Predicate Devices

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a real-time RT-PCR diagnostic panel which uses primers and probes to detect and characterize influenza viruses. There is no mention of AI or ML in the device description, intended use, or performance studies. The technology described is standard molecular diagnostics.

Therapeutic

No
The device is described as a "Diagnostic Panel" intended for "qualitative detection of influenza virus type A or B viral RNA" and "determination of the subtype of seasonal human influenza A viruses," which are diagnostic uses, not therapeutic.

Diagnostic

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states that the kit is "intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument" and is for the "qualitative detection of influenza virus type A or B viral RNA" and "determination of the subtype of seasonal human influenza A viruses," all of which are diagnostic applications.

SaMD (Software as a Medical Device)

No

The device is described as containing "reagents and controls" and is used in "real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument". This indicates it is a physical kit with chemical components and requires specific hardware (a PCR instrument) for its function, not solely software.

IVD (In Vitro Diagnostic)

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

Here's why:

Intended Use/Indications for Use: The intended use explicitly states "intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument" and "For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract clinical specimens... and lower respiratory tract specimens... from human patients". This clearly indicates the device is used in vitro (outside the body) to diagnose or detect a condition (influenza virus RNA) in human specimens.
Device Description: The description states the panel is used "on an in vitro diagnostic real-time PCR system" and for the "in vitro qualitative detection and characterization of influenza virus RNA in respiratory specimens from patients".
Predicate Device: The submission lists a predicate device with the K number K190302, which is named "CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel". This indicates that the device is being compared to a previously cleared IVD.

All of these points strongly support the classification of this device as an In Vitro Diagnostic.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/B Typing Kit (VER 2)
- For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.
- To provide epidemiological information for surveillance of circulating influenza viruses.
CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A Subtyping Kit (VER 3)
- For determination of the subtype of seasonal human influenza A viruses as seasonal A(H3) and/or A(H1)pdm09 from viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
- To provide epidemiological information for surveillance of circulating influenza viruses.
CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/H5 Subtyping Kit (VER 4)
- For the presumptive identification of virus in patients who may be infected with influenza A subtype A(H5) (Asian lineage) from viral RNA in human respiratory specimens and viral culture in conjunction with clinical and epidemiological risk factors;
- To provide epidemiological information for surveillance of circulating influenza viruses.

Product codes (comma separated list FDA assigned to the subject device)

OZE, OOI, NSU, OEP, OQW, NXD

Device Description

The CDC Human Influenza Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR system. The panel is configured in four separate kits. Each kit consists of oligonucleotide primers, fluorescently labeled hydrolysis probes, and controls which are used in rRT-PCR assays for the in vitro qualitative detection and characterization of influenza virus RNA in respiratory specimens from patients presenting with influenza-like illness (ILI). Oligonucleotide primers and probes for detection of influenza A, influenza B, and 2009 influenza A (swine origin) were selected from highly conserved regions of the matrix (M), non-structural (NS), and nucleoprotein (NP) genes, respectively. Oligonucleotide primers and probes for characterization and differentiation of influenza A(H3) and A(H1)pdm(9 viruses and genetic lineages of influenza B were selected from highly conserved regions of their HA genes. Oligonucleotide primers and probes to detect the human RNase P gene (RP) in control samples and clinical specimens is also included in the panel.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.

Indicated Patient Age Range

Not Found

Intended User / Care Setting

All users, analysts, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

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

Analytical Sensitivity- Limit of Detection (LOD):

Sample Size: Triplicate samples of each serial dilution (for LOD equivalency). 20 individually extracted samples for confirmation of LOD.
Data Source: Serial dilutions of "benchmark" strains and current strains of known titer (either Tissue Culture Infectious Dose 50% (TCIDso/mL) or Egg Infectious Dose 50% (EID30/mL)) prepared with a diluent consisting of a suspension of human A549 cells and viral transport medium (VTM).
Annotation Protocol: LOD equivalency acceptance criteria was 100% positivity (3 out of 3 replicates) at either the same endpoint LOD concentration or within a 5-fold dilution of each other against the benchmark virus strain. For confirmation, 20 individually extracted samples were tested for the highest virus dilution where >=95% of all replicates tested positive.

Analytical Sensitivity - Inclusivity:

Sample Size: Triplicate samples.
- Modified pdmInfA and pdmH1 assays: 10 influenza A(H1N)dm09 viruses.
- Modified InfA assay: 24 influenza A viruses (seasonal human, animal origin, pandemic potential).
Data Source: Viruses prepared at a low titer at or near the assay LOD.
Annotation Protocol: Not explicitly stated beyond "Samples were tested in triplicate."

Analytical Specificity - Cross-Reactivity:

Sample Size: Triplicate samples.
Data Source: RNA extracted from high titer preparations (>= 10^6^ TCIDso/mL or EID50/mL) of influenza viruses of different types or subtypes/lineages.
Annotation Protocol: Not explicitly stated beyond "Samples were tested in triplicate."

Analytical Specificity - Exclusivity:

Sample Size: Not explicitly stated, but "Nucleic acids were extracted from high titer preparations... of 35 organisms".
Data Source: Non-influenza human respiratory viruses, bacteria, and yeast. Nucleic acids extracted from high titer preparations (typically >= 10^6^ TCID50/mL or ElD50/mL, >= 10^6^ CFU/mL) of 35 organisms (16 viruses, 18 bacteria, and 1 yeast).
Annotation Protocol: Not explicitly stated.

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

Retrospective Study

Study Type: Retrospective clinical performance evaluation.
Sample Size:
- Modified InfA assay: 62 positive specimens (35 influenza A(H1N1)pdm09, 27 influenza A(H3N2)) and 50 negative specimens.
- Modified pdmInfA and pdmH1 assays: 35 positive specimens for influenza A(H1N1)pdm09 and 50 negative specimens.
Key Results:
- Modified InfA Assay - Retrospective Positive Clinical Study Results:
  - NPS, NS: 51/51 positive agreement (100.0% CI: 93.0-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - NPS/TS: 2/2 positive agreement (100.0% CI: 34.2-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - TS: 4/4 positive agreement (100.0% CI: 51.0-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - NW: 3/3 positive agreement (100.0% CI: 43.9-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - Sputum: 1/1 positive agreement (100.0% CI: 20.7-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - BW: 1/1 positive agreement (100.0% CI: 20.7-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
- Modified InfA Assay - Retrospective Clinical Study Results (Negative Agreement):
  - NPS: 54/54 negative agreement (100.0% CI: 93.4-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
- Modified pdmInfA and pdmH1 Assays - Retrospective Positive Clinical Study Results:
  - BW: 1/1 positive agreement (100.0% CI: 20.7-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - NPS, NS: 28/28 positive agreement (100.0% CI: 87.9-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - NW: 3/3 positive agreement (100.0% CI: 43.9-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
  - TS: 3/3 positive agreement (100.00% CI: 43.9-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.
- Modified pdmInfA and pdmH1 Assays - Retrospective Clinical Study Results (Negative Agreement):
  - NPS: 54/54 negative agreement (100.0% CI: 93.4-100.0) with both Invitrogen SuperScriptTM and Quanta qScriptTM.

