Predicate Devices

Reference Devices

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a standard RT-PCR assay and instrument system. There are no mentions of AI, ML, or any computational methods beyond automated data processing and result generation.

Therapeutic

No.
This device is an in vitro diagnostic (IVD) test intended for the qualitative detection and differentiation of influenza A and B viral RNA. It is used as an aid in diagnosing infections but does not provide therapy or treatment.

Diagnostic

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states that the assay is "intended as an aid in the diagnosis of influenza infections." Additionally, the "Device Description" categorizes it as an "in vitro diagnostic test."

SaMD (Software as a Medical Device)

No

The device is an in vitro diagnostic test that includes reagents and is performed on a specific hardware instrument system (GeneXpert® Instrument Systems). While software is involved in the automated process and result generation, it is not a standalone software-only device.

IVD (In Vitro Diagnostic)

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

The "Intended Use / Indications for Use" section explicitly states: "The Cepheid Xpert® Xpress Flu 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 A and influenza B viral RNA."

The "Device Description" section also reinforces this by stating: "The Xpert Xpress Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A) and influenza B (Flu B) viral RNA directly from nasopharyngeal (NP) swab and nasal swab (NS) specimens."

These statements clearly indicate that the device is intended for use outside of the body to examine specimens for diagnostic purposes, which is the definition of an in vitro diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Cepheid Xpert® Xpress Flu Assay, performed on the GeneXpert® Instrument Systems, 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 A and influenza B viral RNA. The Xpert Xpress Flu Assay uses nasopharyngeal (NP) swab and nasal swab (NS) specimens collected from patients with signs and symptoms of respiratory infection. The Xpert Xpress Flu Assay is intended as an aid in the diagnosis of influenza infections in conjunction with clinical and epidemiological risk factors.

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 2015-2016 influenza season for NP swab specimens and the 2016-2017 influenza season for NS specimens. 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 departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

Product codes

OCC, OOI, JSM

Device Description

The Xpert Xpress Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A) and influenza B (Flu B) viral RNA directly from nasopharyngeal (NP) swab and nasal swab (NS) specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.

The Xpert Xpress Flu Assay includes reagents for the detection and differentiation of influenza A and influenza B viral RNA directly from NP swab and NS specimens from patients with signs and symptoms of respiratory tract infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Instrument System platform. The SPC is present to control for an adequate extraction and processing of the target sequences and to monitor for the presence of inhibitor in the PCR reaction. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The specimens are collected in viral transport medium and transported to the GeneXpert area. The specimen is prepared according to package insert instructions and transferred to the sample chamber (large opening) of the Xpert Xpress Flu Assay cartridge. The GeneXpert cartridge is loaded onto the GeneXpert Xpress System platform, which performs hands-off automated sample processing and real-time RT-PCR for detection of Flu viral RNA. Summary and detailed test results are obtained in approximately 30 minutes or less. The results are automatically generated at the end of the process in a report that can be viewed and printed.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Nasopharyngeal (NP) swab and nasal swab (NS) specimens

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Laboratory users in moderate and high complexity laboratory settings.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Performance characteristics of the Xpert Xpress Flu Assay were evaluated at eleven institutions in the U.S. during the 2015-2016 influenza season for NP swab specimens and at fourteen institutions in the U.S. during the 2016-2017 influenza season for NS specimens. Due to the low prevalence of influenza viruses and the difficulty in obtaining fresh influenza specimens, the specimen population for this study was supplemented with consecutively collected, frozen specimens.

Specimens were collected from:

Individuals exhibiting signs and symptoms of respiratory infection who provided informed consent for the collection of a NP swab or NS specimen.
Individuals with signs and symptoms of respiratory infection and whose routine care called for collection of NP swab specimens for influenza testing. For eligible subjects, aliquots of leftover specimens were obtained for testing with the Xpert Xpress Flu Assay and reference testing, and patient management continued at the site per their standard practice.

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

Total Sample Sizes:
NP Swab Specimens: A total of 2051 NP swab specimens were tested, with 1139 fresh, prospectively collected, and 912 consecutively collected, frozen specimens.
NS Specimens: A total of 1598 NS specimens were tested.

For the reproducibility study, a 5-member specimen panel was used. Testing was performed at three sites (one internal, two external) using the GeneXpert Dx system, the Infinity-48 system, and the Infinity-80 system. Testing was conducted for 6 (not necessarily consecutive) days, with three lots of cartridges and consisted of two testing days per lot. Each site had two operators, one experienced and one inexperienced, who tested each panel in duplicate twice each day.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Non-Clinical Studies:

Analytical Sensitivity (Limit of Detection): LoD established using two influenza A H3N2 strains, two influenza A 2009 H1N1 strains, and two influenza B strains. Viruses were diluted into negative pooled NP swab and NS clinical matrices. LoD is the lowest concentration (tissue culture infective dose. TCID50/mL) 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 in each matrix.
Analytical Specificity (Exclusivity): Evaluated by testing a panel of 44 cultures (16 viral, 26 bacterial, and two yeast strains). Three replicates of all bacterial and yeast strains were tested at concentrations of ≥ 1 x 10^6 CFU/mL (except C. pneumoniae at 1 x 10^5 CFU/mL). Three replicates of all viruses were tested at concentrations of ≥ 1 x 10^5 TCID50/mL. The analytical specificity was 100%.
Analytical Reactivity (Inclusivity): Evaluated against multiple strains of influenza A H1N1 (seasonal pre-2009), influenza A H1N1 (pandemic 2009), influenza A H3N2 (seasonal), avian influenza A, and influenza B (Victoria and Yamagata lineages) at levels near the analytical LoD. A total of 48 strains (35 influenza A and 13 Influenza B) were tested. Three replicates were tested for each strain. All Flu strains tested positive in all three replicates, except one Flu A H1N1 strain (A/New Jersey/8/76) which tested positive in 2 of 3 replicates at 0.1 TCID50/mL.
Potentially Interfering Substances: Evaluated common respiratory substances (blood, nasal secretions, medications, antibiotics, antivirals). Negative samples (n=8) and positive samples (n=8, spiked with six influenza strains at 3X LoD) were tested per substance. None of the substances caused interference. All positive and negative replicates were identified correctly.
Carry-Over Contamination: Demonstrated that single-use, self-contained GeneXpert cartridges prevent carry-over. A negative sample was processed immediately after a very high influenza A sample (2x10^7 TCID50/mL). 20 positive and 21 negative specimens were tested. All correctly reported.
Fresh vs. Frozen Sample Equivalency Study: Evaluated fresh vs. frozen specimen equivalency by testing individual influenza strains at three concentrations (2X LoD, 5X LoD, 10X LoD) in pooled negative NP swab clinical matrix. Replicates of 20 were tested for each specimen type and concentration. No statistically significant effect was observed between fresh virus dilutions and two sequential freeze-thaw cycles.
Competitive Interference Study: Evaluated by testing individual influenza strains near LoD in the presence of different influenza strains at a higher concentration. Observed competitive inhibitory effects on Flu A and Flu B targets in the presence of two targets.

