The Cepheid Xpert Flu/RSV XC Assay is an automated, multiplex real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay intended for the in vitro qualitative detection and differentiation of influenza B, and respiratory syncytial virus (RSV) viral RNA. The Xpert Flu/RSV XC Assay uses nasopharyngeal swab and nasal aspirate/wash specimens collected from patients with signs and symptoms of respiratory infection. The Xpert Flu/RSV XC Assay is intended as an aid in the diagnosis of influenza and respiratory syncytial virus infections in conjunction with clinical and epidemiological risk factors.

Negative results do not preclude influenza virus or respiratory syncytial 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 2013-2014 influenza season. When other novel 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 Description

The Xpert Flu/RSV XC Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A. influenza B, and respiratory syncytial virus (RSV). The assay is performed on the Cepheid GeneXpert Instrument Systems (GeneXpert Dx systems and GeneXpert Infinity Systems). The GeneXpert Instrument System platform automates and integrates sample purification, nucleic acid amplification, and detection of the target sequence in simple or complex samples using real-time PCR and reverse transcriptase PCR (RT-PCR) assays. The systems require the use of singleuse disposable cartridges (the Xpert Flu/RSV XC 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 minimized.

The Xpert Flu/RSV XC Assay includes reagents for the detection and differentiation of influenza A, influenza B, and RSV viral RNA directly from nasopharyngeal (NP) swab and nasal aspirate/wash (NA/W) specimens collected from patients with signs and symptoms of respiratory infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge. 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 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 RSV viral RNA in approximately 60 minutes or less. The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR and RT-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 RT-PCR and detection.

Specimens are collected following the user's institution standard procedures for collecting NA/W specimens and NP swab specimens for influenza and RSV testing. The ancillary Cepheid Xpert Nasopharyngeal Sample Collection Kit (Cepheid catalog #SWAB/B-100) or Cepheid's Sample Collection Kit (Cepheid catalog #NASL-100N-100) are required but not provided for use with the assay. Both kits contain the identical viral transport medium and sterile nylon flocked swab. The NA/W specimen or the NP swab specimen is placed into the Xpert viral transport medium and sent to the GeneXpert® testing area for processing. When stored in the transport medium, the NA/W specimen or NP swab specimen is stable for up to 24 hours at 2-30 ℃ or up to seven days at 2-8 ℃. When ready to test the specimen, the user briefly mixes the specimen by inverting the tube five times, transfers the eluted material to the sample chamber in the top of the disposable fluidic cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off real-time, multiplex polymerase chain reaction (PCR) for detection of RNA. The results are automatically generated at the end of the process in a report that can be viewed and printed.

AI/ML Overview

Here's an analysis of the provided text, focusing on acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal "acceptance criteria" for the clinical performance in terms of specific PPA/NPA thresholds that had to be met for clearance. It presents the performance of the device and claims substantial equivalence to predicate devices. However, we can infer the desired performance from the presented data and the implicit expectation for a diagnostic assay to perform well. The analytical studies (LoD, specificity, inclusivity) demonstrate performance against well-defined criteria.

Inferred Clinical Acceptance Criteria (Based on Comparator Performance and FDA Clearance): The device's performance (PPA and NPA) should be demonstrably similar to or better than previously cleared predicate devices, with high positive and negative agreement. While no explicit thresholds like "PPA > X%" are stated for clinical studies, the demonstration of high agreement values and the claim of "substantially equivalent" implies these levels were considered acceptable by the FDA.

Category	Acceptance Criteria (Inferred from Predicate Equivalence and High Performance)	Reported Device Performance (Xpert Flu/RSV XC Assay)
Analytical Studies
Limit of Detection (LoD)	Lowest concentration with 95% confidence (19/20 positive replicates)	Flu A 2009 H1N1: 0.3-16 TCID50/mLFlu A H3N2: 0.3-0.8 TCID50/mLFlu B: 0.5-0.6 TCID50/mLRSV A: 1.0-1.2 TCID50/mLRSV B: 1.8-2.0 TCID50/mLFlu A H7N9: 21.0 TCID50/mL
Analytical Specificity	100% negative results for common respiratory pathogens or encountered microbes	100% (negative for 44 viral, bacterial, and yeast strains)
Analytical Reactivity	Positive detection for multiple strains of target viruses	100% (positive for 64 strains including various Influenza A, B, and RSV A/B)
Non-Interference	No assay interference from potentially interfering substances	No assay interference observed for 14 tested substances at specified concentrations
Carry-Over Contamination	No carry-over contamination from high positive to subsequent negative samples	100% (40 positive, 42 negative samples all correctly reported)
Fresh vs. Frozen Sample Equivalency	Statistically equivalent performance between fresh and freeze-thaw cycles	No statistically significant effect observed
Clinical Performance (NA/W Specimens)	High PPA and NPA relative to comparator assay	Flu A (Fresh): PPA 100%, NPA 100%Flu B (Fresh): PPA 99.2%, NPA 100%RSV (Fresh): PPA 98.5%, NPA 99.6%Flu A (Frozen): PPA 97.1%, NPA 100%Flu B (Frozen): PPA 100%, NPA 100%RSV (Frozen): PPA 84.6%, NPA 100%
Clinical Performance (NP Swab Specimens)	High PPA and NPA relative to comparator assay	Flu A (Fresh): PPA 85.7%, NPA 98.9%Flu B (Fresh): PPA 100%, NPA 100%RSV (Fresh): PPA 100%, NPA 100%Flu A (Frozen): PPA 99.0%, NPA 92.8%Flu B (Frozen): PPA 98.8%, NPA 100%RSV (Frozen): PPA 90.4%, NPA 99.1%
Acceptable Indeterminate Rate	Low rate of indeterminate results during initial testing and upon retest	1.4% initial indeterminate rate (17/18 retested, 14 yielded valid results, 4 still indeterminate)
Reproducibility	High agreement across sites, operators, and days (qualitative)Low variability in Ct values (quantitative)	Qualitative agreement mostly >90% for positive samples; <80% for "High Neg" samples (near detection limit)Total CVs for Ct values generally <7%
Instrument System Precision	High agreement between GeneXpert Dx and Infinity systemsLow variability in Ct values	Qualitative agreement mostly >80%; >90% for higher positive samplesTotal CVs for Ct values generally <7%

2. Sample Sizes and Data Provenance

Test Set (Clinical Comparison Study):
- NA/W Specimens: 657 total (581 fresh, prospectively collected; 76 frozen, archived).
- NP Swab Specimens: 593 total (190 fresh, prospectively collected; 403 frozen, archived).
- Data Provenance: United States (six institutions), conducted during the 2013-2014 influenza season. Both retrospective (frozen, archived specimens) and prospective (fresh, prospectively collected) data were used.
Reproducibility Study Test Set (a subset of samples with varying concentrations): 10 specimens (dilution panel) * 1 time/day * 10 days * 2 operators * 3 sites = 600 total qualitative results.
Instrument System Precision Study Test Set (a subset of samples with varying concentrations): 10 specimens (dilution panel) * 2 times/day * 12 days * 2 operators * 2 instrument systems = 960 total qualitative results.

3. Number of Experts and Qualifications for Ground Truth (Test Set)

The document does not specify the number of experts or their qualifications for establishing the ground truth during the clinical comparison study. It states that the Xpert Flu/RSV XC Assay performance was compared to a "FDA-cleared comparator assay." This implies the comparator assay's results were considered the ground truth, rather than independent expert adjudication.

4. Adjudication Method for the Test Set

The primary method for establishing the ground truth for the clinical comparison study was comparison against an FDA-cleared comparator assay.
Discordant results between the Xpert Flu/RSV XC Assay and the comparator assay were further analyzed by sequencing using primers different from those used in the Xpert Flu/RSV XC Assay. This serves as an adjudication method to determine the "true" status of discordant samples.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. This study evaluates the device's standalone performance compared to a predicate device, not the improvement in human reader performance with AI assistance. The device is a fully automated diagnostic assay, not an AI-assisted diagnostic tool requiring human interpretation.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire clinical comparison study (NA/W and NP Swab specimens) evaluates the performance of the Xpert Flu/RSV XC Assay algorithm only (as it is a fully automated system) compared to a predicate FDA-cleared assay. The results in Tables 5-12 and 5-13 represent this standalone performance.

