The xTAG Respiratory Viral Panel (RVP) is a qualitative nucleic acid multiplex test intended for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs from individuals suspected of respiratory tract infections. The following virus types and subtypes are identified using RVP: Influenza A. Influenza A subtype H1, Influenza A subtype H3, Influchza B, Respiratory Syncytial Virus subtype A, Respiratory Syncytial Virus subtype B, Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus. Human Metapneumovirus, Rhinovirus, and Adenovirus. The detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection if used in conjunction with other clinical and laboratory findings. It is recommended that specimens found to be negative for Influenza B, Respiratory Synctial Virus subtype A and B, Parainfluenza 2, Parainfluenza 3 and Adenovirus, after examination using RVP be confirmed by cell culture. Negative results do not preclude respiratory virus infection and should not be used as the sole basis for diagnosis, treatment or other management decisions. Positive results do not rule out bacterial infection, or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing (e.g. bacterial culture, immunofluorescence, radiography) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of respiratory viral infection.

Due to seasonal prevalence, performance characteristics for Influenza A/H1 were established primarily with retrospective specimens.

The RVP assay cannot adequately detect Adenovirus species C, or serotypes 7a and 41. The RVP primers for detection of thinovirus cross-react with enterovirus. A rhinovirus reactive result should be confirmed by an alternate method (e.g. cell culture).

Performance characteristics for Influenza A Virus were established when Influenza A/H3 and A/H1 were the predominant Influenza A viruses in circulation. When other Influenza A viruses are emerging, performance characteristics may vary. If infections 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 a 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 xTAG Respiratory Viral Panel includes the following components:

Multiplex PCR primer mix (without dNTPs) .
Multiplex target specific primer extension (TSPE) primers (includes dNTPs) .
Coupled bead mix .
10x buffer
xTAG® Data Analysis Software (TDAS RVP-I) .

AI/ML Overview

Here's a summary of the acceptance criteria and study information for the xTAG® RVP device, based on the provided 510(k) summary:

The 510(k) summary provided primarily focuses on establishing substantial equivalence to a predicate device and specifically details the device's ability to detect novel 2009 Influenza A/H1N1 strains, rather than establishing acceptance criteria against a predefined performance target in a typical clinical trial format.

Key takeaway: The document highlights the device's performance in identifying the 2009 Influenza A/H1N1 strain, which was a new and important consideration at the time of this 510(k) submission. It describes how the device handles this specific strain compared to a reference method (CDC rRT-PCR assay).

1. Table of Acceptance Criteria and Reported Device Performance

The provided document doesn't explicitly state quantitative acceptance criteria (e.g., minimum sensitivity, specificity thresholds) for the device's overall performance as would be expected in a typical clinical study report for initial market clearance. Instead, it demonstrates the device's capability to detect a newly emerging influenza strain. The "acceptance" can be inferred as the ability to effectively detect the 2009 Influenza A/H1N1 strain, often by agreement with a reference method.

Acceptance Criteria (Implied for 2009 Influenza A/H1N1 Detection)	Reported Device Performance (xTAG® RVP)
Detection of 2009 Influenza A/H1N1 (matrix gene)	Study 1 (Ginocchio & George, 2009): - Out of 141 "unsubtypeable" Flu A samples by xTAG RVP, 101 were further tested with CDC rRT-PCR. - 99 out of 101 (98.0%) identified as positive for 2009 Influenza A/H1N1 by CDC rRT-PCR (CT<37). - 2 remaining samples produced weak positive signals (CT>37) by CDC rRT-PCR and by xTAG RVP, and could not be classified as 2009 Influenza A/H1N1 positive. Study 2 (Ginocchio et al., 2009): - Out of 1265 samples positive for Influenza A by xTAG RVP, 1108 were "flu A unsubtypeable". - All 1108 (100%) "flu A unsubtypeable" samples were confirmed to be Influenza A/H1N1 with the CDC rRT-PCR assay.
Identification of other respiratory viruses	The device identified Influenza B (2 samples) and other respiratory viruses including adenovirus, metapneumovirus, Parainfluenza 1, 2, 3, RSV, and rhinovirus (58 samples) in the Ginocchio & George (2009) study, alongside the Influenza A positives.
Subtyping of seasonal Influenza A strains	In the Ginocchio & George (2009) study, 60 Flu A positive samples were identified by xTAG RVP as seasonal strains (2 as H1 and 58 as H3).