Clinical Studies:

Clinical Comparison Study:
- NP Swab Specimens: 2051 total (1139 fresh, 912 frozen). Performance compared to an FDA-cleared molecular comparator assay.
  - Fresh NP Swab: Flu A: PPA 94.6% (82.3-98.5), NPA 99.4% (98.7-99.7). Flu B: PPA 100.0% (91.6-100.0), NPA 99.3% (98.6-99.6).
  - Frozen NP Swab: Flu A: PPA 100.0% (94.7-100.0), NPA 98.0% (96.8-98.7). Flu B: PPA 100.0% (90.4-100.0), NPA 99.0% (98.1-99.5).
  - Combined NP Swab: Flu A: PPA 98.1% (93.3-99.5), NPA 98.8% (98.2-99.2). Flu B: PPA 100.0% (95.3-100.0), NPA 99.1% (98.6-99.5).
- NS Specimens: 1598 total. Performance compared to an FDA-cleared molecular comparator assay. Flu A: PPA 98.9% (96.2-99.7), NPA 97.6% (96.6-98.3). Flu B: PPA 98.4% (91.7-99.7), NPA 99.3% (98.7-99.6).
- Overall Assay Success Rate: 99.3% (3648/3674) for eligible NP swab and NS specimens. Overall indeterminate rate was 0.7%.
Reproducibility Study: Multi-center, blinded study using a 5-member specimen panel tested at three sites (GeneXpert Dx system, Infinity-48 system, Infinity-80 system). Conducted for 6 days with three lots of cartridges. Each site had two operators who tested each panel in duplicate twice daily.
- Agreement by Sample ID:
  - Negative: 100% (144/144)
  - Flu A-Low Pos: 93.6% (131/140)
  - Flu A-Mod Pos: 100% (142/142)
  - Flu B-Low Pos: 95.1% (137/144)
  - Flu B-Mod Pos: 100% (142/142)
- Reproducibility also evaluated in terms of fluorescence signal (Ct values) with mean, SD, and CV between-sites, between-days, between-lots and between-operators.

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

NP Swab Specimens (PPA and NPA):

Fresh:
- Flu A: PPA 94.6% (95% CI 82.3 - 98.5), NPA 99.4% (95% CI 98.7 - 99.7)
- Flu B: PPA 100.0% (95% CI 91.6 - 100.0), NPA 99.3% (95% CI 98.6 - 99.6)
Frozen Consecutively Collected:
- Flu A: PPA 100.0% (95% CI 94.7 - 100.0), NPA 98.0% (95% CI 96.8 - 98.7)
- Flu B: PPA 100.0% (95% CI 90.4 - 100.0), NPA 99.0% (95% CI 98.1 - 99.5)
Combined:
- Flu A: PPA 98.1% (95% CI 93.3 - 99.5), NPA 98.8% (95% CI 98.2 - 99.2)
- Flu B: PPA 100.0% (95% CI 95.3 - 100.0), NPA 99.1% (95% CI 98.6 - 99.5)

NS Specimens (PPA and NPA):

Flu A: PPA 98.9% (95% CI 96.2-99.7), NPA 97.6% (95% CI 96.6-98.3)
Flu B: PPA 98.4% (95% CI 91.7-99.7), NPA 99.3% (95% CI 98.7-99.6)

Predicate Device(s)

Xpert® Flu/RSV XC Assay [510(k) #K142045]

Reference Device(s)

Prodesse ProFlu+ Assay [510(k) #K132129], Lyra Influenza A+B Assay [510(k) #K131728], Cepheid Xpert® Nasopharyngeal Sample Collection Kit for Viruses [510(k) # K171552], Cepheid Xpert® Nasal Sample Collection Kit for Viruses [510(k) # K171552]

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

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.

Summary

0

Indications for Use

510(k) Number (if known)

Device Name

Indications for Use (Describe)

Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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8.0 510(k) Summary

As required by 21 CFR Section 807.92(c).

| Submitted by: | Cepheid
904 Caribbean Drive
Sunnyvale, CA 90489
Phone number: (408) 400-6838 |
|-------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Yi-Ping Lin, PhD |
| Date of Preparation: | May 14, 2018 |
| Device: | |
| Trade name: | Xpert® Xpress Flu |
| Common name: | Xpert Xpress Flu Assay |
| Type of Test: | Automated, multiplex real-time reverse transcription-
polymerase chain reaction (RT-PCR) assay intended for the in vitro qualitative detection and differentiation of influenza A
and influenza B virus. |
| Regulation number/
Classification name/
Product code: | 866.3980/Respiratory viral panel multiplex nucleic acid
assay/OCC
866.2570/Instrumentation for clinical multiplex test
systems/OOI |
| Classification | Class II |
| Advisory Panel | Microbiology (83) |
| Prescription Use | Yes |
| Predicate Devices
Assay: | 1) For the detection and differentiation of influenza A,
influenza B, and RSV A/B viral RNA in nasopharyngeal
swab specimens:
Xpert® Flu/RSV XC Assay [510(k) #K142045]

For the Sample Collection Kits:
Cepheid Xpert® Nasopharyngeal Sample Collection Kit
for Viruses[510(k) # K171552]

Cepheid Xpert® Nasal Sample Collection Kit for
Viruses[510(k) # K171552] |

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Device Description:

The Xpert Xpress Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A) and influenza B (Flu B) viral RNA directly from nasopharyngeal (NP) swab and nasal swab (NS) specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.

The Xpert Xpress Flu Assay includes reagents for the detection and differentiation of influenza A and influenza B viral RNA directly from NP swab and NS specimens from patients with signs and symptoms of respiratory tract infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Instrument System platform. The SPC is present to control for an adequate extraction and processing of the target sequences and to monitor for the presence of inhibitor in the PCR reaction. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The specimens are collected in viral transport medium and transported to the GeneXpert area. The specimen is prepared according to package insert instructions and transferred to the sample chamber (large opening) of the Xpert Xpress Flu Assay cartridge. The GeneXpert cartridge is loaded onto the GeneXpert Xpress System platform, which performs hands-off automated sample processing and real-time RT-PCR for detection of Flu viral RNA. Summary and detailed test results are obtained in approximately 30 minutes or less. The results are automatically generated at the end of the process in a report that can be viewed and printed.