7. Type of Ground Truth Used

For Analytical Studies (LoD, specificity, inclusivity): Known concentrations of cultured viral, bacterial, and yeast strains (measured in TCID50/mL or CFU/mL). For avian influenza A, purified viral RNA was used due to biosafety regulations.
For Clinical Comparison Studies: Results from an FDA-cleared comparator assay, with bi-directional sequencing for discordant results. This is a form of expert reference method.

8. Sample Size for the Training Set

The document does not specify a training set size or how the device was developed. As this is an in vitro diagnostic (IVD) assay based on RT-PCR, it relies on precisely designed primers and probes, rather than machine learning models that require explicit training sets in the same way an AI device would. The "development" process would involve iterative design and testing of these components based on known viral genetic sequences, rather than a quantifiable "training set" in the context of AI/ML.

9. How Ground Truth for the Training Set was Established

As noted above, a distinct "training set" in the AI/ML sense is not described. The ground truth for the design of the assay's primers and probes would be based on known genetic sequences of influenza A, influenza B, and RSV from public databases and clinical isolates, ensuring broad reactivity and specificity. This is intrinsic to the design of nucleic acid amplification tests.

Summary

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

Cepheid Scott Campbell, Ph.D., MBA Executive Director, Clinical Affairs 904 Caribbean Drive Sunnyvale CA 94089-1189

November 22, 2014

Re: K142045

Trade/Device Name: Xpert® Flu/RSV XC Assay Regulation Number: 21 CFR 866.3980 Regulation Name: Respiratory viral panel multiplex nucleic acid assay Regulatory Class: II Product Code: OCC, OOI Dated: October 21, 2014 Received: October 22, 2014

Dear Dr. Campbell:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

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

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

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

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

Sincerely yours,

Uwe Scherf -S for

Sally A. Hojvat Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K142045

Device Name Cepheid Xpert® Flu/RSV XC Assay

Indications for Use (Describe)

Negative results do not preclude influenza virus or respiratory syncytial 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 2013-2014 influenza season. When other novel influenza A viruses are emerging, performance characteristics may vary.

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

区 Prescription Use (Part 21 CFR 801 Subpart D)
□ Over-The-Counter Use (21 CFR 801 Subpart C)

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5.0 510(k) Summary

As required by 21 CFR Section 807.92(c).

Submitted by:	Cepheid904 Caribbean DriveSunnyvale, CA 90489Phone number: (408) 400-8460Fax number: (847) 510-0539
Contact:	Kerry J. Flom, Ph.D.
Date of Preparation:	November 17, 2014
Device:
Trade name:	Xpert® Flu/RSV XC
Common name:	Xpert Flu/RSV XC Assay
Type of Test:	Automated, multiplex real-time reverse transcription-polymerase chain reaction (RT-PCR) assay intended for the invitro qualitative detection and differentiation of influenza A,influenza B, and respiratory syncytial virus.
Regulation number/Classification name/Product code:	866.3980/Respiratory viral panel multiplex nucleic acidassay/OCC866.2570/Instrumentation for clinical multiplex testsystems/OOI
Classification	Class II
Advisory Panel	Microbiology (83)
Prescription Use	Yes
Predicate DevicesAssay:	1) For the detection and differentiation of influenza A,influenza B, and RSV A/B viral RNA in nasopharyngealswab specimens:Hologic Prodesse® ProFlu™+ Assay (ProFlu+ Assay)[510(k) #K1109668 and Special 510(k) #K132129]; and,2) For the detection and differentiation of influenza A andinfluenza B viral RNA in nasal aspirate/wash andnasopharyngeal swab specimens:Cepheid Xpert Flu [510(k) #K123191].
Predicate DevicesAncillary SampleCollection Kit:	Copan Universal Transport Medium (UTM-RT) System[510(k) #K042970]

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Device Description:

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top of the disposable fluidic cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off real-time, multiplex polymerase chain reaction (PCR) for detection of RNA. The results are automatically generated at the end of the process in a report that can be viewed and printed.

Device Intended Use:

Negative results do not preclude influenza virus or respiratory syncytial 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 2013-2014 influenza season. When other novel influenza A viruses are emerging, performance characteristics may vary.

Ancillary Specimen Collection Kit

Xpert® Nasopharyngeal Sample Collection Kit

The Xpert Nasopharyngeal Sample Collection Kit is designed to collect, preserve and transport nasopharyngeal swab specimens and to preserve and transport nasal aspirate/wash specimens from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Flu Assay or the Xpert Flu/RSV XC Assay.

The Xpert Nasopharyngeal Sample Collection Kit has only been cleared for use with the Xpert Flu Assay and Xpert Flu/RSV XC Assays.

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Substantial Equivalence:

The Xpert Flu/RSV XC Assay is substantially equivalent to the ProFlu+ Assay [510(k) # K110968 and #K132139] and to the current Cepheid Xpert Flu Assay (510(k) #K123191). The ProFlu+ Assay and the Xpert Flu/RSV XC Assay detect influenza A, influenza B. and RSV A/B from NP swab specimens. The Xpert Flu Assay detects influenza A and B from both NP swab specimens and NA/W specimens, and the Xpert Flu/RSV XC Assay detects influenza A. influenza B. and RSV from both NP swab specimens and NA/W specimens. All three assays utilize the same technology by determining the presence of the target organisms through real-time RT-PCR amplification and fluorogenic target-specific hybridization detection. A multi-center clinical study was conducted to determine the performance characteristics of the device relative to the primary predicate device, the ProFlu+ Assay, which was validated for use with NA/W specimens, and FDA cleared for NP swab specimens. Discordant results between the Xpert Flu/RSV XC Assay and the ProFlu+ Assay were analyzed by sequencing using primers different from those used in the Xpert Flu/RSV XC Assay. The study results showed the Xpert Flu/RSV XC Assay is acceptable for its intended use and is substantially equivalent to the predicate devices.

Table 5-1 shows the similarities and differences between the Xpert Flu/RSV XC Assav and the predicate assays.