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

Analytical Sensitivity - Limit of Detection (LOD):
- Modified InfA Assay: LODs ranging from 10^1.4^ to 10^3.1^ ID50/mL depending on virus strain and enzyme system.
- Modified pdmInfA and pdmH1 Assays: LODs around 10^2.0^ to 10^2.9^ ID50/mL for A(H1N1)pdm09 strains.
Analytical Sensitivity - Inclusivity: All tested influenza A virus strains showed 3/3 positive replicates (100% inclusivity for the tested strains at low titers).
Analytical Specificity - Cross-Reactivity:
- Modified pdmInfA assay showed cross-reactivity with A/Iowa/1/2006 (A(H1N1)v), A/Texas/14/2008 (A(H1N1)v), A/Ohio/09/2015 (A(H1N1)v), A/Minnesota/19/2011 (A(H1N2)v), A/Ohio/35/2017 (A(H1N2)v), A/Ohio/13/2017 (A(H3N2)v), and A/gyrfalcon/Washington/41088-6/2014 (A(H5N8)).
- Modified pdmH1 assay showed cross-reactivity with A/Iowa/1/2006 (A(H1N1)v), A/Texas/14/2008 (A(H1N1)v), A/Ohio/09/2015 (A(H1N1)v).
- Modified InfA assay showed cross-reactivity with B/Maryland/15/2016 (B/Victoria), B/Colorado/06/2017 (B/Victoria), B/Texas/81/2016 (B/Yamagata), B/Phuket/3073/2013 (B/Yamagata).
Analytical Specificity - Exclusivity: All 35 non-influenza respiratory pathogens or flora tested showed no cross-reactivity with the modified pdmInfA assay.
Clinical Performance (Positive Percent Agreement): 100.0% for all specimen types tested with modified InfA, pdmInfA, and pdmH1 assays.
Clinical Performance (Negative Percent Agreement): 100.0% for NPS specimen type with modified InfA, pdmInfA, and pdmH1 assays.

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

K190302

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

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

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

Received: February 14, 2020

March 10, 2020

Centers for Disease Control and Prevention Yon Yu Regulatory Affairs and Clinical Guidelines Team Lead 1600 Clifton Rd: MS H24-11 Atlanta, Georgia 30329

Re: K200370

Trade/Device Name: CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel, Influenza A/B Typing Kit, CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel, Influenza A Subtyping Kit, CDC Human Influenza Virus Real-time RT-PCR, Influenza A/H5 Subtyping Kit Regulation Number: 21 CFR 866.3980 Regulation Name: Respiratory Viral Panel Multiplex Nucleic Acid Assay Regulatory Class: Class II Product Codes: OZE, OOI, NSU, OEP, OQW, NXD Dated: February 13, 2020

Dear Yon Yu:

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.

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

1

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/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Steven Gitterman, M.D., Ph.D. Deputy Director Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K200370

Device Name

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/B Typing Kit (VER 2), Influenza A Subtyping Kit (VER 3), and Influenza A/H5 Subtyping Kit (VER 4)

Indications for Use (Describe)

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/B Typing Kit (VER 2)

The Influenza A/B Typing Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:

· For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.
· To provide epidemiological information for surveillance of circulating influenza viruses.

Performance characteristics for influenza were established during a seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N) Jodm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions. Conversely, positive results do not rule out bacterial infection with other viruses. The agent detected may not be the definite cause of disease.

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 unless a BSL 3E facility is available to receive and culture specimens.

All users, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A Subtyping Kit (VER 3)

The Influenza A Subtyping Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:

· For determination of the subtype of seasonal human influenza A viruses as seasonal A(H3) and/or A(H1)pdm09 from viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and

3

lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;

· To provide epidemiological information for surveillance of circulating influenza viruses.
Performance characteristics for influenza were established during a seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N) )dm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions. Conversely, positive results do not rule out bacterial infection with other viruses. The agent detected may not be the definite cause of disease.

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 unless a BSL 3E facility is available to receive and culture specimens.

All users, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/H5 Subtyping Kit (VER 4)

The Influenza A/H5 Subtyping Kit contains reagents and controls of the CDC Human Influenza Virus RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:

· For the presumptive identification of virus in patients who may be infected with influenza A subtype A(H5) (Asian lineage) from viral RNA in human respiratory specimens and viral culture in conjunction with clinical and epidemiological risk factors;
· To provide epidemiological information for surveillance of circulating influenza viruses.

Performance characteristics for influenza were established during a seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N) pdm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

Testing with the influenza H5a and H5b primer and probe sets should not be performed unless the most current U.S. Department of Health and Human Services (DHHS) clinical and epidemiological criteria for testing suspect A(H5) specimens. The definitive identification of influenza A(H5) (Asian lineage) either directly from patient specimens or from virus cultures requires additional laboratory testing, along with clinical and epidemiological assessment in consultation with national influenza surveillance experts.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions. Conversely, positive results do not rule out bacterial infection with other viruses. The agent detected may not be the definite cause of disease.

If infection with a novel influenza A virus is suspected based on current clinical and epidemiological screening criteria

4

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 unless a BSL 3E facility is available to receive and culture specimens.

All users, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

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

Requisition Use (Part 31 CFR 801 Subpart B)
Own-Title Contract Use (31 CFR 801 Subpart C)
X Prescription Use (Part 21 CFR 801 Subpart D)

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

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8. 510(k) Summary

GENERAL INFORMATION I.

Submitter: Centers for Disease Control and Prevention 1600 Clifton Road, NE Atlanta, GA 30329

Contact Person: CAPT Yon Yu, Pharm.D. Regulatory Affairs and Clinical Guidelines Team Lead Emergency Preparedness and Response Branch Division of Preparedness and Emerging Infections National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention (Registration Number: 1050190) 1600 Clifton Road, MS H24-11 Atlanta, GA 30329-4027 (404) 639-3046 (office) (404) 235-3575 (fax) fkb8@cdc.gov (Email)

Date Prepared: February 13, 2020

DEVICE INFORMATION II.

| Proprietary Name: | CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel,
Influenza A/B Typing Kit (Ver2), Influenza A Subtyping Kit (Ver3),
Influenza A/H5 Subtyping Kit (Ver4) |
|------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Common Name: | Influenza A/B Typing Kit, Influenza A Subtyping Kit, Influenza A/H5 Subtyping Kit |
| Regulation Section: | 866.3980-Respiratory viral panel multiplex nucleic acid assay |
| Subsequent Regulation
Sections: | 866.3332-Reagents for detection of specific novel influenza A
viruses
862.2570-Instrumentation for clinical multiplex systems |
| Device Classification: | Class II |
| Product Code: | OZE |
| Subsequent Product Codes: | NSU, NXD, OEP, OQW, OOI |
| Panel: | Microbiology |

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III. PREDICATE DEVICE

CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel (K190302)

DEVICE DESCRIPTION IV.