3

Device Intended Use:

The Cepheid Xpert® Xpress Flu Assay, performed on the GeneXpert® Instrument Systems, 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 A and influenza B viral RNA. The Xpert Xpress Flu Assay uses nasopharyngeal (NP) swab and nasal swab (NS) specimens collected from patients with signs and symptoms of respiratory infection. The Xpert Xpress Flu Assay is intended as an aid in the diagnosis of influenza infections in conjunction with clinical and epidemiological risk factors.

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 2015-2016 influenza season for NP swab specimens and the 2016-2017 influenza season for NS specimens. 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 departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

Ancillary Nasopharyngeal Swab Specimen Collection Kit for Viruses

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 containing viruses 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 is designed to collect, preserve, and transport nasopharyngeal swab specimens containing viruses from patients

4

with signs and symptoms of respiratory infection prior to analysis with the Xpert Flu+RSV Xpress Assay, Xpert Xpress Flu/RSV Assay or the Xpert Xpress Flu Assay.

Ancillary Nasal Swab Specimen Collection Kit for Viruses

The Xpert® Nasal Sample Collection Kit is designed to collect, preserve, and transport nasal swab specimens containing viruses from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Xpress Flu Assay.

Substantial Equivalence:

The Xpert Xpress Flu Assay is substantially equivalent to the current Xpert® Flu/RSV XC Assay [510(k) #K142045]. The Xpert Xpress Flu Assay detects influenza A and influenza B from NP swab and NS specimens and the Xpert® Flu/RSV XC Assay detects influenza A, influenza B, and RSV from NP swab specimens and nasal aspirate/wash (NA/W) specimens. Both 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 and obtained data using the Xpert Xpress Flu/RSV Assay which was then reanalyzed with the Xpert Xpress Flu Assay Definition File (ADF). The reanalyzed data was used to determine the performance characteristics of the Xpert Xpress Flu Assay relative to the comparator Flu tests. Discordant results between the Xpert Xpress Flu Assay and the comparator methods Prodesse ProFlu+ Assay [510(k) #K132129] for NP swabs (FDA cleared for NP swabs) and Lyra Influenza A+B Assay [510(k) #K131728] for NS (FDA cleared for NP swabs and NS) were analyzed by bi-directional sequencing using primers different from those used in the Xpert Xpress Flu Assay. The study results showed that the Xpert Xpress Flu Assay is acceptable for its intended use and is substantially equivalent to the predicate device.

Table 8-1 shows the similarities and differences between the Xpert Xpress Flu Assay and the predicate device.

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Similarities
	Device	Predicate
Item	Cepheid Xpert® Xpress Flu	Cepheid Xpert® Flu/RSV XC
510(k)# K142045
Regulation	866.3980	Same
Product Code	OCC, OOI	Same
Device Class	II	Same
Technology
Principle of
Operation	Multiplex real time RT-PCR	Same
Intended Use	The Cepheid Xpert® Xpress
Flu Assay, performed on the
GeneXpert® Instrument
Systems, 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 A
and influenza B viral RNA.
The Xpert Xpress Flu Assay
uses nasopharyngeal (NP)
swab and nasal swab (NS)
specimens collected from
patients with signs and
symptoms of respiratory
infection. The Xpert Xpress
Flu Assay is intended as an
aid in the diagnosis of
influenza infections in
conjunction with clinical and
epidemiological risk factors.	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 A, 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.
Similarities
Item	Device	Predicate
	Cepheid Xpert® Xpress Flu	Cepheid Xpert® Flu/RSV XC
510(k)# K142045
	Negative results do not
preclude influenza virus
infection and should not be
used as the sole basis for
treatment or other patient
management decisions.	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 2015-
2016 influenza season for NP
swab specimens and the 2016-
2017 influenza season for NS
specimens. When other novel
influenza A viruses are
emerging, performance
characteristics may vary.	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
departments for testing. Viral
culture should not be
attempted in these cases
unless a BSL 3+ facility is
available to receive and
culture specimens.	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.

Table 8-1: Comparison of Similarities and Differences of the Xpert Xpress Flu Assay with the Predicate Devices

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7

Similarities
	Device	Predicate
Item	Cepheid Xpert® Xpress Flu	Cepheid Xpert® Flu/RSV XC
510(k)# K142045
Indication for
Use	Patients with signs and
symptoms of respiratory
infection in conjunction with
clinical and epidemiological
risk factors	Same
Nucleic Acid
Extraction	Yes	Same
Extraction
Methods	Sample preparation integrated
in GeneXpert Cartridge and
GeneXpert Instrumentation
System	Same
Assay Results	Qualitative	Same
Instrument
System	Cepheid GeneXpert
Instrument Systems; same
Cepheid I-core technology	Same
Primers and
probes	Primers and probes to detect
the presence of nucleic acid
sequences of influenza A,
influenza B, and RSV. Only
results for influenza A and
influenza B are reported.	Primers and probes to detect
the presence of influenza A,
influenza A subtype H7N9,
influenza B and RSV. Results
for influenza A, influenza B
and RSV analytes are reported.
Laboratory
Users	Laboratory users in moderate
and high complexity
laboratory settings.	Same
Sample
Preparation	Self-contained and automated
after mixed specimen is added
to cartridge. All other
reagents are contained in the
cartridge.	Same

8

Similarities
Item	Device	Predicate
Primers and
probes for
influenza A,
influenza B	Primers and probes to detect
the presence of nucleic acid
sequences of influenza A,
influenza B, and RSV A/B.
The Xpert Xpress Flu Assay
contains primers and probes to
detect additional RNA
segments in order to protect
the assay sensitivity and
specificity from mutations in
the influenza genome due to
antigenic drifts and shifts.
Only results for influenza A
and influenza B are reported.	Primers and probes to detect
the presence of nucleic acid
sequences of influenza A,
influenza B, and RSV A/B.
The Xpert Flu/RSV XC Assay
contains primers and probes to
detect additional RNA
segments in order to protect
the assay sensitivity and
specificity from mutations in
the influenza genome due to
antigenic drifts and shifts.
Target
Sequences	Influenza A: Matrix protein
(MP),basic polymerase (PB2)
and acidic protein (PA)
Influenza B: Matrix protein
(MP) and Non-structural
proteins (NS 1 and NS 2)
RSV A and RSV B:
Nucleocapsid protein
Only results for influenza A
and influenza B are reported.	Influenza A: Matrix protein
(MP),basic polymerase (PB2)
and acidic protein (PA)
Influenza B: Matrix protein
(MP) and Non-structural
proteins (NS 1 and NS 2)
RSV A and RSV B:
Nucleocapsid protein
Internal
Controls	Sample processing control
(SPC) and probe check
control (PCC).	Same
Early assay
termination
function	Yes	Yes
	Cepheid Xpert® Xpress Flu	Cepheid Xpert® Flu/RSV XC
510(k)# K142045
Differences
	Device	Predicate
Item	Cepheid Xpert® Xpress Flu	Cepheid Xpert® Flu/RSV XC
510(k)# K142045
Assay Targets	Influenza A Virus and
Influenza B Virus	Influenza A Virus, Influenza B
Virus, and RSV viral RNA
Specimen
Types	Nasopharyngeal (NP) swab
and nasal swab (NS)
specimens	Nasal aspirate/wash (NA/W)
specimens and
Nasopharyngeal (NP) swab
specimens
Assay Controls	Encapsulated (armored) RNA
pseudovirus as a sample
processing control.
Available but not provided are
inactivated virus controls for
influenza A/B as external
positive controls, and
Coxsackie virus as an external
negative control.	Encapsulated (armored) RNA
pseudovirus as a sample
processing control.
Available but not provided are
inactivated virus controls for
influenza A/B and RSV as
external positive controls, and
Coxsackie virus as an external
negative control.
Time to obtain
test results	Approximately 30 minutes or
less for sample preparation
and RT-PCR	Approximately 60 minutes or
less for sample preparation and
RT-PCR
Combinatorial
Assay
Selections	Not applicable	Yes, user may select combined
assay with all targets or a Flu
only assay or a RSV only
assay.