Similarities
	Device	Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current CepheidXpert Flu	Hologic ProdesseProFlu+ Assay
510(k)Number	#K142045	#K123191	#K110968 and#K132129 (special)
Regulation	866.3980	Same	Same
ProductCode	OCC, OOI	OQW, OCC, OOI	OCC, OOI
DeviceClass	II	Same	Same
TechnologyPrinciple ofOperation	Multiplex real time RT-PCR	Same	Same
Similarities
	Device	Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current CepheidXpert Flu	Hologic ProdesseProFlu+ Assay
IntendedUse	The Cepheid XpertFlu/RSV XC Assay,performed on theGeneXpert InstrumentSystems, is anautomated, multiplexreal-time, reversetranscriptase polymerasechain reaction (RT-PCRassay intended for the invitro qualitative detectionand differentiation ofinfluenza A, influenza B,and respiratory syncytialvirus (RSV) viral RNA.The Xpert Flu/RSV XCAssay uses nasopharyn-geal swab and nasalaspirate/wash specimenscollected from patientswith signs and symptomsof respiratory infection inconjunction with clinicaland epidemiological riskfactors. The XpertFlu/RSV XC Assay isintended as an aid in thediagnosis of influenzaand respiratory syncytialvirus.	The Cepheid Xpert FluAssay,performed on theGeneXpert InstrumentSystems, is anautomated, multiplexreal-time RT-PCRassay intended for thein vitro qualitativedetection anddifferentiation ofinfluenza A, influenzaB and 2009 H1N1influenza viral RNA.The Xpert Flu Assayuses nasalaspirates/washes andnasopharyngeal swabspecimens collectedfrom patients withsigns and symptoms ofrespiratory infection inconjunction withclinical andepidemiological riskfactors. The Xpert FluAssay is intended as anaid in the diagnosis ofinfluenza.	The ProFlu™+ Assayis a multiplex Real-Time PCR (RT-PCR)in vitrodiagnostic test for therapid and qualitativedetection anddiscrimination ofInfluenza A Virus,Influenza B Virus, andRespiratory SyncytialVirus (RSV) nucleicacids isolated andpurified fromnasopharyngeal (NP)swab specimensobtained fromsymptomatic patients.This test is intended foruse to aid in thedifferential diagnosis ofInfluenza A, InfluenzaB and RSV viralinfections in humansand is not intended todetect Influenza C.
	Negative results do notpreclude influenza virusor respiratory syncytialvirus infection andshould not be used as thesole basis for treatmentor other patientmanagement decisions.	Negative results do notpreclude influenzavirus infection andshould not be used asthe sole basis fortreatment or otherpatient managementdecisions.	Negative results do notpreclude influenza orRSV virus infectionand should not be usedas the sole basis fortreatment or othermanagement decisions.Conversely, positiveresults do not rule-outbacterial infection or
Similarities
	Device	Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current CepheidXpert Flu	Hologic ProdesseProFlu+ Assay
			co-infection with otherviruses. The agentdetected may not be thedefinite cause ofdisease. The use ofadditional laboratorytesting and clinicalpresentation must beconsidered in order toobtain the finaldiagnosis of respiratoryviral infection.
	Performancecharacteristics forinfluenza A wereestablished during the2013-2014 influenzaseason. When othernovel influenza A virusesare emerging,performancecharacteristics may vary.	Performancecharacteristics forinfluenza A wereestablished during the2009-2010 influenzaseason when 2009H1N1 influenza wasthe predominantinfluenza A virus incirculation.Performancecharacteristics forinfluenza A wereconfirmed wheninfluenza A/H3 andinfluenza A/2009H1N1 were thepredominant influenzaA viruses in circulation(2009-2010, 2010-2011and 2011-2012). Whenother influenza Aviruses are emerging,performancecharacteristics mayvary.	Performancecharacteristics forInfluenza A Virus wereestablished whenInfluenza A/H3 andA/H1 were thepredominant InfluenzaA viruses in circulation(2006 - 2007respiratory season).Performancecharacteristics forInfluenza A wereconfirmed whenInfluenza A/H1,Influenza A/H3, andInfluenza A/2009H1N1 were thepredominant InfluenzaA viruses in circulation(2008 and 2009). Whenother Influenza Aviruses are emerging,performancecharacteristics mayvary.
Similarities
	Device	Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current CepheidXpert Flu	Hologic ProdesseProFlu+ Assay
	If infection with a novelinfluenza A virus issuspected based oncurrent clinical andepidemiologicalscreening criteriarecommended by publichealth authorities,specimens should becollected withappropriate infectioncontrol precautions fornovel virulent influenzaviruses and sent to stateor local healthdepartment for testing.Viral culture should notbe attempted in thesecases unless a BSL 3+facility is available toreceive and culturespecimens.	If infection with anovel influenza A virusis suspected based oncurrent clinical andepidemiologicalscreening criteriarecommended bypublic healthauthorities, specimensshould be collectedwith appropriateinfection controlprecautions for novelvirulent influenzaviruses and sent to stateor local healthdepartment for testing.Viral culture should notbe attempted in thesecases unless a BSL 3+facility is available toreceive and culturespecimens.	If infection with anovel Influenza A virusis suspected based oncurrent clinical andepidemiologicalscreening criteriarecommended bypublic healthauthorities, specimensshould be collectedwith appropriateinfection controlprecautions for novelvirulent Influenzaviruses and sent to stateor local healthdepartment for testing.Viral culture should notbe attempted in thesecases unless a BSL 3+facility is available toreceive and culturespecimens.
Indicationfor Use	Patients with signs andsymptoms of respiratoryinfection in conjunctionwith clinical andepidemiological riskfactors	Same as XpertFlu/RSV XC Assay	Same - symptomaticpatients
AssayTargets	Influenza A Virus,Influenza B Virus, andRSV viral RNA	Influenza A, influenzaB, and influenza A,subtype 2009 H1N1	Same as XpertFlu/RSV XC Assay
SpecimenTypes	Nasal aspirate/wash(NA/W) specimens andNasopharyngeal (NP)swab specimens	Same as XpertFlu/RSV XC Assay	Nasopharyngeal (NP)swab specimens; use ofProFlu+ Assay withNA/W specimens wasvalidated.
Similarities
	Device	Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current CepheidXpert Flu	Hologic ProdesseProFlu+ Assay
NucleicAcidExtraction	Yes	Same	Same
ExtractionMethods	Sample preparationintegrated in GeneXpertCartridge and GeneXpertInstrumentation System	Same as XpertFlu/RSV XC Assay	Extraction andpurification with RocheMagNA Pure LCSystem or bioMérieuxNucliSENS easyMAGSystem
AssayResults	Qualitative	Same	Same
InstrumentSystem	Cepheid GeneXpertInstrument Systems;same Cepheid I-coretechnology	Same as XpertFlu/RSV XC Assay	Cepheid SmartCycler IISystem; same CepheidI-core technology
AssayControls	Encapsulated (armored)RNA pseudovirus as asample processingcontrol.Available but notprovided are inactivatedvirus controls forinfluenza A/B and RSVas external positivecontrols, and Coxsackievirus as an externalnegative control.	Same as XpertFlu/RSV XC Assay	Internal RNA control.Required and provided:influenza A, influenzaB, RSV A, RSV Bpositive RNA transcriptcontrols
Time toobtain testresults	Approximately 60minutes or less forsample preparation andreal-time RT-PCR.	75 minutes for samplepreparation and real-time RT-PCR	Approximately 4 hoursfor sample preparationand real-time RT-PCR
Primersand probes	Primers and probes todetect the presence ofnucleic acid sequences ofinfluenza A, influenza B,and RSV	Primers and probes todetect the presence ofnucleic acid sequencesof influenza A,influenza B, andinfluenza, subtypeH1N1	Same as XpertFlu/RSV XC Assay
Similarities
	Device	Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current Cepheid Xpert FluHologic Prodesse ProFlu+ Assay
Laboratory Users	Operators in moderate and high complexity labs	Same as Xpert Flu/RSV XC Assay; categorized as CLIA Moderate Complexity.CLIA High Complexity

Table 5-1: Comparison of Similarities and Differences of the Xpert Flu/RSV XC Assay with the Predicate Devices

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Primary Differences(Differences are also Captured in the Similarities Table above)
Item	New DeviceCepheid Xpert Flu/RSV XC	Predicate Devices
		Current CepheidXpert Flu
		Prodesse® ProFluTM+Assay
IntendedUseDifferences	Detects and differentiatesbetween influenza A,influenza B, and RSVviral RNA.	Detects anddifferentiates betweeninfluenza A, influenzaB, and 2009 H1N1influenza viral RNA.Does not detect RSVviral RNA.
SpecimenTypes	Nasal aspirate/wash(NA/W) specimens andNasopharyngeal (NP)swab specimens	Same as XpertFlu/RSV XC Assay
		Nasopharyngeal (NP)swab specimens; notFDA cleared for NA/Wspecimens, butspecimen type wasvalidated for use in theclinical study.
TestCartridge	Disposable single-use,multi-chambered fluidiccartridge with allreagents contained in thecartridge.	Disposable single-use,multi-chamberedfluidic cartridge. Onereagent must be addedto the cartridge.
		Disposable single-usePCR tube. All reagentsand controls must beadded to the PCR tube.
InstrumentSystem	Cepheid GeneXpert DxSystems and GeneXpertInfinity Systems	Same as XpertFlu/RSV XC Assay
		Cepheid SmartCycler
Primary Differences(Differences are also Captured in the Similarities Table above)
	New Device		Predicate Devices
Item	Cepheid Xpert Flu/RSVXC	Current CepheidXpert Flu	Prodesse® ProFlu™+Assay
SamplePreparation	Self-contained andautomated after mixedspecimen is added tocartridge. All otherreagents are contained inthe cartridge.	Self-contained andautomated after mixedspecimen and onesingle-dose reagent areadded to cartridge.	Manual
Primersand probesforinfluenzaA,influenzaB, andinfluenza AsubtypeH1N1	Primers and probes todetect the presence ofnucleic acid sequences ofinfluenza A, influenza B,and RSV A/B. TheXpert Flu/RSV Assaycontains additional RNAsegments in order toprotect the assaysensitivity frommutations in theinfluenza genome due toantigenic drifts and shiftsas compared to the XpertFlu Assay.	Primers and probes todetect the presence ofnucleic acid sequencesof influenza A,influenza B, andinfluenza, subtypeH1N1. The currentXpert Flu Assay doesnot detect RSV	Primers and probes todetect the presence ofnucleic acid sequencesof influenza A,influenza B, and RSVA/B.
TargetSequence	Influenza A: Matrixprotein (MP),Polymerase (PB 2 andPA), and Hemagglutinin(HA for H7N9)Influenza B: Matrixprotein (MP) and Non-structural proteins (NS 1and NS 2)RSV A and RSV B:Nucleocapsid protein	Influenza A: Matrixprotein andHemagglutinin (HA forH1N1)Influenza B:Hemagglutinin (HA)	Influenza A: Matrixprotein (MP)Influenza B: Non-structural protein (NS 1and NS 2)RSV A and RSV B:Polymerase
InternalControls	Sample processingcontrol (SPC) and probecheck control (PCC).	Same as XpertFlu/RSV XC Assay	Internal RNA control
Primary Differences(Differences are also Captured in the Similarities Table above)
	Predicate Devices
Item	Cepheid Xpert Flu/RSV XC	Current Cepheid Xpert Flu	Prodesse® ProFlu™+ Assay
Laboratory Users	Operators with no clinical lab experience to experienced clinical laboratory technologists.	Operators with no clinical lab experience to experienced clinical laboratory technologists; categorized as CLIA Moderate Complexity.	CLIA High Complexity
Time to obtain test results	Approximately 60 minutes or less for sample preparation and RT-PCR	75 minutes for sample preparation and RT-PCR	Approximately 4 hours for sample preparation and RT-PCR
Combinatorial Assay Selections	Yes, user may select combined assay with all targets or a Flu only assay or a RSV only assay.	No	No
Early assay termination function	On Flu only or RSV only assay selections	No	No