The CDC Human Influenza Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR system. The panel is configured in four separate kits. Each kit consists of oligonucleotide primers, fluorescently labeled hydrolysis probes, and controls which are used in rRT-PCR assays for the in vitro qualitative detection and characterization of influenza virus RNA in respiratory specimens from patients presenting with influenza-like illness (ILI). Oligonucleotide primers and probes for detection of influenza A, influenza B, and 2009 influenza A (swine origin) were selected from highly conserved regions of the matrix (M), non-structural (NS), and nucleoprotein (NP) genes, respectively. Oligonucleotide primers and probes for characterization and differentiation of influenza A(H3) and A(H1)pdm(9 viruses and genetic lineages of influenza B were selected from highly conserved regions of their HA genes. Oligonucleotide primers and probes to detect the human RNase P gene (RP) in control samples and clinical specimens is also included in the panel.

V. INTENDED USE

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/B Typing Kit

The Influenza A/B Typing Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:

For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract . clinical specimens (including nasopharyngeal swabs [NPS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash[BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.

. To provide epidemiologic information for surveillance of circulating influenza viruses.
Performance characteristics for influenza were established during a season when seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N1)odm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

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

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

7

local health department for testing. Viral culture should not be attempted unless a BSL 3E facility is available to receive and culture specimens.

All users, analysts, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A Subtyping Kit

The Influenza A Subtyping Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:

. For determination of the subtype of seasonal human influenza A viruses as seasonal A(H3), and/or A(H1)pdm09 from viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
. To provide epidemiologic information for surveillance of circulating influenza viruses.

Performance characteristics for influenza were established during a season when seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N1)pdm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

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

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 unless a BSL 3E facility is available to receive and culture specimens.

All users, analysts, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

8

CDC Human Influenza Real-Time RT-PCR Diagnostic Panel: Influenza A/H5 Subtyping Kit

The Influenza A/H5 Subtyping Kit contains reagents and controls of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with this kit in conjunction with clinical and epidemiological information:

. For the presumptive identification of virus in patients who may be infected with influenza A subtype A(H5) (Asian lineage) from viral RNA in human respiratory specimens and viral culture in conjunction with clinical and epidemiological risk factors;

. To provide epidemiologic information for surveillance of circulating influenza viruses.
Performance characteristics for influenza were established during a season when seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N1)pdm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

Testing with the influenza H5a and H5b primer and probe sets should not be performed unless the patient meets the most current U.S. Department of Health and Human Services (DHHS) clinical and epidemiologic criteria for testing suspect A(H5) specimens. The definitive identification of influenza A(H5) (Asian lineage) either directly from patient specimens or from virus cultures requires additional laboratory testing, along with clinical and epidemiological assessment in consultation with national influenza surveillance experts.

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

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 unless a BSL 3E facility is available to receive and culture specimens.

All users, analysts, and any person reporting results from use of this device should be trained to perform and interpret the results from this procedure by a competent instructor prior to use. CDC Influenza Division will limit the distribution of this device to only those users who have successfully completed a training course provided by CDC instructors or designees.

VI. TECHNOLOGICAL CHARACTERISTICS

The technological characteristics of the modified CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel remain the same as the predicate device. Modifications were made primarily to address recent evolutionary changes in circulating influenza A viruses that may impact the reactivity of the current Influenza A/B Typing Kit, Influenza A Subtyping Kit, and Influenza A/H5 Subtyping

9

Kit. No modifications were made to the assay designs of the Influenza B Lineage Genotyping Kit.

SUBSTANTIAL EQUIVALENCE COMPARISON VII.

The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel (K190302), will serve as the predicate for the proposed change. See tables 8-1 to 8-3 below for a detailed comparison of the modified device to the predicate.

Item	Predicate Device	Proposed Device
	CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel, Influenza A/B Typing Kit [K190302]	CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel, Influenza A/B Typing Kit (Ver2)
	The Influenza A/B Typing Kit contains reagents and controls of the CDC Human Influenza Virus Real- Time RT-PCR Diagnostic Panel and is intended for use in real-time RT-PCR (rRT-PCR) assays on an in vitro diagnostic real-time PCR instrument that has been FDA-cleared for use with the CDC device in conjunction with clinical and epidemiological information:
• For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.
• To provide epidemiologic information for surveillance of circulating influenza viruses.	Same
Intended Use
	Performance characteristics for influenza were established during a season when seasonal influenza viruses A(H1N1) and A(H3N2) were the predominant influenza A viruses in circulation and during a season when the A(H1N1)pdm09 influenza virus was the predominant influenza A virus in circulation. Performance characteristics may vary with other emerging influenza A viruses.

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

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 | |
| Viral culture should not be attempted unless a BSL
3E facility is available to receive and culture
specimens. | | |
| All users, analysts, and any person reporting results from use of this device should be
trained to perform and interpret the results from this procedure by a competent
instructor prior to use. CDC Influenza Division will limit the distribution of this device
to only those users who have successfully completed a training course provided by
CDC instructors or designees. | | |
| Organism
Detected | Influenza A viruses (animal and human), influenza
B viruses | Same |
| Specimen Types | Nasopharyngeal swabs, nasal swabs, throat
swabs, nasal aspirates, nasal washes and dual
nasopharyngeal/throat swabs, bronchoalveolar
lavages, bronchial aspirates, bronchial washes,
tracheal aspirates, sputum, and lung tissue from
human patients with signs and symptoms of
respiratory infection and/or from viral culture | Same |
| Technological
Characteristics | Real-time RT-PCR based assay | Same |
| Nucleic Acid
Extraction | • QIAamp® DSP Viral RNA Mini Kit, QIAGEN
• MagNA Pure Compact -Nucleic Acid Isolation Kit
I, Roche
• MagNA Pure Compact - RNA Isolation Kit, Roche
• MagNA Pure LC - Total Nucleic Acid Kit, Roche
• QIAcube - QIAamp® DSP Viral RNA Mini Kit, QIAGEN
• NucliSENS® easyMAG®, bioMérieux
• EMAG®, bioMérieux
• EZ1 Advanced XL – EZ1 DSP Virus Kit and EZ1
RNA Tissue Mini Kit, QIAGEN
• MagNA Pure 96 - DNA and Viral NA Small
Volume Kit, Roche | Same |
| Enzyme Master
Mix | Invitrogen SuperScript™ III Platinum® One-Step
Quantitative RT-PCR Kit (with or without ROX) OR
Quanta BioSciences qScript™ One-Step qRT-PCR
• Kit, Low ROX | Same |
| Required
Instrumentation | • Applied Biosystems™ 7500 Fast Dx Real-
Time PCR Instrument with SDS software
version 1.4
• Applied Biosystems™ QuantStudio™ Dx
with version 1.0.3 software
• QIAGEN Rotor-Gene® Q MDx with
AssayManager® 1.0.4 and Epsilon version 1.0.1
software | Same |