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The Xpert Xpress Flu Assay and the predicate device have the same general intended use and technological characteristics, and both detect influenza Aand influenza B viral RNA from NP swab specimens. The clinical study demonstrates that the Xpert Xpress Flu Assay is acceptable for its intended use and is substantially equivalent to the predicate device.

The predicate device for the ancillary specimen collection kit, the Xpert Nasopharyngeal Sample Collection Kit for Viruses is the Cepheid Nasopharyngeal Sample Collection Kit for Viruses, [510(k) # K171552]. The similarities are shown in Table 8-2. There is no difference between the Nasopharyngeal Sample Collection Kit for Viruses cleared in 510(k) # K171552 and this 510(k).

The predicate device for the ancillary specimen collection kit, the Xpert Nasal Sample Collection Kit for Viruses is the Xpert Nasal Sample Collection Kit for Viruses, [510(k) # K171552]. The similarities are shown in Table 8-3. There is no difference between the Nasal Sample Collection Kit for Viruses cleared in 510(k) # K171552 and this 510(k).

11

Similarities
	Device	Predicate
Item	Xpert® Nasopharyngeal
Sample Collection Kit for
Viruses	Xpert® Nasopharyngeal
Sample Collection Kit for
Viruses
510(k)# K171552
Intended Use	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
containing viruses 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 is designed to
collect, preserve, and transport
nasopharyngeal swab specimens
containing viruses from patients
with signs and symptoms of
respiratory infection prior to
analysis with the Xpert
Flu+RSV Xpress Assay, Xpert
Xpress Flu/RSV Assay or the
Xpert Xpress Flu Assay.	Same
Single-use Device	Yes	Same

Table 8-2: Comparison of Similarities of the Xpert Nasopharyngeal Sample Collection Kit with the Predicate Device

12

Similarities
Item	Device	Predicate
	Xpert® Nasopharyngeal
Sample Collection Kit for
Viruses	Xpert® Nasopharyngeal
Sample Collection Kit for
Viruses
510(k)# K171552
Transport Medium
Formulation	Hank's Balanced Salt
Solution Bovine Serum
Albumin
L-cysteine
Gelatin
Sucrose
L-glutamic acid
HEPES buffer
Vancomycin
Amphotericin B
Colistin
Phenol red	Same
pH	$7.3 \pm 0.2$	Same
Storage Temperature	2 - 25°C (refrigerated
and room temperature)	Same
Volume	3 ml	Same
Glass Beads	3 x 3 mm	Same
Container	Plastic (medical-grade
polypropylene)	Same
Product Configuration	Medium Tube in Kit with
individually-wrapped sterile
swab.	Same

13

Similarities
	Device	Predicate
Item	Xpert® Nasal Sample
Collection Kit for Viruses	Xpert® Nasal Sample
Collection Kit for Viruses
510(k)# K171552
Intended Use	The Xpert® Nasal Sample
Collection Kit is designed to
collect, preserve, and transport
nasal swab specimens
containing viruses from patients
with signs and symptoms of
respiratory infection prior to
analysis with the Xpert Xpress
Flu Assay.	Same
Single-use Device	Yes	Same
Transport Medium
Formulation	Hank's Balanced Salt
Solution Bovine Serum
Albumin
L-cysteine
Gelatin
Sucrose
L-glutamic acid
HEPES buffer
Vancomycin
Amphotericin B
Colistin
Phenol red	Same
pH	$7.3 \pm 0.2$	Same
Storage Temperature	2 - 25°C (refrigerated
and room temperature)	Same
Volume	3 ml	Same
Glass Beads	3 x 3 mm	Same
Container	Plastic (medical-grade
polypropylene)	Same
Similarities
Item	Device	Predicate
Product Configuration	Xpert® Nasal Sample Collection Kit for Viruses
Medium Tube in Kit with
individually-wrapped sterile swab.	Xpert® Nasal Sample Collection Kit for Viruses
510(k)# K171552
Swab	Nylon flocked	Same

Table 8-3: Comparison of Similarities and Differences of the Xpert Nasal Sample Collection Kit for Viruses with the Predicate Device

14

The proposed collection kits and predicate collection kits have the same general intended use and the same technology to collect, store and transport clinical specimens, including viruses, to the laboratory for further testing. The prospective component of the multicenter clinical study of the Xpert Xpress Flu Assay was conducted using Xpert Nasopharyngeal Sample Collection Kit for Viruses [510(k) # K171552] and Xpert Nasal Sample Collection Kit for Viruses [510(k) # K171552] demonstrating that the Xpert Nasopharyngeal Sample Collection Kit for Viruses and Xpert Nasal Sample Collection Kit for Viruses are acceptable for their intended use and substantially equivalent to the predicate devices.