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The Xpert Flu/RSV XC Assay has the same intended use as the primary predicate device and the same technological characteristics as both predicate devices. The clinical study demonstrates that the Xpert Flu/RSV XC Assay is acceptable for its intended use and is substantially equivalent to the predicate devices.

The predicate device for the ancillary specimen collection kit, the Xpert® Nasopharyngeal Sample Collection Kit, is the Copan Universal Transport Medium (UTM-RT) System, [510(k) # K042970]. The similarities and differences are shown in Table 5-2.

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Similarities
Item	Device	Predicate
Intended Use	The Xpert® NasopharyngealSample Collection Kit isdesigned to collect, preserve andtransport nasopharyngeal swabspecimens and to preserve andtransport nasal aspirate/washspecimens from patients withsigns and symptoms ofrespiratory infection prior toanalysis with the Xpert FluAssay or the Xpert Flu/RSV XCAssay.The Xpert® NasopharyngealSample Collection Kit has onlybeen cleared for use with theXpert Flu and Xpert Flu/RSVXC Assays.	Copan Universal TransportMedium (UTM-RT) System isintended for the collection andtransport of clinical specimenscontaining viruses, chlamydiae,mycoplasma or ureaplasmafrom the collection site to thetesting laboratory. UTM-RTcan be processed using standardclinical laboratory operatingprocedures for viral, chlamydial,mycoplasma and ureaplasmaculture.
Single-use Device	Yes	Same
Medium Formulation	Hank's Balanced Salt SolutionBovine Serum AlbuminL-cysteineGelatinSucroseL-glutamic acidHEPES bufferVancomycinAmphotericin BColistinPhenol red	Same
pH	$7.3 \pm 0.2$	Same
Storage Temperature	2 - 25°C (refrigeratedand room temperature)	Same
Volume	3 ml	1.5 ml; 3 ml; or 10 ml
Glass Beads	3 x 3 mm	Same

Table 5-2: Comparison of Similarities and Differences of the Xpert Nasopharyngeal Sample Collection Kit with the Predicate Device

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Container	Plastic (medical-gradepolypropylene)	Plastic
Product Configuration	Medium Tube in Kit withindividually-wrapped sterileswab.	Medium Tubes;Kit with Medium Tubes andSwab Options
Differences
Item	Device	Predicate
Intended Use(differences)	For collection, preservationand transport ofnasopharyngeal swabspecimens and to preserve andtransport nasal aspirate/washspecimens containing virusesfrom patients with signs andsymptoms of respiratoryinfection prior to analysiswith the Xpert Flu and XpertFlu/RSV XC Assay.	For collection, transport (andpreservation of viability) ofswab collected clinicalspecimens containing viruses,chlamydiae, mycoplasma orureaplasma. UTM-RT can beprocessed using standardclinical laboratory operatingprocedures for viral, chlamydial,mycoplasma and ureaplasmaculture.
Swab	Nylon flocked (samecollection swab as used withthe current Xpert Flu Assay).	Polyester

Both devices have the same general intended use and use the same technology to collect, store and transport clinical specimens, including viruses, to the laboratory for further testing. The prospective component of the multi-center clinical study of the Xpert Flu/RSV XC was conducted using Copan-manufactured UTM-RT and sterile nylon flocked swab demonstrating that the Xpert Nasopharyngeal Sample Collection Kit is acceptable for its intended use and substantially equivalent to the predicate device.

Non-Clinical Studies:

Analytical Sensitivity (Limit of Detection)

Studies were performed to determine the analytical limit of detection (LoD) of the Xpert Flu/RSV XC Assay with two lots of reagents across three testing days. The higher LoD observed per strain and per lot was selected for verification. Verification of the estimated LoD claim was performed on one reagent lot across a minimum of three testing days. LoD was established using two influenza A H3N2 strains, two influenza A 2009 H1N1 strains, two influenza B strains, two respiratory syncytial virus A (RSV A) strains, two respiratory syncytial virus B (RSV B) strains, and one influenza A H7N9 strain diluted into a negative pooled clinical matrix. The LoD is

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defined as the lowest concentration (tissue culture infective dose, TCID50/mL) per sample that can be reproducibly distinguished from negative samples with 95% confidence or the lowest concentration at which 19 of 20 replicates were positive. Each strain was tested in replicates of 20 per concentration of virus.

The LoD was determined empirically as the first concentration that had 19/20 or 20/20 positive results. The LoD point values for each strain tested are summarized in 5-3 to Table 5-8.

Strain ID	Confirmed LOD(TCID50/mL)(at least 19/20 positive)
Influenza A/California/7/2009	0.3 (20/20)
Influenza A/Florida/27/2011	16 (19/20)

Table 5-3: Confirmed LoD (TCID50/mL): Influenza A 2009 H1N1

Table 5-4: Confirmed LoD (TCID50/mL): Influenza A H3N2

Strain ID	Confirmed LOD(TCID50/mL)(at least 19/20 positive)
Influenza A/Perth/16/2009	0.3 (20/20)
Influenza A/Victoria/361/2011	0.8 (20/20)

Table 5-5: Confirmed LoD (TCID50/mL): Influenza B

Strain ID	Confirmed LOD(TCID50/mL)(at least 19/20 positive)
Influenza B/Massachusetts/2/2012	0.5(20/20)
Influenza B/Wisconsin/01/2011	0.6 (20/20)

Table 5-6: Confirmed LoD (TCID56/mL): Respiratory Syncytial Virus A

Strain ID	Confirmed LOD(TCID50/mL)(at least 19/20 positive)
RSV A/2/Australia/61	1.2 (20/20)
RSV A/Long/MD/56	1.0 (19/20)

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Strain ID	Confirmed LOD(TCID50/mL)(at least 19/20 positive)
RSV B/Washington/18537/62	1.8 (20/20)
RSV B/9320/Massachusetts/77	2.0 (19/20)

Table 5-7: Confirmed LoD (TCID50/mL): Respiratory Syncytial Virus B

Table 5-8: Confirmed LoD (TCID50/mL): Influenza A H7N9

Strain ID	Confirmed LOD(TCID50/mL)(at least 19/20 positive)
Influenza A/Anhui/1/2013	21.0 (19/20)

Analytical Specificity (Exclusivity)

The analytical specificity of the Xpert Flu/RSV XC Assay was evaluated by testing a panel of 44 cultures consisting of 16 viral, 26 bacterial, and two yeast strains representing common respiratory pathogens or those potentially encountered in the nasopharynx. Three replicates of all bacterial and yeast strains were tested at concentrations of ≥ 106 CFU/mL with the exception of one strain which was tested at 10° CFU/mL (Chlamydia pneumoniae). Three replicates of all viruses were tested at concentrations of ≥ 105 TCID50/mL. The analytical specificity was 100%. Results are shown in Table 5-9.