Table 8-1: Device Comparison

10

Table 8-2: Device Comparison

| | Predicate
Device | Proposed
Device |
|---------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|
| Item | CDC Human Influenza Virus Real-Time RT-
PCR Diagnostic Panel, Influenza A
Subtyping Kit (Ver2) [K190302] | CDC Human Influenza Virus Real-
Time RT- PCR Diagnostic Panel,
Influenza A Subtyping Kit (Ver3) |
| Intended Use | The Influenza A Subtyping Kit contains reagents
and controls of the CDC Human Influenza Virus
Real- Time RT-PCR Diagnostic Panel and is
intended for use in real-time RT-PCR (rRT-PCR)
assays on an in vitro diagnostic real-time PCR
instrument that has been FDA-cleared for use with
the CDC device in conjunction with clinical and
epidemiological information:

• For determination of the subtype of seasonal
human influenza A viruses as seasonal A(H3),
and/or A(H1)pdm09 from viral RNA in upper
respiratory tract clinical specimens (including
nasopharyngeal swabs [NPS], nasal swabs [NS],
throat swabs [TS], nasal aspirates [NA], nasal | Same |
| | | |
| | washes [NW] and dual nasopharyngeal/throat
swabs [NPS/TS]) and lower respiratory tract
specimens (including bronchoalveolar lavage
[BAL], bronchial wash [BW], tracheal aspirate
[TA], sputum, and lung tissue) from human
patients with signs and symptoms of respiratory
infection and/or from viral culture; | |
| | • To provide epidemiologic information for
surveillance of circulating influenza viruses. | |
| | Performance characteristics for influenza were
established during a season when seasonal
influenza viruses A(H1N1) and A(H3N2) were the
predominant influenza A viruses in circulation and
during a season when the A(H1N1)pdm09
influenza virus was the predominant influenza A
virus in circulation. Performance characteristics
may vary with other emerging influenza A viruses. | |
| | Negative results do not preclude influenza virus
infection and should not be used as the sole basis
for treatment or other patient management
decisions. Conversely, 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. | |
| | 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 unless a BSL
3E facility is available to receive and culture
specimens. | |
| | All users, analysts, and any person reporting results from use of this device should be
trained to perform and interpret the results from this procedure by a competent
instructor prior to use. CDC Influenza Division will limit the distribution of this device
to only those users who have successfully completed a training course provided by
CDC instructors or designees | |
| Organism
Detected | Influenza A viruses (animal and human), Swine-
origin influenza A viruses, Influenza A
subtypes: seasonal A(H3), A(H1)pdm09 | Same |
| Specimen Types | Nasopharyngeal swabs, nasal swabs, throat
swabs, nasal aspirates, nasal washes and dual
nasopharyngeal/throat swabs, bronchoalveolar
lavages, bronchial aspirates, bronchial washes,
tracheal aspirates, sputum, and lung tissue from
human patients with signs and symptoms of
respiratory infection and/or from viral
culture | Same |
| Technological
Characteristic | Real-time RT-PCR based assay | Same |
| Nucleic Acid
Extraction | • QIAamp® DSP Viral RNA Mini Kit, QIAGEN
• MagNA Pure Compact –Nucleic Acid Isolation Kit I, Roche
• MagNA Pure Compact – RNA Isolation Kit, Roche
• MagNA Pure LC – Total Nucleic Acid Kit, Roche
• QIAcube – QIAamp® DSP Viral RNA Mini Kit, QIAGEN
• NucliSENS® easyMAG®, bioMérieux
• EMAG®, bioMérieux
• EZ1 Advanced XL – EZ1 DSP Virus Kit and EZ1 RNA Tissue Mini Kit, QIAGEN
• MagNA Pure 96 – DNA and Viral NA Small Volume Kit, Roche | Same |
| Enzyme Master Mix | Invitrogen SuperScript™ III Platinum® One-Step
Quantitative RT-PCR Kit (with or without ROX)
OR Quanta BioSciences qScript™ One-Step qRT-PCR Kit, Low ROX | Same |
| Required
Instrumentation | • Applied Biosystems™ 7500 Fast Dx Real-Time PCR Instrument with SDS software version 1.4
• Applied Biosystems™ QuantStudio™ Dx with version 1.0.3 software
• QIAGEN Rotor-Gene® Q MDx with AssayManager® 1.0.4 and Epsilon version | Same |

11

12

Table 8-3: Device Comparison

Item	Predicate Device	Proposed Device
	CDC Human Influenza Virus Real-Time RT-PCR
Diagnostic Panel, Influenza A/H5 Subtyping
Kit (Ver3) [K190302]	CDC Human Influenza Virus Real-Time
RT-
PCR Diagnostic Panel, Influenza
A/H5 Subtyping Kit (Ver4)
Intended Use	The Influenza A/H5 Subtyping Kit contains reagents
and controls of the CDC Human Influenza Virus
Real-Time RT-PCR Diagnostic Panel and is
intended for use in real-time RT-PCR (rRT-PCR)
assays on an in vitro diagnostic real-time PCR
instrument that has been FDA-cleared for use with
the CDC device in conjunction with clinical and
epidemiological information:

• For the presumptive identification of virus in
patients who may be infected with influenza A
subtype A(H5) (Asian lineage) from viral RNA in
human respiratory specimens and viral culture in
conjunction with clinical and epidemiological risk
factors;

• To provide epidemiologic information for
surveillance of circulating influenza viruses.

Performance characteristics for influenza were
established during a season when seasonal
influenza viruses A(H1N1) and A(H3N2) were the
predominant influenza A viruses in circulation and
during a season when the A(H1N1)pdm09
influenza virus was the predominant influenza A
virus in circulation. Performance characteristics
may vary with other emerging influenza A viruses.