Non-Clinical Studies:

Analytical Sensitivity (Limit of Detection)

Studies were performed to determine the analytical limit of detection (LoD) of the Xpert Xpress Flu 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 and two influenza B strains. Viruses were diluted into negative pooled NP swab and NS clinical matrices for testing. The LoD is defined as the lowest concentration (tissue culture infective dose. TCID50/mL) per sample that can be

15

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 in each matrix in NP swab and NS clinical matrix. The LoD point values for each strain tested are summarized in Table 8-4 through Table 8-6.

| Virus Strain | Confirmed LoD Probit
(TCID50/mL) | |
|-------------------------------|-------------------------------------|-------|
| | NP Swab | NS |
| Influenza A/California/7/2009 | 0.020 | 0.018 |
| Influenza A/Florida/27/2011 | 0.040 | 0.04 |

Table 8-4: Confirmed LoD (TCID50/mL): Influenza A 2009 H1N1

Table 8-5: Confirmed LoD (TCID50/mL): Influenza A H3N2

| Virus Strain | Confirmed LoD
Probit
(TCID50/mL) | |
|-------------------------------|----------------------------------------|-------|
| | NP Swab | NS |
| Influenza A/Perth/16/2009 | 0.013 | 0.006 |
| Influenza A/Victoria/361/2011 | 0.750 | 0.21 |

	Table 8-6: Confirmed LoD (TCID50/mL): Influenza B
--	---------------------------------------------------

| Virus Strain | Confirmed LoD
Probit
(TCID50/mL) | |
|-------------------------------|----------------------------------------|------|
| | NP Swab | NS |
| Influenza B/Mass/2/2012 | 0.400 | 0.07 |
| Influenza B/Wisconsin/01/2011 | 0.190 | 0.17 |

16

Analytical Specificity (Exclusivity)

The analytical specificity of the Xpert Xpress Flu 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 nasal passage and nasopharynx. Three replicates of all bacterial and yeast strains were tested at concentrations of ≥ 1 x 106 CFU/mL with the exception of one strain that was tested at 1 x 105 CFU/mL (Chlamydia pneumoniae). Three replicates of all viruses were tested at concentrations of ≥ 1 x 105 TCID50/mL. The analytical specificity was 100%. Results are shown in Table 8-7.

17

		Result
Organism	Concentration
(per cartridge)	Influenza
A	Influenza
B
No Template Control	N/A	NEG	NEG
Adenovirus Type 1	1.12E+06 TCID50/mL	NEG	NEG
Adenovirus Type 7	1.87E+05 TCID50/mL	NEG	NEG
Human coronavirus OC43	2.85E+05 TCID50/mL	NEG	NEG
Human coronavirus 229E	1.00E+05 TCID50/mL	NEG	NEG
Cytomegalovirus	1.00E+05 TCID50/mL	NEG	NEG
Echovirus	3.31E+07 TCID50/mL	NEG	NEG
Enterovirus	3.55E+05 TCID50/mL	NEG	NEG
Epstein Barr Virus	7.16E+07 TCID50/mL	NEG	NEG
HSV	8.90E+05 TCID50/mL	NEG	NEG
Measles	6.31E+05 TCID50/mL	NEG	NEG
Human metapneumovirus	1.00E+05 TCID50/mL	NEG	NEG
Mumps virus	6.31E+06 TCID50/mL	NEG	NEG
Human parainfluenza Type 1	1.15E+06 TCID50/mL	NEG	NEG
Human parainfluenza Type 2	6.31E+05 TCID50/mL	NEG	NEG
Human parainfluenza Type 3	3.55E+06 TCID50/mL	NEG	NEG
Rhinovirus Type 1A	1.26E+05 TCID50/mL	NEG	NEG
Acinetobacter baumannii	1.00E+06 CFU/mL	NEG	NEG
Burkholderia cepacia	3.30E+06 CFU/mL	NEG	NEG
Candida albicans	3.20E+06 CFU/mL	NEG	NEG
Candida parapsilosis	3.00E+06 CFU/mL	NEG	NEG
Bordetella pertussis	3.30E+06 CFU/mL	NEG	NEG
Chlamydia pneumoniae	1.00E+05 CFU/mL	NEG	NEG
Citrobacter freundii	3.30E+06 CFU/mL	NEG	NEG
Corynebacterium sp.	3.30E+06 CFU/mL	NEG	NEG
Escherichia coli	1.00E+07 CFU/mL	NEG	NEG
Enterococcus faecalis	1.30E+06 CFU/mL	NEG	NEG
Hemophilus influenzae	1.00E+06 CFU/mL	NEG	NEG
Lactobacillus reuteri	1.00E+06 CFU/mL	NEG	NEG
Legionella spp.	1.00E+06 CFU/mL	NEG	NEG
Moraxella catarrhalis	1.00E+07 CFU/mL	NEG	NEG
Organism	Concentration
(per cartridge)	Result
		Influenza
A	Influenza
B
Mycobacterium tuberculosis
(avirulent)	1.00E+06 CFU/mL	NEG	NEG
Mycoplasma pneumoniae	1.00E+06 CFU/mL	NEG	NEG
Neisseria meningitides	2.15E+06 CFU/mL	NEG	NEG
Neisseria mucosa	1.00E+07 CFU/mL	NEG	NEG
Propionibacterium acnes	2.40E+07 CFU/mL	NEG	NEG
Pseudomonas aeruginosa	3.70E+06 CFU/mL	NEG	NEG
Staphylococcus aureus (protein A
producer)	2.20E+06 CFU/mL	NEG	NEG
Staphylococcus epidermidis	3.40E+06 CFU/mL	NEG	NEG
Staphyloccus haemolyticus	4.00E+06 CFU/mL	NEG	NEG
Streptococcus agalactiae	3.50E+06 CFU/mL	NEG	NEG
Streptococcus pneumoniae	1.00E+06 CFU/mL	NEG	NEG
Streptococcus pyogenes	1.00E+07 CFU/mL	NEG	NEG
Streptococcus salivarius	1.00E+07 CFU/mL	NEG	NEG
Streptococcus sanguinis	3.10E+06 CFU/mL	NEG	NEG

Table 8-7: Analytical Specificity of the Xpert Xpress Flu/RSV Assay

18

19

Analytical Reactivity (Inclusivity)

The analytical reactivity of the Xpert Xpress Flu 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) and influenza B (representing strains from both Victoria and Yamagata lineages) at levels near the analytical LoD. A total of 48 strains comprised of 35 influenza A and 13 Influenza B strains were tested in this study with the Xpert Xpress Flu Assay. Three replicates were tested for each strain. All Flu strains tested positive in all three replicates, except for one Flu A H1N1 strain (A/New Jersey/8/76), which tested positive in 2 of 3 replicates at 0.1 TCID50/mL. Results are shown in Table 8-8.

Predicted cross reactivity from in silico analyses showed 100% sequence homology for additional pandemic H1N1 strains.