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Organism	Concentration	Influenza A	Influenza B	RSV
No Template Control		NEG	NEG	NEG
Adenovirus Type 1	1.12x107 TCID50/mL	NEG	NEG	NEG
Adenovirus Type 7	1.87x105 TCID50/mL	NEG	NEG	NEG
Human coronavirus OC43	2.85x105 TCID50/mL	NEG	NEG	NEG
Human coronavirus 229E	1x105 TCID50/mL	NEG	NEG	NEG
Cytomegalovirus	7.24x105 TCID50/mL	NEG	NEG	NEG
Echovirus	3.31x107 TCID50/mL	NEG	NEG	NEG
Enterovirus	1x105 TCID50/mL	NEG	NEG	NEG
Epstein Barr Virus	7.16x107 TCID50/mL	NEG	NEG	NEG
HSV	8.9x106 TCID50/mL	NEG	NEG	NEG
Measles	6.3x105 TCID50/mL	NEG	NEG	NEG
Human metapneumovirus	3.8x105 TCID50/mL	NEG	NEG	NEG
Mumps virus	6.31x106 TCID50/mL	NEG	NEG	NEG
Human parainfluenza Type 1	1.15x106 TCID50/mL	NEG	NEG	NEG
Human parainfluenza Type 2	1x105 TCID50/mL	NEG	NEG	NEG
Human parainfluenza Type 3	3.55x107 TCID50/mL	NEG	NEG	NEG
Rhinovirus Type 1A	1.26x105 TCID50/mL	NEG	NEG	NEG
Acinetobacter baumannii	>1x106 CFU/mL	NEG	NEG	NEG
Burkholderia cepacia	>1x106 CFU/mL	NEG	NEG	NEG
Candida albicans	>1x106 CFU/mL	NEG	NEG	NEG
Candida parapsilosis	>1x106 CFU/mL	NEG	NEG	NEG
Bordetella pertussis	1x108 CFU/mL	NEG	NEG	NEG
Organism	Concentration	Influenza A	Influenza B	RSV
Chlamydia pneumoniae	3.16x105 CFU/mL	NEG	NEG	NEG
Citrobacter freundii	>1x106 CFU/mL	NEG	NEG	NEG
Corynebacterium sp.	>1x106 CFU/mL	NEG	NEG	NEG
Escherichia coli	>1x106 CFU/mL	NEG	NEG	NEG
Enterococcus faecalis	>1x106 CFU/mL	NEG	NEG	NEG
Hemophilus influenzae	1x106 CFU/mL	NEG	NEG	NEG
Lactobacillus sp.	1x106 CFU/mL	NEG	NEG	NEG
Legionella spp.	1x108 CFU/mL	NEG	NEG	NEG
Moraxella catarrhalis	>1x106 CFU/mL	NEG	NEG	NEG
Mycobacterium tuberculosis(avirulent)	1.15x106 CFU/mL	NEG	NEG	NEG
Mycoplasma pneumoniae	1x107 CFU/mL	NEG	NEG	NEG
Neisseria meningitides	>1x106 CFU/mL	NEG	NEG	NEG
Neisseria mucosa	>1x106 CFU/mL	NEG	NEG	NEG
Propionibacterium acnes	>1x106 CFU/mL	NEG	NEG	NEG
Pseudomonas aeruginosa	>1x106 CFU/mL	NEG	NEG	NEG
Staphylococcus aureus(protein A producer)	>1x106 CFU/mL	NEG	NEG	NEG
Staphylococcus epidermidis	>1x106 CFU/mL	NEG	NEG	NEG
Staphylococcus haemolyticus	>1x106 CFU/mL	NEG	NEG	NEG
Streptococcus agalactiae	>1x106 CFU/mL	NEG	NEG	NEG
Streptococcus pneumoniae	>1x106 CFU/mL	NEG	NEG	NEG
Streptococcus pyogenes	>1x106 CFU/mL	NEG	NEG	NEG
Streptococcus salivarius	>1x106 CFU/mL	NEG	NEG	NEG
Streptococcus sanguinis	>1x106 CFU/mL	NEG	NEG	NEG

Table 5-9: Analytical Specificity of Xpert Flu/RSV XC Assay

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Analytical Reactivity (Inclusivity)

The analytical reactivity of the Xpert Flu/RSV XC Assay was evaluated against multiple strains of 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 levels near the analytical LoD. A total of 64 strains including 54 influenza viruses and 10 RSV strains were tested in this study with the Xpert Flu/RSV XC Assay.

Three replicates were tested for each strain. Results are shown in Table 5-10.

Virus	Strain	Concentration	Result
			FluA	FluB	RSV
No Template Control			NEG	NEG	NEG
	A/swine/Iowa/15/30	32.0 TCID50/mL	POS	NEG	NEG
	A/WS/33	32.0 TCID50/mL	POS	NEG	NEG
	A/PR/8/34	32.0 TCID50/mL	POS	NEG	NEG
	A/Mal/302/54	32.0 TCID50/mL	POS	NEG	NEG
Influenza AH1N1 (pre-2009)	A/Denver/1/57	32.0 TCID50/mL	POS	NEG	NEG
	A/New Jersey/8/76	32.0 TCID50/mL	POS	NEG	NEG
	A/New Caledonia/20/1999	32.0 TCID50/mL	POS	NEG	NEG
	A/New York/55/2004	32.0 TCID50/mL	POS	NEG	NEG
	A/Soloman Island/3/2006	32.0 TCID50/mL	POS	NEG	NEG
	A/Taiwan/42/06	32.0 TCID50/mL	POS	NEG	NEG
	A/Brisbane/59/2007	32.0 TCID50/mL	POS	NEG	NEG
	A/California/7/2009	32.0 TCID50/mL	POS	NEG	NEG
Influenza AH1N1(pdm2009)	A/swine/NY/02/2009	32.0 TCID50/mL	POS	NEG	NEG
	A/Florida/27/2011	32.0 TCID50/mL	POS	NEG	NEG
	A/Colorado/14/2012	32.0 TCID50/mL	POS	NEG	NEG
	A/Washington/24/2012	80.0 a TCID50/mL	POS	NEG	NEG
	A/Aichi/2/68	1.6 TCID50/mL	POS	NEG	NEG
Influenza AH3N2(Seasonal)	A/HongKong/8/68	1.6 TCID50/mL	POS	NEG	NEG
	A/Port Chalmers/1/73	1.6 TCID50/mL	POS	NEG	NEG
	A/Hawaii/15/2001	1.6 TCID50/mL	POS	NEG	NEG
	A/Wisconsin/67/05	1.6 TCID50/mL	POS	NEG	NEG
	A/Brisbane/10/2007	1.6 TCID50/mL	POS	NEG	NEG
	A/Perth/16/2009	1.6 TCID50/mL	POS	NEG	NEG
	Strain	Concentration	Result
Virus			FluA	FluB	RSV
	A/Minnesota/11/2010 (H3N2)v	1.6 TCID50/mL	POS	NEG	NEG
	A/Indiana/08/2011 (H3N2)v	1.6 TCID50/mL	POS	NEG	NEG
	A/Victoria/361/2011	1.6 TCID50/mL	POS	NEG	NEG
	A/Texas/50/2012	1.6 TCID50/mL	POS	NEG	NEG
	A/duck/Hunan/795/2002 (H5N1)	≤ 1pg/μLb	POS	NEG	NEG
	A/chicken/Hubei/327/2004 (H5N1)	≤ 1pg/μLb	POS	NEG	NEG
	A/Anhui/01/2005 (H5N1)	≤ 1pg/μLb	POS	NEG	NEG
	A/Japanese whiteeye/HongKong/1038/2006 (H5N1)	≤ 1pg/μLb	POS	NEG	NEG
	A/mallard/WI/34/75 (H5N2)	≤ 1pg/μLb	POS	NEG	NEG
	A/chicken/CA431/00 (H6N2)	≤ 1pg/μLb	POS	NEG	NEG
Avianinfluenza A	A/duck/LTC-10-82743/1943 (H7N2)	≤ 1pg/μLb	POS	NEG	NEG
	A/chicken/NJ/15086-3/94 (H7N3)	≤ 1pg/μLb	POS	NEG	NEG
	A/Anhui/1/2013 (H7N9)	N/Ac	POS	NEG	NEG
	A/Shanghai/1/2013 (H7N9)	N/Ac	POS	NEG	NEG
	A/chicken/Korea/38349-p96323/ 1996(H9N2)	≤ 1pg/μLb	POS	NEG	NEG
	A/Mallard/NY/6750/78 (H2N2)	≤ 1pg/μLb	POS	NEG	NEG
	B/Lee/40	1.2 TCID50/mL	NEG	POS	NEG
	B/Allen/45	1.2 TCID50/mL	NEG	POS	NEG
	B/GL/1739/54	1.2 TCID50/mL	NEG	POS	NEG
	B/Maryland/1/59	1.2 TCID50/mL	NEG	POS	NEG
	B/Panama/45/90d	3.0 TCID50/mLe	NEG	POS	NEG
Influenza B	B/Florida/07/2004f	1.2 TCID50/mL	NEG	POS	NEG
	B/Florida/02/06d	1.2 TCID50/mL	NEG	POS	NEG
	B/Florida/04/06f	1.2 TCID50/mL	NEG	POS	NEG
	B/Wisconsin/01/2011d	1.2 TCID50/mL	NEG	POS	NEG
	B/Massachusetts/2/2012f	1.2 TCID50/mL	NEG	POS	NEG
	B/Hong Kong/5/72	1.2 TCID50/mL	NEG	POS	NEG
Virus	Strain	Concentration	Result
			FluA	FluB	RSV
	B/Wisconsin/01/2010f	1.2 TCID50/mL	NEG	POS	NEG
	B/Malaysia/2506/04d	1.2 TCID50/mL	NEG	POS	NEG
	B/Taiwan/2/62	1.2 TCID50/mL	NEG	POS	NEG
	B/Brisbane/60/2008d	1.2 TCID50/mL	NEG	POS	NEG
RSV A	RSV-A/Long/MD/56	2.4 TCID50/mL	NEG	NEG	POS
	RSV-A/2/Australia/61	2.4 TCID50/mL	NEG	NEG	POS
	RSV-A/NY (Clinical unknown)	2.4 TCID50/mL	NEG	NEG	POS
	RSV-A/WI/629-8-2/2007	2.4 TCID50/mL	NEG	NEG	POS
	RSV-A/WI/629-11-1/2008	2.4 TCID50/mL	NEG	NEG	POS
RSV B	RSV-B/Wash/18537/62	4.0 TCID50/mL	NEG	NEG	POS
	RSV-B/9320/MA/77	4.0 TCID50/mL	NEG	NEG	POS
	RSV-B/WV14617/85	4.0 TCID50/mL	NEG	NEG	POS
	RSV-B/CH93(18)-18	20.0 TCID50/mLg	NEG	NEG	POS
	RSV-B/WI/629-5B/0607	4.0 TCID50/mL	NEG	NEG	POS