13

14

VIII. ANALYTICAL PERFORMANCE EVALUATION

Analytical Sensitivity- Limit of Detection (LOD)

Analytical sensitivity and improved reactivity of the modified InfA, pdmInfA, and pdmH1 assays were determined in LOD studies. An LOD equivalency comparison between the modified and currently cleared InfA, pdmInfA and pdmH1 assays from the FDA-cleared CDC Human Influenza Real-Time RT-PCR Diagnostic Panel were examined. Serial dilutions of "benchmark" strains and current strains (see Table 8-4) of known titer Jeither Tissue Culture Infectious Dose 50% (TCIDso/mL) or Egg Infectious Dose 50% (EID30/mL)] were prepared with a diluent consisting of a suspension of human A549 cells and viral transport medium (VTM). Triplicate samples of each serial dilution were tested using both the modified and cleared assays. The benchmark strains represented viruses previously characterized with the cleared InfA, pdmInfA, and pdmH1 assays. Current strains with reduced reactivity with the cleared InfA, and pdmH1 assays were included to show the equivalent or improved reactivity of the modified InfA, pdmInfA, and pdmH1 assays. The acceptance criteria for LOD equivalency between the current FDA cleared assays and the modified assays was defined as demonstrating 100% positivity (3 out of 3 replicates) at either the same endpoint LOD concentration or within a 5-fold dilution of each other against the benchmark virus strain. Summary results for the modified InfA, and pdmH1 assays with each virus strain are shown in Tables 8-5 through 8-14.

| Virus | Type/subtype | Stock Titer (EID50/mL
or TCID50/mL | Assay Tested |
|---------------------------------|--------------|---------------------------------------|----------------------|
| A/Michigan/45/2015* | A(H1N1)pdm09 | 108.3 | InfA, pdmInfA, pdmH1 |
| A/Illinois/20/2018 | A(H1N1)pdm09 | 107.8 | InfA, pdmInfA, pdmH1 |
| A/Hong Kong/4801/2014* | A(H3N2) | 107.9 | InfA |
| A/Abu Dhabi/240/2018 | A(H3N2) | 109.1 | InfA |
| A/duck/Vietnam/NCVD-1544/2012* | A(H5N1) | 109.5 | InfA |
| A/duck/Vietnam/NCVD-17A231/2016 | A(H5N6) | 109.3 | InfA |

Table 8-4: Virus Selection for LOD Equivalency and Confirmation Studies

*Indicates a benchmark strain previously characterized with the FDA-cleared InfA, and pdmH1 assays.

Table 8-5: LOD Equivalency- InfA - A/Michigan/45/2015 (Presented as number of positive replicates out of three total replicates tested per condition)

Titer (EID50/mL)	Invitrogen SuperscriptTM		Quanta qScriptTM
	InfA IVD	InfA
Modified	InfA IVD	InfA
Modified
104.3	3/3	3/3	3/3	3/3
103.6	3/3	3/3	3/3	3/3
102.9	3/3	3/3	3/3	3/3
102.2	3/3	3/3	3/3	3/3
101.5	1/3	2/3	3/3	3/3
100.8	0/3	0/3	0/3	1/3

15

Table 8-6: LOD Equivalency- InfA - A/Illinois/20/2018 (Presented as number of positive replicates out of three total replicates tested per condition)

| Titer

(TCID50/mL)	Invitrogen SuperscriptTM		Quanta qScriptTM
	InfA IVD	InfA
Modified	InfA IVD	InfA
Modified
$10^{3.4}$	3/3	3/3	3/3	3/3
$10^{2.7}$	3/3	3/3	3/3	3/3
$10^{2.0}$	3/3	3/3	3/3	3/3
$10^{1.3}$	2/3	3/3	3/3	3/3
$10^{0.6}$	2/3	2/3	2/3	1/3
$10^{-0.1}$	0/3	0/3	0/3	0/3

Table 8-7: LOD Equivalency- InfA - A/Hong Kong/4801/2014
(Presented as number of positive replicates out of three total
replicates tested per condition)

	Invitrogen SuperscriptTM		Quanta qScriptTM
Titer (EID50/mL)	InfA IVD	InfA
Modified	InfA IVD	InfA
Modified
$10^{2.8}$	3/3	3/3	3/3	3/3
$10^{2.1}$	3/3	3/3	3/3	3/3
$10^{1.4}$	3/3	3/3	3/3	3/3
$10^{0.7}$	2/3	2/3	1/3	3/3
$10^{0.2}$	1/3	1/3	1/3	2/3
$10^{-0.7}$	0/3	0/3	0/3	0/3

Table 8-8: LOD Equivalency- InfA - A/Abu Dhabi/240/2018 (Presented as number of positive replicates out of three total replicates tested per condition)

	Invitrogen SuperscriptTM		Quanta qScriptTM
Titer (EID50/mL)	InfA IVD	InfA
Modified	InfA IVD	InfA
Modified
103.4	3/3	3/3	3/3	3/3
102.7	3/3	3/3	3/3	3/3
102.0	2/3	3/3	2/3	3/3
101.3	2/3	2/3	0/3	1/3
100.6	0/3	1/3	0/3	0/3
10-0.1	0/3	0/3	0/3	0/3

16

Table 8-9: LOD Equivalency- InfA - A/duck/Vietnam/NCVD-1544/2012 (Presented as number of positive replicates out of three total replicates tested per condition)

Titer (EID50/mL)	Invitrogen SuperscriptTM		Quanta qScriptTM
	InfA IVD	InfA Modified	InfA IVD	InfA Modified
104.5	3/3	3/3	3/3	3/3
103.8	3/3	3/3	3/3	3/3
103.1	3/3	3/3	3/3	3/3
102.4	3/3	1/3	3/3	3/3
101.7	1/3	1/3	1/3	1/3
101.0	0/3	0/3	0/3	0/3

Table 8-10: LOD Equivalency- InfA - A/duck/Vietnam/NCVD-17A231/2016 (Presented as number of positive replicates out of three total replicates tested per condition)

	Invitrogen SuperscriptTM		Quanta qScriptTM
Titer (EID50/mL)	InfA IVD	InfA
Modified	InfA IVD	InfA
Modified
104.3	3/3	3/3	3/3	3/3
103.6	3/3	3/3	3/3	3/3
102.9	3/3	3/3	3/3	3/3
102.2	3/3	0/3	3/3	2/3
101.5	1/3	0/3	0/3	0/3
100.8	0/3	0/3	0/3	1/3

Table 8-11: LOD Equivalency- pdmInfA - A/Michigan/45/2015 (Presented as number of positive replicates out of three total replicates tested per condition)

	Invitrogen SuperscriptTM		Quanta qScriptTM
Titer (EID50/mL)	pdmInfA
IVD	pdmInfA
Modified	pdmInfA
IVD	pdmInfA
Modified
104.3	3/3	3/3	3/3	3/3
103.6	3/3	3/3	3/3	3/3
102.9	3/3	3/3	3/3	3/3
102.2	3/3	3/3	3/3	3/3
101.5	1/3	2/3	0/3	1/3
100.8	0/3	0/3	0/3	0/3