20

| Virus | Strain Concentration | Result | |
|---------------------------------------|----------------- | | No Template Control | Influenza
A H1N1
(pre-
2009) | A/swine/Iowa/15/30 | | A/WS/33 | | A/PR/8/34 | | A/Mal/302/54 | | A/Denver/1/57 | | A/New Jersey/8/76 | | A/New Caledonia/20/1999 | | A/New York/55/2004 | | A/Soloman Island/3/2006 | | A/Taiwan/42/06 | | A/Brisbane/59/2007 | Influenza
A H1N1
(pdm2009) | A/swine/NY/02/2009 | | A/Colorado/14/2012 | | A/Washington/24/2012 | Influenza
A H3N2
(Seasonal) | A/Aichi/2/68 | | A/HongKong/8/68 | | A/Port Chalmers/1/73 | | A/Hawaii/15/2001 | | A/Wisconsin/67/05 | | A/Brisbane/10/2007 | | A/Minnesota/11/2010 (H3N2)v | | A/Indiana/08/2011 (H3N2)v | | A/Texas/50/2012 | | Avian
influenza A | A/duck/Hunan/795/2002 | A/chicken/Hubei/327/2004
(H5N1) | | A/Anhui/01/2005 (H5N1) | | | | Virus | Strain | | A/Japanese Kong/ 1038/2006 (H5N1) | ≤ 1pg/μLa | | A/mallard/WI/34/75 (H5N2) | | A/chicken/CA431/00 (H6N2) | | A/duck/LTC-10-82 (H7N2) | ≤ 1pg/μLa | | A/chicken/NJ/150 (H7N3) | ≤ 1pg/μLa | | A/Anhui/1/2013 (H7N9) | | A/Shanghai/1/2013 (H7N9) | | A/chicken/Korea/ p96323/1996 (H9N2) | ≤ 1pg/μLa | | A/Mallard/NY/6750/78 (H2N2) | Influenza B | B/Lee/40 | | B/Allen/45 | | B/GL/1739/54 | | B/Maryland/1/59 | | B/Panama/45/90C | | B/Florida/07/2004d | | B/Florida/02/06C | | B/Florida/04/06d | | B/Hong Kong/5/72 | | B/Wisconsin/01/2010d | | B/Malaysia/2506/04c | | B/Taiwan/2/62 | | B/Brisbane/60/2008c | Target
-------------------------------------|------------------------------|-----------|-------|
| n/a | NEG | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 0.1 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
| 2.0 TCID50/mL | POS | NEG |
(H5N1) | ≤ 1pg/μLa | POS |
| ≤ 1pg/μLa | POS | NEG |
| ≤ 1pg/μLa | POS | NEG |
| Target | Result | |
| Concentration | Flu A | Flu B |
white eye/ Hong
| POS | NEG |
| ≤ 1pg/μLa | POS | NEG |
| ≤ 1pg/μLa | POS | NEG |
743/1943
| POS | NEG |
86-3/94
| POS | NEG |
| N/Ab | POS | NEG |
| N/Ab | POS | NEG |
38349-
| POS | NEG |
| ≤ 1pg/μLa | POS | NEG |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |
| 1.0 TCID50/mL | NEG | POS |

Table 8-8: Analytical Reactivity (Inclusivity) of the Xpert Xpress Flu/RSV Assay

21

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

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

c. Known Victoria lineage.
d. Known Yamagata lineage.

22

Potentially Interfering Substances

In a non-clinical study, potentially interfering substances that may be present in the nasal passage and nasopharynx were evaluated directly relative to the performance of the Xpert Xpress Flu Assay. Potentially interfering substances in the nasal passage and 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 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) strains spiked at 3X the analytical LoD determined for each strain. All results were compared to positive and negative simulated background matrix controls. The simulated background matrix consisted of 2.5% (w/v) porcine mucin, 1% (v/v) human whole blood in 0.85% sodium chloride (NaCl) formulated in 1x PBS solution with 15% glycerol, which was then diluted 1:5 in UTM.

The evaluated substances are listed in Table 8-9 with active ingredients and concentrations tested shown. None of the substances caused interference of the assay at the concentrations tested in this study. All positive and negative replicates were identified correctly using the Xpert Xpress Flu Assay.

| Substance/Class | Description/Active
Ingredient | Concentration
Tested |
|------------------------------------------|----------------------------------|-------------------------------------------------|
| Control | Simulated background
matrix | 100% (v/v) |
| Beta-adrenergic bronchodilator | Albuterol Sulfate | 0.83 mg/mL
(equivalent to 1
dose per day) |
| Blood | Blood (Human) | 2% (v/v) |
| BDTM Universal Viral
Transport System | 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) |

Table 8-9: Potentially Interfering Substances in the Xpert Xpress Flu Assay

23

Substance/Class	Description/Active Ingredient	Concentration Tested
Remel M6®	Transport Media	100% (v/v)
Throat lozenges, oral
anesthetic and analgesic	Benzocaine, Menthol	1.7 mg/mL
Mucin	Purified Mucin protein
(Bovine or porcine
submaxillary gland)	2.5% (w/v)
Antibiotic, nasal ointment	Mupirocin	10 mg/mL
Saline Nasal Spray	Sodium Chloride (0.65%)	15% (v/v)
Anefrin Nasal Spray	Oxymetazoline, 0.05%	15% (v/v)
PHNY Nasal Drops	Phenylephrine, 0.5%	15% (v/v)
Tamiflu Anti-viral drug	Zanamivir	7.5 mg/mL
Antibacterial, systemic	Tobramycin	4 µg/mL
Zicam Nasal Gel	Luffa opperculata,
Galphimia glauca,
Histaminum
hydrochloricum Sulfur	15% (w/v)
Nasal corticosteroid	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 of negative samples if preceded by very high positive samples in the same GeneXpert module. The study consisted of a negative sample processed in the same GeneXpert module immediately following a very high influenza A sample (A/Victoria/361/2011, 2x107 TCID50/mL) spiked into a simulated background matrix. This testing scheme was repeated 20 times on two GeneXpert modules for a total of 41 runs resulting in 20 positive and 21 negative specimens for each virus type. All 20 positive samples were correctly reported as Flu A POSITIVE; Flu B NEGATIVE. All 21 negative samples were correctly reported as Flu A NEGATIVE; Flu B NEGATIVE.

Fresh vs. Frozen Sample Equivalency Study

Fresh and frozen specimen equivalency in the Xpert Xpress Flu Assay was evaluated by testing individual influenza strains at three different concentrations representing low positives (2X LoD), moderate positives (5X LoD), and high positives (10X LoD) in

24

pooled negative NP swab clinical matrix. Negative samples consisted of pooled negative NP swab clinical matrix only. Fresh and frozen specimen equivalency was determined using one seasonal Flu A H3N2 strain (A/Victoria/361/2011) and one Flu B strain (B/Mass/2/2012). 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 Xpress Flu 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 Xpress Flu Assay.

