(79 days)
No
The device description and performance studies focus on standard RT-PCR technology and do not mention any AI or ML components.
No
The device is a diagnostic tool used to detect and characterize influenza viruses, not to treat a condition or disease.
Yes
The text explicitly states in the "Intended Use / Indications for Use" section that it is a "real-time RT-PCR (rRT-PCR) assay" and is intended "for qualitative detection of influenza virus type A or B" and "For determination of the subtype of seasonal human influenza A viruses". This indicates that the device is used to detect and characterize specific biological markers to determine the presence or absence of a condition, which is the definition of a diagnostic device. The "Device Description" also clearly calls it a "Diagnostic Panel".
No
The device description explicitly states that the device consists of "oligonucleotide primers and dual-labeled hydrolysis (TaqMan®) probes," which are physical reagents, not software. The device is used in real-time RT-PCR assays on a specific hardware instrument (ABI 7500 Fast Dx), but the device itself includes physical components.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states "For qualitative detection of influenza virus type A or B from viral RNA in upper respiratory tract clinical specimens... and lower respiratory tract specimens... from human patients..." and "For determination of the subtype of seasonal human influenza A viruses... from viral RNA in upper respiratory tract clinical specimens... and lower respiratory tract specimens... from human patients...". These are all tests performed in vitro (outside the body) on clinical specimens to diagnose or characterize a disease.
- Device Description: The device description states it is used in "real-time RT-PCR assays (rRT-PCR) ... for the in vitro qualitative detection and characterization of human influenza viruses from viral RNA in respiratory specimens from patients presenting with influenza-like illness (ILI)." The phrase "in vitro" is explicitly used.
- Clinical Specimens: The device is intended for use with various types of respiratory tract clinical specimens (swabs, aspirates, washes, lavage, sputum, lung tissue), which are collected from the human body for diagnostic purposes.
- Diagnostic Purpose: The intended use clearly outlines the purpose of the device as a "Diagnostic Panel" for detecting and subtyping influenza viruses in patients with signs and symptoms of respiratory infection.
All of these points align with the definition of an In Vitro Diagnostic device, which is a medical device intended for use in the examination of specimens derived from the human body to provide information for diagnostic, monitoring, or compatibility purposes.
N/A
Intended Use / Indications for Use
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is intended for use in real-time RT-PCR (rRT-PCR) assays on an Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument in conjunction with clinical and epidemiological information:
- For qualitative detection of influenza virus type A or B 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.
- For determination of the subtype of seasonal human influenza A viruses as seasonal A/H1, A/H3, and/or A/H1pdm09 from viral RNA in upper respiratory tract clinical specimens (including NPS, NS, TS, NA, NW and NPS/TS) and lower respiratory tract specimens (including BAL, BW, TA, sputum and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
- 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 season when seasonal influenza viruses A/H1 and A/H3 were the predominant influenza A viruses in circulation and during a season when the A/H1pdm09 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 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 or co-infection with other viruses. The agent detected may not be the definite cause of disease.
Product codes (comma separated list FDA assigned to the subject device)
OOW, NSU, NXD, OEP
Device Description
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR assays (rRT-PCR) on the ABI 7500 Fast Dx Real-Time PCR Instrument. The device consists of oligonucleotide primers and dual-labeled hydrolysis (TaqMan®) probes to be used in rRT-PCR for the in vitro qualitative detection and characterization of human influenza viruses from viral RNA in respiratory specimens from patients presenting with influenza-like illness (ILI).
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is based on technology which is used in many molecular diagnostic assays. rRT-PCR assays are one-tube assays that first reverse-transcribe specific regions of RNA into cDNA copies. The cDNA then serves as a template for a polymerase chain reaction that utilizes thermocyclic heating and cooling of the reaction to logarithmically amplify a specific region of DNA. The probe anneals to a specific internal target sequence located between the target loci of the forward and reverse primers. During the extension phase of the PCR cycle, the 5' exonuclease activity of Taq polymerase degrades any probe molecules hybridized to amplified target sequence, causing the reporter dye to separate from the quencher dye, and generating a fluorescent signal. With each cycle, additional reporter dye molecules are cleaved from their respective probes, increasing the fluorescence intensity. Fluorescence intensity is monitored at each PCR cycle. The amplification of each target is reflected by a logarithmic increase in fluorescence in comparison to the background signal.
The intended change will add another enzyme kit option for users of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel. The new enzyme kit option, Quanta BioSciences qScript™ One-Step qRT-PCR Kit, Low ROX functions in the same manner as the current enzyme kit used with the CDC device.