2. Sample Sizes Used for the Test Set and Data Provenance

Study 1 (Ginocchio & George, 2009):
- Initial samples tested with various methods: 1,382 nasopharyngeal swab samples.
- Samples further tested with xTAG RVP: 375 samples (positive for Influenza A by other methods or from high-risk patients).
- Samples identified as "unsubtypeable" Flu A by xTAG RVP: 141.
- Test Set for 2009 H1N1 confirmation: 101 frozen residual samples out of the 141 unsubtypeable samples.
- Data Provenance: Retrospective specimens from the 2009 Influenza A H1N1 (swine flu) outbreak in New York.
Study 2 (Ginocchio et al., 2009):
- Test Set: 2,715 nasopharyngeal swab samples.
- Data Provenance: Not explicitly stated, but context suggests it's related to 2009 Influenza A/H1N1 surveillance, likely also retrospective and from the outbreak regions.

3. Number of Experts Used to Establish Ground Truth and Qualifications

The studies described use a highly sensitive and specific laboratory reference method, not expert human readers, to establish ground truth.

Ground truth was established by the CDC rRT-PCR assay for 2009 Influenza A H1N1 (swine flu). This is a highly specialized molecular diagnostic test, and the "experts" would be the trained laboratory personnel performing and interpreting this assay. Specific qualifications beyond performing the reference assay are not detailed.

4. Adjudication Method for the Test Set

Not applicable. The ground truth was established by a laboratory reference method (CDC rRT-PCR assay), not through human reader adjudication.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. The device is a diagnostic assay, and its performance is typically evaluated against laboratory reference standards or clinical outcomes, not against variations in human reader interpretation of images or signals.

6. Standalone (Algorithm Only Without Human-in-the-Loop) Performance

Yes, the studies describe the standalone performance of the xTAG RVP assay. While the assay requires laboratory personnel to run the test and interpret results from the xTAG® Data Analysis Software (TDAS RVP-I), the performance metrics reported (e.g., number of positives concordant with CDC rRT-PCR) reflect the assay's direct detection capabilities, independent of human clinical interpretation of symptoms or subsequent reader adjustments.

7. Type of Ground Truth Used

The primary ground truth used for confirming the detection of 2009 Influenza A/H1N1 was a laboratory reference method: the CDC rRT-PCR assay for 2009 Influenza A H1N1. This is a highly sensitive and specific molecular test, considered the gold standard for identifying this specific viral strain at the time.

For other viruses, the general intended use suggests confirmation by cell culture for negative results of certain viruses, but the performance studies specifically for 2009 H1N1 used the CDC PCR assay as ground truth.

8. Sample Size for the Training Set

The document does not specify a separate training set or its sample size. The studies described are performance evaluations on clinical samples, likely acting as a test set for the already developed assay. Diagnostic molecular assays typically establish their core design and parameters through internal development and validation, and these clinical studies serve to demonstrate performance on real-world samples.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as a distinct training set with its own ground truth establishment is not detailed in the provided summary. The clinical samples evaluated in the studies served as performance verification, using the CDC rRT-PCR as the ground truth comparator.

Summary

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K091667

510(k) Summary

1.0 Submitted By:

JUN 25 2009

Gloria Lee, Ph.D. Manager, Regulatory Affairs (Global Submissions) Luminex Molecular Diagnostics Inc. 439 University Ave. Toronto, Ontario M5G 1Y8 Canada Tel: 416.593.4323 x374 Fax: 416.593.1001 Email: glee@luminexcorp.com

2.0 Date Submitted

June 3, 2009

3.0 Device Name(s):

Proprictary Name: xTAG® RVP Classification Name: Respiratory Viral Panel Multiplex Nucleic Acid Assay [866.3980]

Legally Marketed Device 4.0

xTAG® RVP claims substantial equivalence to the xTAG® RVP originally cleared under FDA 510(k) K063765 and cleared under Special 510(k) K081483.

5.0 Device Description

The xTAG Respiratory Viral Panel includes the following components:

Multiplex PCR primer mix (without dNTPs) .
Multiplex target specific primer extension (TSPE) primers (includes dNTPs) .
Coupled bead mix .
10x buffer �
xTAG® Data Analysis Software (TDAS RVP-I) .

6.0 Intended Use

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Adenovirus, after examination using RVP be confirmed by cell culture. Negative results do not preclude respiratory virus infection and should not be used as the sole basis for diagnosis, treatment or other management decisions. Positive results do not rule out bacterial infection, or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing (e.g. bacterial culture, immunofluorescence, radiography) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of respiratory viral infection.

Due to seasonal prevalence, performance characteristics for Influenza A/H1 were established primarily with retrospective specimens.

Comparison to the Predicate (Description of the Modification to the Legally 7.0 Marketed Device)

The xTAG Respiratory Viral Panel performance parameters remain unchanged.