Competitive Interference Study

Competitive interference of the assay caused by the presence of two targets in the Xpert Xpress Flu Assay was evaluated by testing individual influenza strains near the LoD in the presence of different influenza strains at a higher concentration in a simulated background matrix. Analytical competitive interference was assessed using one (1) seasonal Flu A H3 strain (H3/Victoria/361/2011) at 0.8 TCID50/mL and one (1) Flu B strain (B/Mass/2/2012) at 0.45 TCID50/mL; the strains were tested at in the presence of competing strains at either 1 x 102 TCID50/mL or 1 x 103 TCID50/mL. Replicates of 20 were tested for each target strain and each competitive strain combination. The normal binomial distribution with 20 replicate samples at LoD is between 17 and 20 positive results based on the binomial distribution with N=20, p=0.95 (X~Bin(20,0.95)). Therefore, sets of 20 with 16 or less positives would be rare and an indication of a competitive inhibitory effect due to high levels of a competing analyte.

. With Flu A/Victoria/361/2011 at a concentration of 0.8 TCID50/mL no competitive inhibitory effects were observed in the presence of 1x103 TCID50/mL of Flu B/Mass/2/2012.
With Flu B/Mass/2/2012 at a concentration of 0.45 TCID50/mL competitive . inhibitory effects were observed in the presence of 1x103 TCID50/mL of Flu

25

A/Victoria/361/2011. No competitive inhibitory effects were observed in the presence of 1x102 TCID50/mL of Flu A/Victoria/361/2011.

Under the conditions of this study, internal competitive inhibitory effects were observed on the targets (Flu A and Flu B) in the presence of two targets for the Xpert Xpress Flu Assay. The competitive inhibitory effect on the Xpert Xpress Flu targets is addressed in the Limitations section of this package insert.

Clinical Studies

Clinical Comparison Study

Performance characteristics of the Xpert Xpress Flu Assay were evaluated at eleven institutions in the U.S. during the 2015-2016 influenza season for NP swab specimens and at fourteen institutions in the U.S. during the 2016-2017 influenza season for NS specimens. Due to the low prevalence of influenza viruses and the difficulty in obtaining fresh influenza specimens, the specimen population for this study was supplemented with consecutively collected, frozen specimens.

Specimens were collected from the following:

. Individuals exhibiting signs and symptoms of respiratory infection who provided informed consent for the collection of a NP swab or NS specimen.
. Individuals with signs and symptoms of respiratory infection and whose routine care called for collection of NP swab specimens for influenza testing. For eligible subjects, aliquots of leftover specimens were obtained for testing with the Xpert Xpress Flu Assay and reference testing, and patient management continued at the site per their standard practice.

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

26

Overall Results – NP Swab Specimens

A total of 2051 NP swab specimens were tested for influenza A and influenza B by the Xpert Xpress Flu Assay and the comparator assay. Of the 2051 NP swab specimens. 1139 were fresh, prospectively collected and 912 were consecutively collected, frozen specimens.

For the fresh, prospectively collected NP swab specimens, the Xpert Xpress Flu Assay demonstrated a PPA and NPA of 94.6% and 99.4% for the detection of influenza A and 100% and 99.3% for influenza B, respectively (Table 8-10).

For the consecutively collected, frozen NP swab specimens, the Xpert Xpress Flu Assay demonstrated a PPA and NPA of 100% and 98.0% for the detection of influenza A, respectively; 100% and 99.0% for influenza B, respectively (Table 8-10).

For the combined dataset, the Xpert Xpress Flu Assay demonstrated a PPA and NPA of 98.1% and 98.8% for the detection of influenza A and 100% and 99.1% for influenza B, respectively (Table 8-10).

27

| Specimen
Type | Target | n | TP | FN | TN | FP | PPA
(95% CI) | NPA
(95% CI) |
|--------------------------------------|--------|------|-----|----|------|-----|--------------------------|------------------------|
| Fresh | Flu A | 1139 | 35 | 2a | 1095 | 7b | 94.6%
(82.3 - 98.5) | 99.4%
(98.7 - 99.7) |
| Fresh | Flu B | 1139 | 42 | 0 | 1089 | 8c | 100.0%
(91.6 - 100.0) | 99.3%
(98.6 - 99.6) |
| Frozen
Consecutively
Collected | Flu A | 912 | 68 | 0 | 827 | 17d | 100.0%
(94.7 - 100.0) | 98.0%
(96.8 - 98.7) |
| Frozen
Consecutively
Collected | Flu B | 912 | 36 | 0 | 867 | 9e | 100.0%
(90.4 - 100.0) | 99.0%
(98.1 - 99.5) |
| Combined | Flu A | 2051 | 103 | 2a | 1922 | 24f | 98.1%
(93.3 - 99.5) | 98.8%
(98.2 - 99.2) |
| Combined | Flu B | 2051 | 78 | 0 | 1956 | 17g | 100.0%
(95.3 - 100.0) | 99.1%
(98.6 - 99.5) |

Table 8-10: Xpert Xpress Flu Assay Performance on NP Swab Specimens

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

b. Testing results by sequencing: 3 of 7were Flu A Positive; 3 of 7 were Flu A Negative; 1 of 7 insufficient specimen for sequencing.

c. Testing results by sequencing: 6 of 8 were Flu B Positive: 1 of 8 were Flu B Negative; 1 of 8 insufficient specimen for sequencing.

d. Testing results by sequencing: 7 of 17 were Flu A Positive; 7 of 17 were Flu A Negative; 3 of 17 insufficient specimen for sequencing.

e. Testing results by sequencing: 7 of 9 were Flu B Positive; 0 of 9 were Flu B Negative; 2 of 9 insufficient specimen for sequencing.

f. Testing results by sequencing: 10 of 24 were Flu A Positive; 10 of 24 were Flu A Negative; 4 of 24 insufficient specimen for sequencing.

g. Testing results by sequencing: 13 of 17 were Flu B Positive; 1 of 17 were Flu B Negative; 3 of 17 insufficient specimen for sequencing.

For the 98 pre-selected frozen NP swab specimens that were excluded from the analysis above, the Xpert Xpress Flu Assay demonstrated a PPA and NPA of 100% and 97.8%, for influenza A, respectively; and 100% and 96.6% for influenza B, respectively.

Overall Results - NS Specimens

A total of 1598 NS specimens were tested for influenza A and influenza B by the Xpert Xpress Flu Assay and the comparator assay.

The Xpert Xpress Flu Assay demonstrated a PPA and NPA of 98.9% and 97.6% for the detection of influenza A, and 98.4% and 99.3% for influenza B, respectively, relative to the comparator assay (Table 8-11).

28

| Targeta | N | TP | FN | TN | FP | PPA
(95% CI) | NPA
(95% CI) |
|---------|------|-----|----|------|-----|----------------------|----------------------|
| Flu A | 1598 | 186 | 2a | 1376 | 34b | 98.9%
(96.2-99.7) | 97.6%
(96.6-98.3) |
| Flu B | 1598 | 63 | 1c | 1523 | 11d | 98.4%
(91.7-99.7) | 99.3%
(98.7-99.6) |

Table 8-11: Xpert Xpress Flu Assav Performance on NS Specimens
----------------------------------------------------------------	--	--	--	--	--	--	--	--

aDiscrepant Testing: 1 of 2 Flu A NEG; 1 of 2 Flu A POS.

bDiscrepant Testing: 16 of 34 Flu A NEG; 11 of 34 Flu A POS; 7 of 34 inconclusive.