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 [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)
Indicated Patient Age Range
0-16, 17-54, ≥ 55, Unknown (for study population)
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.
Clinical sites
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
A prospective clinical study was conducted during the 2011-2012 influenza season to compare the performance of the CDC Human Influenza rRT-PCR Diagnostic Panel using Quanta qScript™ and Invitrogen Superscript™. Residual material from a total of 1,002 respiratory specimens from patients who were symptomatic for influenza-like illness (ILI) was collected and tested at 6 clinical sites. Nine hundred thirty-one specimens were included in the data analysis after exclusion of samples with inconclusive results (42), technician or instrument error (25), or unspecified specimen type (4).
The study population and specimen types are summarized by age range and specimen type in Table 8-5.
NA=nasal aspirate, NW=nasal wash, NS=nasal swab, NPS=nasopharyngeal swab, NPS/TS=dual nasopharyngeal and throat swab, TS=throat swab, LR=lower respiratory specimens including bronchoalveolar lavage, bronchial wash, tracheal aspirate, sputum, or lung tissue.
Due to the absence of seasonal influenza A/H1N1, retrospective specimens from a previous clinical study conducted during the 2006-2007 influenza season were used to supplement the clinical evaluation. The study director used historical study results to select specimens containing varying concentrations of seasonal influenza A/H1N1. No negative specimens were selected since the prospective study provided sufficient numbers of negative specimens for comparing the specificity of the investigational enzyme with the A/H1 marker assay.
Due to the lack of available clinical specimens containing influenza A/H5N1, evaluation of the performance of the H5a and H5b primer and probe sets was addressed with an alternative approach. Samples for the retrospective study were prepared according to a method using a characterized and titered stock of influenza A/H5N1 virus and human A549 cells (Lednicky et al.). The stock virus was added to the A549 cell suspension in high, moderate, and low concentrations with 12 samples at each concentration. The low virus concentration was prepared to approximate the LOD of the A/H5 assay.
Fifty negative specimens were obtained from a previous clinical study conducted during the 2006-2007 influenza season wherein respiratory specimens were collected and stored under the same conditions and acceptance criteria as the prospective study.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Analytical Performance Evaluation - Limit of Detection Study (LOD):
Analytical sensitivity was demonstrated by determining the LOD of each primer and probe set in the CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel using Quanta qScript™ to demonstrate equivalency to the LOD using Invitrogen SuperScript™. Serial dilutions of two different influenza virus strains representing influenza B, A/H1, A/H3, A/H5 and A/H1pdm09 were tested to identify an end-point for detection using both enzymes. RNA was purified from each of the characterized viruses using one of the cleared extraction procedures. The LOD for each primer and probe set was calculated to indicate the range of the lowest detectable concentration of influenza virus (EID50 /mL or TCID30 /mL) at which ≥ 95% of all replicates tested positive.
Key results: In all cases, the resulting LOD was either the same or within one 5-fold dilution of the comparator (Invitrogen SuperScript™).
Analytical Sensitivity - Inclusivity Testing:
The inclusivity of the CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel using Quanta qScript™ was examined by testing two influenza viruses of each type and subtype against the corresponding target assay within the panel at concentrations at or near the established LOD. Virus RNA was isolated using one of the cleared extraction chemistries and serially diluted to approximately 102 EIDso /mL. The performance of Quanta qScript™ was compared to Invitrogen SuperSprimance testing each virus RNA preparation in triplicate with the CDC Human Influenza Virus RT-PCR Diagnostic Panel.
Key results: The results of the inclusivity testing with the CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel using Quanta qScript™ were 100% concordant with the predicate.
Clinical Performance Evaluation - Prospective Study Comparison:
Study type: Prospective clinical study.
Sample size: 931 specimens (from an initial 1,002 collected).
The performance of each assay within the panel, with the exception of the H5a and H5b assays, was demonstrated at each clinical site using both enzymes.
Clinical Performance Evaluation - Retrospective Study Comparison (A/H1):
Study type: Retrospective study.
Sample size: 30 positive specimens.
Key results: For A/H1, 30/30 (100.0%) positive agreement.
Clinical Performance Evaluation - Retrospective Study Comparison (A/H5):
Study type: Retrospective study using simulated samples.
Sample size: 12 samples at high, moderate, and low concentrations respectively.
Key results:
High Virus Concentration: 12/12 positive with Quanta qScript™ when Invitrogen SuperScript™ was positive.
Moderate Virus Concentration: 12/12 positive with Quanta qScript™ when Invitrogen SuperScript™ was positive.