17

Table 8-12: LOD Equivalency- pdmInfA - A/Illinois/20/2018 (Presented as number of positive replicates out of three total replicates tested per condition)

Titer (EID50/mL)	Invitrogen SuperscriptTM		Quanta qScript™
	pdmInfA
IVD	pdmInfA
Modified	pdmInfA
IVD	pdmInfA
Modified
103.4	3/3	3/3	3/3	3/3
102.7	3/3	3/3	3/3	3/3
102.0	3/3	3/3	3/3	3/3
101.3	3/3	0/3	3/3	1/3
100.6	1/3	0/3	0/3	0/3
10-0.1	0/3	0/3	0/3	0/3

Table 8-13: LOD Equivalency- pdmH1 - A/Michigan/45/2015 (Presented as number of positive replicates out of three total replicates tested per condition)

Titer (EID50/mL)	Invitrogen Superscript™		Quanta qScript™
	pdmH1
IVD	pdmH1
Modified	pdmH1
IVD	pdmH1
Modified
104.3	3/3	3/3	3/3	3/3
103.6	3/3	3/3	3/3	3/3
102.9	3/3	3/3	3/3	3/3
102.2	3/3	3/3	3/3	3/3
101.5	3/3	3/3	2/3	3/3
100.8	1/3	0/3	1/3	0/3

Table 8-14: LOD Equivalency- pdmH1 - A/Illinois/20/2018 (Presented as number of positive replicates out of three total replicates tested per condition)

Titer (EID50/mL)	Invitrogen Superscript™		Quanta qScript™
	pdmH1 IVD	pdmH1 Modified	pdmH1 IVD	pdmH1 Modified
103.4	3/3	3/3	3/3	3/3
102.7	3/3	3/3	3/3	3/3
102.0	1/3	3/3	3/3	3/3
101.3	0/3	1/3	0/3	3/3
100.6	0/3	0/3	0/3	0/3
10-0.1	0/3	0/3	0/3	0/3

A confirmation of the LOD for the modified InfA, pdmInfA, and pdmH1 assays was determined by preparing and testing 20 individually extracted samples for the highest virus dilution where ≥95% of all replicates tested positive. An LOD was determined with both Invitrogen Superscript™ and Quanta qScript™enzyme systems that are cleared for use with CDC Human Influenza Real-Time RT-PCR Diagnostic Panel. One of the currently cleared nucleic acid extraction methods was used to extract RNA and testing was performed on the Applied Biosystems 7500 Fast Dx. The results are summarized in Tables 8-15 and 8-16.

18

| Influenza A

Virus Subtype	Influenza Strain Designation	LOD (ID50/mL)
		Invitrogen
SuperScriptTM	Quanta
qScriptTM
A(H1N1)pdm09	A/Michigan/45/2015	102.2	102.2
A/Illinois/20/2018	102.0	102.0
A(H3N2)	A/Hong Kong/4801/2014	101.4	101.4
A/Abu Dhabi/240/2018	102.7	102.7
A(H5)	A/duck/Vietnam/NCVD-1544/2012	102.4	103.1
A/duck/Vietnam/NCVD-17A231/2016	102.2	102.9

Table 8-15: LOD Confirmation Summary - modified InfA Assay

Table 8-16: LOD Confirmation Summary - modified pdmInfA and pdmH1 Assays*

| Influenza A

Virus Subtype	Influenza Strain Designation	LOD (ID50/mL)
		Invitrogen
SuperScriptTM	Quanta
qScriptTM
A(H1N1)pdm09	A/Michigan/45/2015	102.9	102.9
A(H1N1)pdm09	A/Illinois/20/2018	102.0	102.0

'The LOD of the pdmInfA and pdmH1 assays is presented as the lowest virus concentration where InfA and both pdmInfA and pdmH1 primer and probe sets demonstrate uniform detection with ≥95% of all replicates testing positive.

Analytical Sensitivity - Inclusivity

The inclusivity of the modified pdmInfA and pdmH1 assays was examined using 10 influenza A(H1N))dm09 viruses representing temporal, geographic, and genetic diversity within the subtype and prepared at a low titer at or near the assay LOD. Samples were tested in triplicate. Results are summarized in Table 8-17. Similarly, the inclusivity of the modified InfA assay was examined with 24 influenza A viruses prepared at low titer at or near the LOD representing seasonal human viruses as well as influenza viruses of animal origin and of concern for their pandemic potential. Results are summarized in Table 8-18. Inclusivity studies were performed with both enzymes cleared with the CDC Human Influenza Real-Time RT-PCR Diagnostic Panel and one cleared extraction method. Testing was performed on the Applied Biosystems 7500 Fast Dx.

Table 8-17: Inclusivity of the modified pdmInfA and pdmH1 Assays (Presented as number of positive replicates out of three total replicates tested per condition)

| Influenza Virus
Strain Designation | EID50/mL
or
TCID50/mL | | Invitrogen
SuperScript™ | Quanta qScript™ | |
|---------------------------------------|-----------------------------|----------------|----------------------------|-----------------|-------------------|
| | | pdmInfA
IVD | pdmInfA
Modified | pdmH1
IVD | pdmH1
Modified |
| A/Florida/81/2018 | $10^{3.1}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Alaska/35/2018 | $10^{3.5}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Hawaii/17/2018 | $10^{4.0}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/West Virginia/01/2016 | $10^{1.4}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Washington/24/2012 | $10^{2.5}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Florida/62/2014 | $10^{3.3}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Bangladesh/2021/2012 | $10^{4.1}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Utah/13/2016 | $10^{2.5}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/Colorado/14/2012 | $10^{1.1}$ | 3/3 | 3/3 | 3/3 | 3/3 |
| A/North Carolina/4/2014 | $10^{3.3}$ | 3/3 | 3/3 | 3/3 | 3/3 |