°Discrepant Testing: 1 of 1 inconclusive.

dDiscrepant Testing: 5 of 11 Flu B POS; 6 of 11 inconclusive.

Of the Xpert Xpress Flu Assay runs performed with eligible NP swab and NS specimens, 97.8% (3594/3674) of these specimens were successful on the first attempt. The remaining 80 gave indeterminate results on the first attempt (39 ERROR, 32 INVALID, and 9 NO RESULT). Sixty of the 80 indeterminate cases were retested, of which 54 yielded valid results upon repeat testing; 20 specimens were not retested. The overall rate of assay success was 99.3% (3648/3674). The overall indeterminate rate was 0.7%.

Reproducibility Study

Reproducibility was established in a multi-center, blinded study using a 5-member specimen panel. Testing was performed at three sites (one internal, two external) using the GeneXpert Dx system, the Infinity-48 system, and the Infinity-80 system. Testing was conducted for 6 (not necessarily consecutive) days, with three lots of cartridges and consisted of two testing days per lot. Each site had two operators, one experienced and one inexperienced, who tested each panel in duplicate twice each day. Results are summarized in Table 8-12.

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| Sample ID | Titer of
Virus
(TCID50/mL | Site 1/Infinity-80 | | | | Site 2/DX | | Site 3/Infinity-48 | % Total | | |
|-----------|---------------------------------|--------------------|-----------------|-----------------|-----------------|-----------------|-----------------|--------------------|-----------------|-----------------|-------------------------|
| | | Op 1 | Op 2 | Site | Op 1 | Op 2 | Site | Op 1 | Op 2 | Site | Agreement by
Sample® |
| Negative | 0 | 100%
(24/24) | 100%
(24/24) | 100%
(48/48) | 100%
(24/24) | 100%
(24/24) | 100%
(48/48) | 100%
(24/24) | 100%
(24/24) | 100%
(48/48) | 100%
(144/144) |
| Flu A- | 0.75 | 87.0% | 95.8% | 91.5% | 95.7% | 91.7% | 93.6% | 100% | 91.3% | 95.7% | 93.6% |
| Low Pos | | (20/23) | (23/24) | (43/47) | (22/23) | (22/24) | (44/47) | (23/23) | (21/23) | (44/46) | (131/140)b |
| Flu A- | 1.5 | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| Mod Pos | | (24/24) | (24/24) | (48/48) | (23/23) | (23/23) | (46/46) | (24/24) | (24/24) | (48/48) | (142/142)b |
| Flu B- | 0.2 | 95.8% | 95.8% | 95.8% | 95.8% | 95.8% | 95.8% | 95.8% | 91.7% | 93.8% | 95.1% |
| Low Pos | | (23/24) | (23/24) | (46/48) | (23/24) | (23/24) | (46/48) | (23/24) | (22/24) | (45/48) | (137/144) |
| Flu B- | 0.4 | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| Mod Pos | | (23/23) | (24/24) | (47/47) | (24/24) | (24/24) | (48/48) | (24/24) | (23/23) | (47/47) | (142/142)b |

Table 8-12: Summary of Reproducibility Results

Agreement calculated based on expected result: Negative (targeted positivity: 0%); Positive for Low Pos (targeted positivity: 95%) and a. Mod Pos (targeted positivity: 100%) samples.

Eight samples indeterminate [Flu A Low Pos (4); Flu A Mod Pos (2); Flu B Mod Pos (2)] b.

The reproducibility of the Xpert Xpress Flu 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, between-lots and between-operators for each panel member are presented in Table 8-13.

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| | Assay
Channel
(Analyte) | Na | Mean
Ct | Between-
Site | | Between-Lot | | Between-
Day | | Between-
Operator | | Within-
Assay | | Total | |
|-------------------|-------------------------------|-----|------------|------------------|-----------|-------------|-----------|-----------------|-----------|----------------------|-----------|------------------|-----------|-------|-----------|
| Sample | | | | SD | CV
(%) | SD | CV
(%) | SD | CV
(%) | SD | CV
(%) | SD | CV
(%) | SD | CV
(%) |
| Negative | SPC | 144 | 32.3 | 0 | 0 | 0.7 | 2.1 | 0.1 | 0.4 | 0 | 0 | 0.6 | 1.9 | 0.9 | 2.8 |
| Flu A-
Low Pos | FluA1 | 131 | 35.3 | 0 | 0 | 0.6 | 1.6 | 0 | 0 | 0 | 0 | 1.1 | 3.0 | 1.2 | 3.4 |
| Flu A-
Mod Pos | FluA1 | 142 | 33.1 | 0 | 0 | 0 | 0.1 | 0.2 | 0.6 | 0 | 0 | 0.6 | 1.8 | 0.6 | 1.9 |
| Flu B-
Low Pos | FluB | 137 | 34.6 | 0 | 0 | 0 | 0 | 0.5 | 1.3 | 0.4 | 1.2 | 1.3 | 3.9 | 1.5 | 4.2 |
| Flu B-
Mod Pos | FluB | 142 | 32.3 | 0.1 | 0.3 | 0.3 | 0.8 | 0 | 0 | 0.3 | 0.8 | 0.8 | 2.4 | 0.9 | 2.7 |

Table 8-13: Summary of Reproducibility Data

Results with non-zero Ct values of 144. a.

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Conclusions

The results of the nonclinical analytical and clinical performance studies summarized above demonstrate that the Xpert Xpress Flu Assay is substantially equivalent to the predicate device.

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Image /page/32/Picture/0 description: The image contains the logo of the U.S. Food & Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

August 15, 2018

Cepheid Jim Kelly, Ph.D. Executive Director, Regulatory Affairs 904 Caribbean Drive Sunnyvale, CA 94089

Re: K181289

Trade/Device Name: Xpert Xpress Flu, Xpert Nasopharyngeal Sample Collection Kit, Xpert Nasal Sample Collection Kit, GeneXpert Dx Systems (GX-I, GX-II, GX-IV, GX-XVI), GeneXpert Infinity-48S System and GeneXpert Infinity-80 System Regulation Number: 21 CFR 866.3980 Regulation Name: Respiratory viral panel multiplex nucleic acid assay Regulatory Class: Class II Product Code: OCC, OOI, JSM Dated: May 14, 2018 Received: May 17, 2018

Dear Jim Kelly:

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. 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 located 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.

33

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 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

for

Uwe Scherf, Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure