation. When other<br>Influenza A viruses are<br>emerging, performance<br>characteristics may vary.<br>If infection with a novel<br>Influenza A virus is<br>suspected based on current<br>clinical and<br>epidemiological screening<br>criteria recommended by<br>public health authorities,<br>specimens should be<br>collected with appropriate<br>infection control<br>precautions for novel<br>virulent Influenza viruses<br>and sent to state or local<br>health department for<br>testing. Viral culture should<br>not be attempted in these<br>cases unless a BSL 3+<br>facility is available to<br>receive and culture<br>specimens |
| | Device | Predicates | |
| Item | Cepheid Xpert Flu | Gen-Probe Prodesse,<br>Inc. ProFLU+\ | Focus Simplexa<br>Influenza A H1N1 |
| Indication for Use | Patients with signs and<br>symptoms of respiratory<br>infection in conjunction<br>with clinical and<br>epidemiological risk factors. | Symptomatic patients | Patients with signs and<br>symptoms of respiratory<br>infection in conjunction<br>with clinical and<br>epidemiological risk factors |
| Assay Targets | Influenza A,<br>influenza B, and influenza<br>A, subtype 2009 H1N1 | Influenza A, influenza<br>B. Respiratory<br>Syncytial Virus Type A<br>and Type B | Influenza A/<br>2009 H1N1 influenza |
| Specimen Types | Nasal aspirates/washes<br>(NA/W) and<br>Nasopharyngeal (NP) swabs | NP swab | NP swab, Nasal Swab (NS)<br>and nasopharyngeal<br>aspirates (NA/W) |
| Technological<br>Principles | RT/PCR | RT/PCR | RT/PCR |
| Nucleic Acid<br>Extraction | Yes | Yes | Yes |
| Extraction<br>Methods | Sample preparation<br>integrated in GeneXpert<br>Cartridge and GeneXpert<br>Instrumentation System | Roche MagNA Pure<br>LC Total NA Isolation<br>Kit | Roche MagNA Pure LC<br>Total NA Isolation Kit,<br>QIAGEN QIAamp Viral<br>RNA mini Kit |
| Assay Results | Qualitative | Qualitative | Qualitative |
| Instrument System | Cepheid GeneXpert<br>Instrument Systems | Cepheid Smartcycler®<br>II | 3M Integrated cycler |
| Assay Controls | Encapsulated (armored)<br>RNA pseudovirus as a<br>sample processing<br>control.<br>Available but not<br>provided are inactivated<br>virus controls for Flu A/B<br>and Flu A H1N1 as<br>external positive controls<br>and Coxsackie virus as an<br>external negative control. | Inf A RNA Control, Inf<br>B RNA Control, RSV<br>A RNA Control, RSV<br>B RNA Control and an<br>internal | Armored RNA Internal<br>Control, No Template<br>Control, and H1N1 Positive<br>Control provided |
| Test results | Total 75 minutes for sample<br>preparation and<br>rRT-PCR | Total 205 minutes<br>(~45 minutes for<br>sample preparation<br>~2.0 hours for<br>rRT-PCR) | Total 115 minutes<br>(~45 minutes for sample<br>preparation<br>~70 minutes for<br>rRT-PCR) |
| | Device…