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| Influenza Virus
Designation or
TCID50/mL | Invitrogen
SuperScript
TM | Quanta
qScript™ |
|----------------------- | A/Florida/81/2018 | A/Alaska/35/2018 | A/Hawaii/17/2018 | A/Utah/13/2016 | A/West Virginia/01/2016 | A/Switzerland/8060/2017 | A/Kansas/14/2017 | A/Idaho/33/2016 | A/Singapore/INFIMH-16-
0019/2016 | A(H3N2) | A/Texas/88/2016 | A/Ohio/35/2017 | A/chicken/Pennsylvania/29810
1-4/2004 | A(H2N2) | A/Ohio/13/2017 | A/equine/Ohio/01/2003 | A/canine/Florida/43/2004 | A/chicken/Alabama/1975 | A/Northern
pintail/Washington/40964/2014 | A/gyrfalcon/Washington/41088
-6/2014 | A(H5N8) | A/chicken/California/32213-
1/2000 | A(H6N2) | A/feline/New York/16-040082-
1/2016 | A(H7N2) | A/Taiwan/1/2017 | A/Anhui/1/2013 | A/duck/Vietnam/NCVD-
227/2009 | A/Bangladesh/0994/2011 | Subtype | EID50/mL
----------------------|--------------|-----------------------------|---------------------------------|--------------------|
| A(H1N1)pdm09 | 10 3.1 | 3/3 | 3/3 |
| A(H1N1)pdm09 | 10 3.5 | 3/3 | 3/3 |
| A(H1N1)pdm09 | 10 4.0 | 3/3 | 3/3 |
| A(H1N1)pdm09 | 10 2.5 | 3/3 | 3/3 |
| A(H1N1)pdm09 | 10 1.4 | 3/3 | 3/3 |
| A(H3N2) | 10 2.2 | 3/3 | 3/3 |
| A(H3N2) | 10 2.9 | 3/3 | 3/3 |
| A(H3N2) | 10 2.9 | 3/3 | 3/3 |
| 10 3.2 | 3/3 | 3/3 |
| A(H3N2) | 10 2.5 | 3/3 | 3/3 |
| A(H1N2)v | 10 1.9 | 3/3 | 3/3 |
| 10 3.5 | 3/3 | 3/3 |
| A(H3N2)v | 10 1.9 | 3/3 | 3/3 |
| A(H3N8) | 10 2.4 | 3/3 | 3/3 |
| A(H3N8) | 10 3.1 | 3/3 | 3/3 |
| A(H4N8) | 10 3.9 | 3/3 | 3/3 |
| A(H5N2) | 10 3.4 | 3/3 | 3/3 |
| 10 3.8 | 3/3 | 3/3 |
| 10 2.2 | 3/3 | 3/3 |
| 10 4.2 | 3/3 | 3/3 |
| A(H7N9) | 10 2.5 | 3/3 | 3/3 |
| A(H7N9) | 10 4.9 | 3/3 | 3/3 |
| A(H9N2) | 10 3.4 | 3/3 | 3/3 |
| A(H9N2) | 10 3.5 | 3/3 | 3/3 |

Table 8-18: Inclusivity of the modified InfA Assay (Presented as number of positive replicates out of three total replicates tested per condition)

Analytical Specificity - Cross-Reactivity

The cross-reactivity of the modified pdmInfA and pdmH1 assays was examined using influenza viruses of different types and subtypes or lineages. Samples were tested in triplicate with RNA extracted from high titer preparations of each virus (≥ 10° TCIDso/mL or EID50/mL) using one of the cleared extraction methods. Testing was performed on the ABI 7500 Fast Dx using one of the enzyme systems cleared with the CDC Human Influenza Real-Time RT-PCR Diagnostic Panel. Results are summarized in Table 8-19. Cross-reactivity was seen with the modified pdmInfA assay with one non-targeted influenza virus at very high-titer.

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| Influenza Virus
Designation | Subtype | EID50/mL
or
TCID50/mL | Invitrogen
SuperScript™ | |
|---------------------------------------------|----------|-----------------------------|----------------------------|-------|
| | | | pdmInfA | pdmH1 |
| A/Perth/16/2009 | A(H3N2) | 10 8.3 | - | - |
| A/Victoria/361/2011 | A(H3N2) | 10 9.2 | - | - |
| A/Iowa/1/2006 | A(H1N1)v | 10 8.2 | + | + |
| A/Texas/14/2008 | A(H1N1)v | 10 8.3 | + | + |
| A/Ohio/09/2015 | A(H1N1)v | 10 7.7 | + | + |
| A/Minnesota/19/2011 | A(H1N2)v | 10 7.1 | + | - |
| A/Ohio/35/2017 | A(H1N2)v | 10 6.9 | + | - |
| A/fowl/New Jersey/38092/2014 | A(H2N2) | 10 9.2 | - | - |
| A/Ohio/13/2017 | A(H3N2)v | 10 6.6 | + | - |
| A/equine/Ohio/01/2003 | A(H3N8) | 10 8.4 | - | - |
| A/Northern
pintail/Washington/40964/2014 | A(H5N2) | 10 9.4 | - | - |
| A/gyrfalcon/Washington/41088
-6/2014 | A(H5N8) | 10 9.8 | + | - |
| A/Anhui/01/2013 | A(H7N9) | 10 10.9 | - | - |
| A/Bangladesh/0994/2011 | A(H9N2) | 10 10.5 | - | - |

Table 8-19: Modified pdmInfA and pdmH1 Assay Cross-Reactivity

The cross-reactivity of the modified InfA assay was examined using influenza viruses of different types or lineages. Samples were tested in triplicate with RNA extracted from high titer preparations of each virus (≥ 10° TCID50/mL or EID50/mL). Testing was performed using one of the enzyme systems cleared with the CDC Human Influenza Real-Time RT-PCR Diagnostic Panel, one cleared extraction method, and the Applied Biosystems 7500 Fast Dx. The results are summarized in Table 8-20.

| Influenza Virus
Designation | Type and subtype
or lineage | EID50/mL | Invitrogen
SuperScriptTM | |
|--------------------------------|--------------------------------|----------|-----------------------------|---|
| B/Maryland/15/2016 | B/Victoria | 10 8.5 | + | - |
| B/Colorado/06/2017 | B/Victoria | 10 9.4 | + | - |
| B/Texas/81/2016 | B/Yamagata | 10 8.3 | + | - |
| B/Phuket/3073/2013 | B/Yamagata | 10 8.9 | + | - |
| C/Minnesota/1/2016 | Influenza C | nd1 | - | - |

Table 8-20: Modified InfA Assay Cross-Reactivity

1Infectious dose titer not determined for influenza C.

Analytical Specificity - Exclusivity

The exclusivity of the pdmInfA assay was evaluated with additional non-influenza respiratory pathogens to verify that the incorporation of non-specific AT-rich overhangs do not impact the specificity of the assay design. The pdmInfA assay was tested for cross-reactivity with non-influenza human respiratory viruses, bacteria, and yeast. Nucleic acids were extracted from high titer preparations (typically ≥ 106 TCID50/mL or ElD50/mL, ≥ 106 CFU/mL) of 35 organisms (16 viruses, 18 bacteria, and 1 yeast) representing common respiratory pathogens or flora commonly present in human respiratory specimens. Testing was performed using one of the enzyme systems cleared with

21

the CDC Human Influenza Real-Time RT-PCR Diagnostic Panel, one cleared extraction method, and the Applied Biosystems 7500 Fast Dx. The results are summarized in Table 8-21.