Low Virus Concentration: 1/3 positive with Quanta qScript™ when Invitrogen SuperScript™ was positive; 8/9 inconclusive with Quanta qScript™ when Invitrogen SuperScript™ was inconclusive.
Clinical Performance Evaluation - Negative Specimens:
Sample size: Fifty negative specimens.
Key results: The results with the negative specimens showed 100% agreement with a 95% confidence interval of 92.9-100.0.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Prospective Study Comparison:
InfB: % Positive Agreement = 96.3 (95% CI: 89.5 – 98.7); % Negative Agreement = 100.0 (95% CI: 99.6 – 100.0)
A/H1: % Positive Agreement = NA; % Negative Agreement = 100.0 (95% CI: 99.6 – 100.0)
A/H3: % Positive Agreement = 98.8 (95% CI: 97.0 – 99.5); % Negative Agreement = 99.8 (95% CI: 99.1 – 100.0)
A/H1pdm09: % Positive Agreement = 100.0 (95% CI: 91.8 – 100.0); % Negative Agreement = 100.0 (95% CI: 99.6 – 100.0)
Retrospective Study Comparison (A/H1):
A/H1: % Positive Agreement = 100.0 (95% CI: 88.7 – 100.0); % Negative Agreement = NA
Negative Specimens:
Specificity: 100% agreement (95% confidence interval of 92.9-100.0).
Predicate Device(s)
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 866.3332 Reagents for detection of specific novel influenza A viruses.
(a)
Identification. Reagents for detection of specific novel influenza A viruses are devices that are intended for use in a nucleic acid amplification test to directly detect specific virus RNA in human respiratory specimens or viral cultures. Detection of specific virus RNA aids in the diagnosis of influenza caused by specific novel influenza A viruses in patients with clinical risk of infection with these viruses, and also aids in the presumptive laboratory identification of specific novel influenza A viruses to provide epidemiological information on influenza. These reagents include primers, probes, and specific influenza A virus controls.(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Reagents for Detection of Specific Novel Influenza A Viruses.” See § 866.1(e) for information on obtaining this document.
(2) The distribution of these devices is limited to laboratories with experienced personnel who have training in standardized molecular testing procedures and expertise in viral diagnosis, and appropriate biosafety equipment and containment.
0
510(k) Summary
Submitted By Centers for Disease Control and Prevention 1600 Clifton Road, NE Atlanta, GA 30333
Contact Person
CAPT Hye-Joo Kim, Pharm.D. Associate Director for Regulatory Affairs Office of the Director National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention 1600 Clifton Road, NE, MS C-18 Atlanta, GA 30333 (404) 639-4643 (office) (404) 639-1275 (fax) hek6@cdc.gov
Proprietary Name
CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel
Common or Usual Name
Human Influenza Virus Real-Time RT-PCR Diagnostic Panel
Regulatory Information
Classification Regulation Section: 866.3332- Reagents for detection of specific novel influenza A viruses Subsequent Regulation Sections: 866.3980- Respiratory viral panel multiplex nucleic acid assay 862.2570- Instrumentation for clinical multiplex test systems
Classification: Class II Classification Product Code: OOW Subsequent Product Codes: NSU, NXD, OEP Panel: Microbiology
Predicate Device
CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel (K111507)
Device Description
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR assays (rRT-PCR) on the ABI 7500 Fast Dx Real-Time PCR Instrument. The device consists of oligonucleotide primers and dual-labeled hydrolysis (TaqMan®) probes to be used in rRT-PCR for the in virro qualitative detection and characterization of human influenza viruses from viral RNA in respiratory specimens from patients presenting with influenza-like illness (ILI).
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is based on technology which is used in many molecular diagnostic assays. rRT-PCR assays are one-tube assays that first reversetranscribe specific regions of RNA into cDNA copies. The cDNA then serves as a template for a polymerase chain reaction that utilizes thermocyclic heating and cooling of the reaction to
MAY 2 2 2013
1
logarithmically amplify a specific region of DNA. The probe anneals to a specific internal target sequence located between the target loci of the forward and reverse primers. During the extension phase of the PCR cycle, the 5' exonuclease activity of Taq polymerase degrades any probe molecules hybridized to amplified target sequence, causing the reporter dye to separate from the quencher dye, and generating a fluorescent signal. With each cycle, additional reporter dye molecules are cleaved from their respective probes, increasing the fluorescence intensity. Fluorescence intensity is monitored at each PCR cycle. The amplification of each target is reflected by a logarithmic increase in fluorescence in comparison to the background signal.
Intended Use
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is intended for use in rRT-PCR assays on an ABI 7500 Fast Dx Real-Time PCR instrument 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.