Summary of Performance Data 8.0

The xTAG RVP can detect the matrix gene of 2009 Influenza A/H1N1 but can not identify the hemagglutinin gene of the 2009 Influenza A/H1N1 in clinical specimens. The studies summarized below demonstrate that xTAG RVP is an effective aid in the detection of 2009 influenza A/HIN1 strains (Ginocchio & George, 2009; Ginocchio et al. 2009):

In a study carried out during the 2009 Influenza A HINI (swine flu) outbreak in New York (Ginocchio & George, 2009), a total of 1,382 patient nasopharyngeal swab samples were initially tested with a variety of method including rapid antigen tests (n=1095), direct immunofluorescence (n=1164), and rapid virus culture (n=1140). Samples that tested positive for Influenza A with any of these methods, or derived from patients with a high potential to be infected with the 2009 Influenza A HINI strain, were further tested with xTAG RVP (n=375). A total of 201 of these samples were identified as Flu A positive by the RVP assay, two samples contained Influenza B, and other respiratory viruses in 58 samples (adenovirus, metapheumovirus. Parainfluenza 1. 2. 3. RSV, and rhinovirus). Sixty of the 201 Flu A positive samples were identified by xTAG RVP as seasonal strains (2 as H1 and 58 as H3). The remaining 14 Flu A positive samples were negative for both H1 and H3 by xTAG RVP (unsubtypeable). Frozen residual portions of 101 of the 141 unsubtypeable samples were forwarded to the Laboratory of Viral Diseases (Albany, NY) for further testing with the CDC rRT-PCR assay for 2009 Influenza A HINI (swine flu). A total of 99 of the 101 specimens tested with the CDC assay were identified as positive for 2009 Influenza A/H/N1 (CT<37). The two remaining specimens produced weak positive signals (CT>37) on one or more of the influenza targets and could not be classified as positive for the 2009 Influenza A/H/N/ strain. These two samples also produced weak positive signals in the RVP assay.

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A study by Ginocchio et al. (2009) evaluated the performance of a variety of diagnostic assays, including the xTAG RVP, for the 2009 Influenza A/H1N1 surveillance. In this study, a total of 2,715 patient nasopharyngeal swab samples were tested by xTAG RVP and 1265 of these were positive for influenza A. Of the 1265, 1108 were "flu A unsubtypeable", 151 were seasonal H3N2 and 6 were seasonal H1N1. Of the 1108 flu A unsubtypeable with the xTAG RVP, all were confirmed to be Influenza A/H1N1 with the CDC rRT-PCR assay.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/3/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three tail feathers, representing the three levels of government: federal, state, and local. The eagle is enclosed in a circle with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter.

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

JUN 25 2009

Gloria Lee, Ph.D. Manager, Regulatory Affairs Luminex Molecular Diagnostics Inc. 439 University Avenue Suite 2000 Toronto, ON M5G 1Y8 Canada

Re: K091667 Trade/Device Name: xTAG® Respiratory Viral Panel Regulation Number: 21 CFR 866.3980 Regulation Name: Respiratory viral panel multiplex nucleic acid assay Regulatory Class: Class II Product Code: OCC,OEM,OEP Dated: June 3, 2009 Received: June 9, 2009

Dear Dr. Lee:

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. Ilsting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at 240-276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at 240-276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at 240-276-3464. You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Sally attaym

Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Section 7.0 Indication for Use Statement

510(k) Number (if known): K091667 Device Name: xTAG® Respiratory Viral Panel Indication For Use:

The xTAG Respiratory Viral Panel (RVP) is a qualitative nucleic acid multiplex test intended for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs from individuals suspected of respiratory tract infections. The following virus types are identified using RVP: Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza B; Respiratory Syncytial Virus subtype A, Respiratory Syncytial Virus subtype B, Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus, Human Metapneumovirus, Rhinovirus, and Adenovirus. The detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection if used in conjunction with other clinical and laboratory findings. It is recommended that specimens found to be negative for Influenza B, Respiratory Synctial Virus subtype A and B, Parainfluenza 1, Parainfluenza 3 and Adenovirus, after examination using RVP be confirmed by cell culture. Negative results do not preclude respiratory virus infection and should not be used as the sole basis for diagnosis, treatment or other management decisions. Positive results do not rule out bacterial infection, or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing (e.g. bacterial culture, immunofluorescence, radiography) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of respiratory viral infection.

Due to seasonal prevalence, performance characteristics for Influenza A/H were established primarily with retrospective specimens.

The RVP assay cannot adequately detect Adenovirus species C, or serotypes 7a and 41. The RVP primers for detection of rhinovirus cross-react with enterovirus. A rhinovirus reactive result should be confirmed by an alternate method (e.g. cell culture).

Performance characteristics for Influenza A Virus were established when Influenza A/H3 and A/H1 were the predominant Influenza A viruses in circulation. When other Influenza A viruses are emerging, performance characteristics may vary. If infections with a novel Influenza A virus is suspected based on current clinical and enidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to a 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.

Prescription Use X (21 CFR Part 801 Subpart D)

And/Or

Over the Counter Use (21 CFR Part 801 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

Uwe Schuf

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety 1091661 510(k)

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.