Organism Tested
Bacteria and Yeast	Strain	cfu / mL	Invitrogen
SuperScript™
Bordetella pertussis	Tahoma	10 10.0	-
Candida albicans	3147	10 8.5	-
Chlamydia pneumoniae1	CM-1	40 IFU/mL	-
Corynebacterium diphtheriae2	NCTC 13129	57.4 ng/ µL	-
Escherichia coli	K12	10 9.6	-
Haemophilus influenzae	M15709	10 6.4	-
Lactobacillus plantarum	NA3	10 8.8	-
Legionella pneumophila	Philadelphia-1	10 8.4	-
Moraxella catarrhalis	M15757	10 9.5	-
Mycobacterium tuberculosis	H37Ra	10 10.5	-
Mycoplasma pneumoniae	PI 1428	10 9.0	-
Neisseria elongata	NA3	10 5.0	-
Neisseria meningitidis	M2578	10 7.9	-
Pseudomonas aeruginosa	NA3	10 10.5	-
Staphylococcus epidermidis	NA3	10 10.5	-
Staphylococcus aureus	NA3	10 10.7	-
Streptococcus pneumoniae	249-06 (Thailand)	10 6.6	-
Streptococcus pyogenes	7790-06	10 7.5	-
Streptococcus salivarius2	DSM 13084	109 ng/ µL	-
Viruses	Strain	TCID50/mL	Invitrogen
SuperScript™
Enterovirus	Echo 6	10 6.9	-
Human Adenovirus, type 1	Ad.71	10 9.2	-
Human Adenovirus, type 7a	S-1058	10 7.1	-
Human Coronavirus virus2	OC43	50.4 ng/µL	-
Human Coronavirus virus2	299E	31.6 ng/µL	-
Human Rhinovirus A	1A	10 5.8	-
Human Parainfluenza 1 virus2	NA3	3.0 ng/ µL	-
Human Parainfluenza 2 virus	Greer	10 3.1	-
Human Parainfluenza 3 virus	C-243	10 7.9	-
Respiratory Syncytial virus	CH93-18b	10 6.8	-
Herpes Simplex Virus	KOS	10 8.4	-
Varicella-zoster Virus	AV92-3	10 4.4	-
Epstein Barr Virus2	B95-8	1.7 ng/µL	-
Measles Virus	Edmonston	10 5.2	-
Mumps Virus	Enders	10 7.2	-
Cytomegalovirus	AD-169	10 6.9	-

Table 8-21: Modified pdmInfA Assay exclusivity with respiratory viruses, bacteria, and yeast

1 Organism quantified by Infectious Forming Units (IFU)

² Organism quantified by spectrophotometry (ng/μL)

3 NA = not applicable

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IX. CLINICAL PERFORMANCE EVALUATION

Retrospective Study

The clinical performance of the modified InfA, pdmInfA, and pdmH1 assays was evaluated using residual human respiratory clinical specimens collected from patients during previous influenza seasons in the United States in 2011-12 and 2013-14 and tested with the CDC Human Influenza Real-Time RT-PCR Diagnostic Panel. The modified InfA assay was tested with a total of 62 positive and 50 negative specimens identified with the cleared CDC Human Influenza Real-Time RT-PCR Diagnostic Panel. The positive specimens consisted of 35 influenza A(H1N1)pdm09 and 27 influenza A(H3N2). The modified pdmInfA and pdmH1 assays were tested with a total of 35 positive specimens for influenza A(H1N1)pdm09 and 50 negative specimens. Testing was performed using both enzymes cleared for use with the CDC Human Influenza Real-Time RT-PCR Diagnostic Panel, one of the cleared extraction methods, and the Applied Biosystems 7500 Fast Dx. Results are summarized in Tables 8-22 through 8-25.

	Invitrogen SuperScriptTM		Quanta qScriptTM
Specimen Type	# of
Positives1	% Positive Agreement
(95% CI)	# of
Positives1	% Positive Agreement
(95% CI)
NPS, NS	51/51	100.0 (93.0-100.0)	51/51	100.0 (93.0-100.0)
NPS/TS	2/2	100.0 (34.2-100.0)	2/2	100.0 (34.2-100.0)
TS	4/4	100.0 (51.0-100.0)	4/4	100.0 (51.0-100.0)
NW	3/3	100.0 (43.9-100.0)	3/3	100.0 (43.9-100.0)
Sputum	1/1	100.0 (20.7-100.0)	1/1	100.0 (20.7-100.0)
BW	1/1	100.0 (20.7-100.0)	1/1	100.0 (20.7-100.0)

Table 8-22: Modified InfA Assay-Retrospective Positive Clinical Study Results

1Proportion of positive samples correctly identified versus the comparator.

Table 8-23: Modified InfA Assay-Retrospective Clinical Study Results

	Invitrogen SuperScript™		Quanta qScript™
Specimen Type	# of
Negatives1	% Negative Agreement
(95% CI)	# of
Negatives1	% Negative Agreement
(95% CI)
NPS	54/54	100.0 (93.4-100.0)	54/54	100.0 (93.4-100.0)

·Proportion of negative samples correctly identified versus the comparator.

23

	Invitrogen SuperScript™		Quanta qScript™
Specimen Type	# of
Positives1	% Positive Agreement
(95% CI)	# of
Positives1	% Positive Agreement
(95% CI)
BW	1/1	100.0 (20.7-100.0)	1/1	100.0 (20.7-100.0)
NPS, NS	28/28	100.0 (87.9-100.0)	28/28	100.0 (87.9-100.0)
NW	3/3	100.0 (43.9-100.0)	3/3	100.0 (43.9-100.0)
TS	3/3	100.00 (43.9-100.0)	3/3	100.00 (43.9-100.0)

Table 8-24: Modified pdmInfA and pdmH1 Assays-Retrospective Positive Clinical Study Results

1 Proportion of positive samples correctly identified versus the comparator.

Table 8-25: Modified pdmInfA and pdmH1 Assays-Retrospective Clinical Study Results

	Invitrogen SuperScript™		Quanta qScript™
Specimen Type	# of
Negatives1	% Negative Agreement
(95% CI)	# of
Negatives1	% Negative Agreement
(95% CI)
NPS	54/54	100.0 (93.4-100.0)	54/54	100.0 (93.4-100.0)

1Proportion of negative samples correctly identified versus the comparator.

CONCLUSION X.

The modification of the CDC Human Influenza Virus rRT-PCR Diagnostic Panel, Influenza A/B Typing Kit, Influenza A Subtyping Kit, and Influenza A/H5 Subtyping Kit to ensure comprehensive detection of influenza A viruses does not substantially change the device. Analytical and clinical data demonstrate that the performance of the device to detect influenza A viruses is accomplished with high positive and negative percent agreement in a manner substantially equivalent to the predicate. The change raises no new issues of safety and effectiveness and the indications for use remain the same.