Table 5-10: Analytical Reactivity (Inclusivity) of Xpert Flu/RSV XC Assay

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4Influenza A/Washington/24/2012 was tested at 5X LoD (80.0 TCIDsy/mL) to obtain 3 of 3 Flu A POSITIVE result calls.

"Purified viral RNA in simulated background matrix was used for avian influenza A viruses due to biosafety regulations.

SInactivated avian influenza A (H7N9) viruses without viral titer was diluted 100,000 fold in simulated background matrix and tested due to biosafety regulations.

dKnown Victoria lineage.

Sinfluenza B/Panama/45/90 was tested at 5X LoD (3.0 TCID30mL) to obtain 3/3 Flu B POSITIVE result calls. 1Known Yamagata lineage.

6RSV-B/CH93(18)-18 was tested at 10X LoD (20.0 TCID50/mL) to obtain 3/3 RSV POSITIVE result calls.

Although this test has been shown to detect the novel avian influenza A (H7N9) cultured material, the performance characteristics of this device with clinical specimens that are positive for the novel avian influenza A (H7N9) virus have not been established. The Xpert Flu/RSV XC Assay can distinguish between influenza A and B viruses, but it cannot differentiate influenza subtypes.

Potentially Interfering Substances

In a non-clinical study, potentially interfering substances that may be present in the nasopharynx were evaluated directly relative to the performance of the Xpert Flu/RSV XC Assay. Potentially interfering substances in the nasopharynx may include, but are not limited to: blood, nasal secretions or mucus, and nasal and throat medications used to relieve congestion, nasal dryness, irritation, or asthma and allergy symptoms, as well as antibiotics and antivirals. Negative samples (n = 8) were tested per each substance

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to determine the effect on the performance of the sample processing control (SPC). Positive samples (n = 8) were tested per substance with six influenza (four influenza A and two influenza B) and four RSV (two RSV A and two RSV B) strains spiked at 2X the analytical LoD determined for each strain. All results were compared to positive and negative Universal Transport Medium (UTM) controls.

These evaluated substances are listed in Table 5-11 with active ingredients and concentrations tested shown. There was no assay interference in the presence of the substances at the concentrations tested in this study. All positive and negative replicates were correctly identified using the Xpert Flu/RSV XC Assay.

FluMist vaccine samples were correctly reported as Flu A POSITIVE: FLU B POSITIVE; RSV NEGATIVE as expected. Samples containing FluMist may cause false positive results. This is addressed in Section 17, Limitations.

Substance/Class	Description/ActiveIngredient	ConcentrationTested
Beta-adrenergicbronchodilator	Albuterol Sulfate	0.83 mg/mL(equivalent to1 dose per day)
Blood	Blood (Human)	2% (v/v)
BD™ UniversalViral TransportSystem	Transport Media	100% (v/v)
Remel M4®	Transport Media	100% (v/v)
Remel M4RT®	Transport Media	100% (v/v)
Remel M5®	Transport Media	100% (v/v)
Throat lozenges,oral anestheticand analgesic	Benzocaine, Menthol	1.7 mg/mL
Mucin	Purified Mucin protein(Bovine or porcinesubmaxillary gland)	2.5% (w/v)
Antibiotic, nasalointment	Mupirocin	10 mg/mL
Saline NasalSpray	Sodium Chloride (0.65%)	15% (v/v)
Anefrin NasalSpray	Oxymetazoline, 0.05%	15% (v/v)
Nasal Drops	Phenylephrine, 0.5%	15% (v/v)
Tamiflu®/Anti-viral drugs	Zanamivir	7.5 mg/mL
Antibacterial,systemic	Tobramycin	4 µg/mL

Table 5-11. Potentially Interfering Substances in Xpert Flu/RSV XC Assay

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Substance/Class	Description/ActiveIngredient	ConcentrationTested
Zicam®/NasalGel	Luffa opperculata,Galphimia glauca,Histaminumhydrochloricum Sulfur	15% (w/v)
FluMist®	Live intranasal influenzavirus vaccine	6.7% (v/v)
Nasalcorticosteroid	Fluticasone Propionate	5 μg/mL

Carry-Over Contamination

A study was conducted to demonstrate that single-use, self-contained GeneXpert cartridges prevent carry-over contamination in negative samples run followed by very high positive samples in the same GeneXpert module. The study consisted of a negative sample processed in the same GeneXpert module immediately followed by a very high influenza A sample (approximately 106 TCID50/test) or a very high RSV A sample (approximately 106 TCID50/test). This testing scheme was repeated 20 times on two GeneXpert modules for a total of 82 runs resulting in 40 positive and 42 negative specimens for each virus type. All 40 positive samples were correctly reported as Flu A POSITIVE; Flu B NEGATIVE; RSV NEGATIVE or Flu A NEGATIVE; Flu B NEGATIVE; RSV POSITIVE. All 42 negative samples were correctly reported as Flu A NEGATIVE; Flu B NEGATIVE; RSV NEGATIVE.

Fresh vs. Frozen Sample Equivalencv Study

Fresh and frozen specimen equivalency in the Xpert Flu/RSV XC Assay was evaluated by testing individual influenza and RSV strains at three different concentrations representing low positives (2X LoD), moderate positives (5X LoD), and high positives (10X LoD) in simulated background matrix. Negative samples consisted of simulated background matrix only. Fresh and frozen specimen equivalency was determined using one seasonal Flu A H3N2 strain (A/Victoria/361/2011), one Flu B strain (B/Wisconsin/01/11), one RSV A strain (RSV A/Long/MD/56), and one RSV B strain (RSV B/9320/MA/77). Replicates of 20 were tested for each specimen type and concentration. All positive and negative specimens were tested fresh, after one freezethaw cycle, and after two freeze-thaw cycles.

There was no statistically significant effect in the performance of the Xpert Flu/RSV XC Assay between fresh virus dilutions and two sequential freeze thaw cycles for positive and negative samples. All positive and negative replicates were correctly identified using the Xpert Flu/RSV XC Assay.

Linearitv

Not applicable, the Xpert Flu/RSV XC Assay is a qualitative assay.

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Clinical Studies

Clinical Comparison Study

Performance characteristics of the Xpert Flu/RSV XC Assay were evaluated at six institutions in the U.S during the 2013-2014 influenza season. Due to the low prevalence of influenza viruses and the difficulty in obtaining fresh influenza and RSV-positive specimens, the specimen population for this study was supplemented with frozen prospective, and frozen pre-selected archived specimens.

Subjects included individuals with signs and symptoms of respiratory infection and whose routine care called for collection of nasal aspirate/wash (NA/W) specimens or nasopharyngeal (NP) swab specimens for influenza and/or RSV testing. For eligible subjects, aliquots of leftover specimens were obtained for testing with the Xpert Flu/RSV XC Assay and reference testing, and patient management continued at the site per their standard practice.

The Xpert Flu/RSV XC Assay performance was compared to a FDA-cleared comparator assay. Bi-directional sequencing was performed on specimens where the Xpert Flu/RSV XC Assay and the comparator assay were discrepant, and is provided for informational purposes only.

Overall Results

NA/W Specimens

A total of 657 NA/W specimens were tested for influenza A, influenza B and RSV by the Xpert Flu/RSV XC Assay and the comparator assay. Of the 657 NA/W specimens, 581 were fresh, prospectively collected and 76 were frozen, archived specimens.

On fresh, prospectively collected NA/W specimens, the Xpert Flu/RSV XC Assay demonstrated a PPA and NPA for detection of influenza A of 100% and 100%, respectively, relative to the comparator assay (Table 5-12). The Xpert Flu/RSV XC Assay PPA and NPA for influenza B were 99.2% and 100%, respectively (Table 5-12). The Xpert Flu/RSV XC Assay PPA and NPA for RSV were 98.5% and 99.6%, respectively (Table 5-12).

On frozen, archived NA/W specimens, the Xpert Flu/RSV XC Assay demonstrated a PPA and NPA for detection of influenza A of 97.1% and 100%, respectively, relative to the comparator assay (Table 5-12). The Xpert Flu/RSV XC Assay PPA and NPA for influenza B were 100% and 100%, respectively (Table 5-12). The Xpert Flu/RSV XC Assay PPA and NPA for RSV were 84.6% and 100%, respectively (Table 5-12).

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SpecimenType	Target	n	TP	FP	TN	FN	PPA %(95 CI)	NPA %(95 CI)
Fresh	Flu A	581	35	0	546	0	100(90.0-100)	100(99.3-100)
	Flu B	581	126	0	454	1a	99.2(95.7-100)	100(99.2-100)
	RSV	581	128	2b	449	2c	98.5(94.6-99.8)	99.6(98.4-99.9)
Frozen	Flu A	76	34	0	41	1d	97.1(85.1-99.9)	100(91.4-100)
	Flu B	76	1	0	75	0	100(2.5-100)	100(95.2-100)
	RSV	76	11	0	63	2e	84.6(54.6-98.1)	100(94.3-100)

Table 5-12: Xpert Flu/RSV XC Assay Performance on NA/W Specimens

a Testing results by sequencing: NA; sample not sequenced.

Testing results by sequencing: 2 of 2 were RSV positive.

CTesting results by sequencing: 1 of 2 was RSV positive; 1 of 2 was RSV negative.

a Testing results by sequencing: 1 of 1 was Flu A negative.

Testing results by sequencing: 1 of 2 was RSV positive; 1 of 2 was RSV negative.

NP Swab Specimens

A total of 593 NP swab specimens were tested for influenza A, influenza B and RSV by the Xpert Flu/RSV XC Assay and the comparator assay. Of the 593 NP swab specimens, 190 were fresh, prospectively collected and 403 were frozen, archived specimens.

On fresh, prospectively collected NP swab specimens, the Xpert Flu/RSV XC Assay demonstrated a PPA and NPA for detection of influenza A of 85.7% and 98.9%, respectively, relative to the comparator assay (Table 5-13). The Xpert Flu/RSV XC Assay PPA and NPA for influenza B were 100% and 100%, respectively (Table 5-13). The Xpert Flu/RSV XC Assay PPA and NPA for RSV were 100% and 100%, respectively (Table 5-13).

On frozen, archived NP swab specimens, the Xpert Flu/RSV XC Assay demonstrated a PPA and NPA for detection of influenza A of 99.0% and 92.8%, respectively, relative to the comparator assay (Table 5-13). The Xpert Flu/RSV XC Assay PPA and NPA for influenza B were 98.8% and 100%, respectively (Table 5-13). The Xpert Flu/RSV XC Assay PPA and NPA for RSV were 90.4% and 99.1%, respectively (Table 5-13).

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SpecimenType	Target	n	TP	FP	TN	FN	PPA %(95 CI)	NPA %(95 CI)
Fresh	Flu A	190	6	2a	181	1b	85.7(42.1-99.6)	98.9(96.1-99.9)
	Flu B	190	3	0	187	0	100(29.2-100)	100(98.0-100)
	RSV	190	10	0	180	0	100(69.2-100)	100(98.0-100)
Frozen	Flu A	403	96	22c	284	1d	99.0(94.4-100)	92.8(89.3-95.4)
	Flu B	403	85	0	317	1e	98.8(93.7-100)	100(98.8-100)
	RSV	403	47	3f	348	5g	90.4(79.0-96.8)	99.1(97.5-99.8)

Table 5-13: Xpert Flu/RSV XC Assay Performance on NP Swab Specimens

a Testing results by sequencing: 2 of 2 were Flu A positive.

bTesting results by sequencing: 1 of 1 was Flu A negative.

CTesting results by sequencing: 17 of 22 were Flu A positive; 5 of 22 were Flu A negative.

dTesting results by sequencing: 1 of 1 was Flu A negative.

Testing results by sequencing: 1 of 1 was Flu B negative.

"Testing results by sequencing: 2 of 3 were RSV positive; 1 of 3 was RSV negative.

8Testing results by sequencing: 1 of 5 was RSV positive; 4 of 5 were RSV negative.

Of the Xpert Flu/RSV XC Assay runs performed with eligible specimens, 98.6% (1236/1254) of these specimens were successful on the first attempt. The initial indeterminate rate was 1.4% (95% CI 0.9-2.3%). The remaining 18 gave indeterminate results on the first attempt (11 ERROR, 3 INVALID and 4 NO RESULT). Seventeen of the 18 specimens were retested, of which 14 yielded valid results after a single retest. There were four NA/W specimens with indeterminate results upon retest which were excluded in the analyses.

Reproducibility Study

A panel of 10 specimens with varying concentrations of influenza A, influenza B, and RSV was tested on ten different days by two different operators, at each of three sites (10 specimens x 1 time/day x 10 days x 2 operators x 3 sites). One lot of Xpert Flu/RSV XC Assay cartridges was used at each of the 3 testing sites. The Xpert Flu/RSV XC Assay was performed according to the Xpert Flu/RSV XC Assay procedure. Results are summarized in Table 5-14.

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SampleID	Site 1/GX Dx			Site 2/Infinity-80			Site 3/Infinity-48			% TotalAgreement bySamplea
	Op 1	Op 2	Site	Op 1	Op 2	Site	Op 1	Op 2	Site
Negative	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(60/60)
Flu A-High Neg	70.0%(7/10)	60.0%(6/10)	65.0%(13/20)	80.0%(8/10)	80.0%(8/10)	80.0%(16/20)	60.0%(6/10)	70.0%(7/10)	65.0%(13/20)	70.0%(42/60)
Flu A-Low Pos	100%(10/10)	90.0%(9/10)	95.0%(19/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	90.0%(9/10)	95.0%(19/20)	96.7%(58/60)
Flu A-Mod Pos	100%(10/10)	90.0%(9/10)	95.0%(19/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	100%(10/10)	100%(20/20)	98.3%(59/60)
Flu B-High Neg	90.0%(9/10)	70.0%(7/10)	80.0%(16/20)	100%(10/10)	70.0%(7/10)	85.0%(17/20)	50.0%(5/10)	80.0%(8/10)	65.0%(13/20)	76.7%(46/60)
Flu B-Low Pos	100%(10/10)	90.0%(9/10)	95.0%(19/20)	90.0%(9/10)	70.0%(7/10)	80.0%(16/20)	100%(10/10)	90.0%(9/10)	95.0%(19/20)	90.0%(54/60)
Flu B-Mod Pos	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(60/60)
RSV-High Neg	60.0%(6/10)	50.0%(5/10)	55.0%(11/20)	90.0%(9/10)	60.0%(6/10)	75.0%(15/20)	70.0%(7/10)	70.0%(7/10)	70.0%(14/20)	66.7%(40/60)
RSV-Low Pos	77.8%b(7/9)	100%(10/10)	89.5%(17/19)	80.0%(8/10)	80.0%(8/10)	80.0%(16/20)	90.0%(9/10)	90.0%(9/10)	90.0%(18/20)	86.4%(51/59)
RSV-Mod Pos	100%c(9/9)	100%(10/10)	100%(19/19)	100%(10/10)	100%(10/10)	100%(20/20)	100%(10/10)	100%(10/10)	100%(20/20)	100%(59/59)

Table 5-14: Summary of Reproducibility Results

A greement calculated based on expected result: Negative (targeted positivity: 0%) and High Neg (targeted positivity: 20-80%) samples; Positive for Low Pos (targeted positivity: 95%) and Mod Pos (targeted positivity: 100%) samples. one sample indeterminate on initial testing; retest not done.

°One sample 2x indeterminate.

The reproducibility of the Xpert Flu/RSV XC Assay was also evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) between-sites, between-days, and between-operators for each panel member are presented in Table 5-15. One replicate was performed per day per operator, therefore, operator and assay (within-run) precision are confounded.

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Sample	AssayChannel(Analyte)	Na	MeanCt	Between-Site		Between-Day		Between-Operator+ Within-Assay		Total
				SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Negative	SPC	60	30.8	0.06	0.2	0	0	0.29	0.9	0.29	0.9
Flu A- High Neg	FluA1	18	38.0	0	0	1.55	4.1	0.85	2.2	1.77	4.6
	FluA2	0	NA	NA	NA	NA	NA	NA	NA	NA	NA
	Flu A-Low Pos	FluA1	58	34.9	0.38	1.1	0.10	0.3	1.28	3.7	1.34
FluA2		0	NA	NA	NA	NA	NA	NA	NA	NA	NA
Flu A- Mod Pos	FluA1	59	33.5	0.49	1.5	0	0	1.29	3.9	1.38	4.1
	FluA2	10	36.3	NA	NA	NA	NA	NA	NA	NA	NA
Flu B- High Neg	FluB	14	36.6	0.80	1.4	0	0	2.83	7.7	2.94	8.0
Flu B-Low Pos	FluB	54	33.4	0	0	1.07	3.2	1.76	5.3	2.06	6.2
Flu B- Mod Pos	FluB	60	32.1	0	0	0.38	1.2	1.47	4.6	1.51	4.7
RSV-High Neg	RSV	20	37.4	0	0	0.14	0.4	1.68	4.5	1.68	4.5
RSV-Low Pos	RSV	51	36.2	0.22	0.6	0	0	1.75	4.8	1.76	4.9
RSV- Mod Pos	RSV	60	35.1	0	0	0.24	0.9	1.20	3.4	1.24	3.5

Table 5-15: Summary of Reproducibility Data

4Results with non-zero Ct values out of 60.

Instrument System Precision

An in-house precision study was conducted to compare the performance of the GeneXpert Dx and the GeneXpert Infinity instrument systems. A panel of 10 specimens with varying concentrations of influenza A, influenza B, and RSV was tested on 12 different days by two operators. Each operator conducted four runs of each panel specimen per day on each of the two instrument systems (10 specimens x 2 times/ day x 12 days x 2 operators x 2 instrument systems). Three lots of Xpert Flu/RSV XC Assay cartridges were used for the study. The Xpert Flu/RSV XC Assay was performed according to the Xpert Flu/RSV XC Assay procedure. Results are summarized in Table 5-16.

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Sample	GeneXpert Dx			Infinity			% TotalAgreementby Samplea
	Op 1	Op 2	Inst	Op 1	Op 2	Inst
Negative	100%(48/48)	100%(48/48)	100%(96/96)	100%(48/48)	100%(48/48)	100%(96/96)	100%(192/192)
Flu A-High Neg	75.0%(36/48)	77.1%(37/48)	76.0%(73/96)	87.5%(42/48)	75.0%(36/48)	81.3%(78/96)	78.7%(151/192)
Flu A-Low Pos	68.8%(33/48)	97.9%(47/48)	83.3%(80/96)	91.7%(44/48)	93.8%(45/48)	92.7%(89/96)	88.0%(169/192)
Flu A-Mod Pos	97.9%(47/48)	100%(48/48)	99.0%(95/96)	93.8%(45/48)	97.9%(47/48)	95.8%(92/96)	97.4%(187/192)
Flu B-High Neg	81.3%(39/48)	79.2%(38/48)	80.2%(77/96)	89.6%(43/48)	79.2%(38/48)	84.4%(81/96)	82.3%(158/192)
Flu B-Low Pos	89.6%(43/48)	95.8%(46/48)	92.7%(89/96)	89.6%(43/48)	87.5%(42/48)	88.5%(85/96)	90.6%(174/192)
Flu B-Mod Pos	97.9%(47/48)	100%(48/48)	99.0%(95/96)	100%(48/48)	100%(48/48)	100%(96/96)	99.5%(191/192)
RSV-High Neg	89.6%(43/48)	77.1%(37/48)	83.3%(80/96)	87.5%(42/48)	83.3%(40/48)	85.4%(82/96)	84.4%(162/192)
RSV-Low Pos	93.8%(45/48)	93.8%(45/48)	93.8%(90/96)	87.5%(42/48)	89.6%(43/48)	88.5%(85/96)	91.1%(175/192)
RSV-Mod Pos	100%(48/48)	100%(48/48)	100%(96/96)	97.9%(47/48)	100%(48/48)	99.0%(95/96)	99.5%(191/192)

Table 5-16: Summary of Instrument System Precision Results (Dx vs. Infinity)

4 Agreement calculated based on expected result: Negative for Negative (targeted positivity: 0%) and High Neg (targeted positivity: 20-80%) samples; Positive for Low Pos (targeted positivity: 95%) and Mod Pos (targeted positivity: 100%) samples.

The precision of the Xpert Flu/RSV XC Assay was also evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) between-instruments, between-lots, between-days, between-operators, and within-assays for each panel member are presented in Table 5-17.

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Sample	AssavChannel(Analyte)	Na	MeanCt	Between-Instrument		Between-Lot		Between-Day		Between-Operator		Within-Assay		Total
				SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Negative	SPC	192	30.6	0	0	0.19	0.6	0.06	0.2	0.02	0.1	0.36	1.2	0.41	1.3
Flu A-High Neg	FluA1	41	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
	FluA2	0	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Flu A-Low Pos	FluA 1	169	35.6	0	0	0.42	1.2	0.93	2.6	0.28	0.8	1.61	4.5	1.93	5.4
	FluA2	1	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Flu A-Mod Pos	FluA l	187	34.1	0	0	0.41	1.2	0.95	2.8	0	0	1.54	4.5	1.86	ર : ર
	FluA2	14	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Flu B-High Neg	FluB	34	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Flu B-Low Pos	FluB	174	33.2	0	0	0.47	1.4	0	0	0.66	2.0	2.03	6.1	2.18	6.6
Flu B-Mod Pos	FluB	191	32.1	0	0	0.17	0:5	0.25	0.8	0	0	1.73	5.4	1.75	ર : ર
RSV-High Neg	RSV	30	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
RSV-Low Pos	RSV	ા તર	36.0	0	0	0.75	2.1	0	0	0.36	1.0	1.47	4.1	1.69	4.7
RSV-Mod Pos	RSV	191	34.7	0	0	0.57	1.7	0.16	0:5	0	0	1.23	3.6	1.37	3.9

Table 5-17. Summary of Precision Data

4Results with non-zero Ct values out of 192.

Conclusions

The results of the nonclinical analytical and clinical performance studies summarized above demonstrate that the Xpert Flu/RSV XC Assay is substantially equivalent to the predicate devices.

Regulation Number and Section

§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.

(a)
Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.