- For determination of the subtype of seasonal human influenza A viruses as seasonal A/H1, ● A/H3, and/or A/H1pdm09 from viral RNA in upper respiratory tract clinical specimens (including NPS, NS, TS, NA, NW, and NPS/TS) and lower respiratory tract specimens (including BAL, BW, TA, sputum and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.
- 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 season when seasonal influenza viruses A/H1 and A/H3 were the predominant influenza A viruses in circulation and during a season when the A/H1pdm09 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 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 or co-infection with other viruses. The agent detected may not be the definite cause of disease.
2
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 3+ 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.
Indications for Use
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is intended for use in realtime RT-PCR (rRT-PCR) assays on an Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument in conjunction with clinical and epidemiological information:
- . For qualitative detection of influenza virus type A or B 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;
- For determination of the subtype of seasonal human influenza A viruses as seasonal A/H1, . A/H3, and/or A/H1pdm09 from viral RNA in upper respiratory tract clinical specimens (including NPS, NS, TS, NA, NW and NPS/TS) and lower respiratory tract specimens (including BAL, BW, TA, sputum and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
- 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. ●
Technological Characteristics
The changes proposed to the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel subject to this 510(k) do not change the device's design or technological attributes.
Substantial Equivalence Comparison
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel (K111507) will serve as the predicate for the intended change. See Table 8-1 for a detailed comparison.
3
Table 8-1: Device Comparison
| Table 8-1: Device Comparison | ||
|---|---|---|
| CDC Human Influenza Virus Real-Time RT-PCR | ||
| Diagnostic Panel (K111507) | CDC Human Influenza Virus Real-Time | |
| RT-PCR Diagnostic Panel (used with the | ||
| Quanta BioSciences qScript™ One-Step | ||
| qRT-PCR Kit, Low ROX) | ||
| The CDC Human Influenza Virus Real-Time RT-PCR | ||
| Diagnostic Panel is intended for use in Real-time RT-PCR | ||
| assays on an Applied Biosystems (ABI) 7500 Fast Dx Real- | ||
| Time PCR Instrument in conjunction with clinical and | ||
| epidemiological information: | ||
| • For qualitative detection of influenza virus type A or B | ||
| from viral RNA in upper respiratory tract clinical specimens | ||
| (including nasopharyngeal swabs, nasal swabs, throat swabs, | ||
| nasal aspirates, nasal washes and dual nasopharyngeal/throat | ||
| swabs), and lower respiratory tract specimens (including | ||
| bronchoalveolar lavages, bronchial washes, tracheal | ||
| aspirates, sputum, and lung tissue) from human patients with | ||
| signs and symptoms of respiratory infection and/or from | ||
| viral culture | ||
| Intended | ||
| Use | • For determination of the subtype of seasonal human | |
| influenza A viruses as seasonal A/H1, A/H3, and/or | ||
| A/H1pdm09 from viral RNA in upper respiratory tract | ||
| clinical specimens (including nasopharyngeal swabs, nasal | ||
| swabs, throat swabs, nasal aspirates, nasal washes and dual | ||
| nasopharyngeal/throat swabs), and lower respiratory tract | ||
| specimens (including bronchoalveolar lavages, bronchial | ||
| washes, tracheal aspirates, sputum, and lung tissue) from | ||
| human patients with signs and symptoms of respiratory | ||
| infection and/or from viral culture | Same | |
| • 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 | ||
| Organism | ||
| Detected | the circulating influenza viruses. | |
| Universal influenza A viruses (animal and human), Swine- | ||
| origin influenza A viruses, Influenza B viruses, and | ||
| Influenza A subtypes: seasonal A/H1, A/H3, A/H1pdm09, | ||
| and A/H5 | 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 and virus culture. | Same | |
| Nucleic Acid | ||
| Extraction | Yes | Same |
| Extraction | ||
| Method | • QIAamp® Viral RNA Mini Kit, Qiagen Inc. | |
| • MagNA Pure Compact -Total Nucleic Acid Kit, Roche | ||
| Applied Science | ||
| • MagNA Pure Compact – RNA Isolation Kit, Roche | ||
| Applied Science | ||
| • MagNA Pure LC - RNA Isolation Kit II, Roche Applied | ||
| Science | ||
| • Qiagen QIAcube with QIAamp® Viral RNA Mini Kit, | ||
| Qiagen Inc. | ||
| • NucliSENS® easyMAG®, bioMerieux | Same | |
| Enzyme | ||
| Master Mix | Invitrogen SuperScript™ III Platinum® One-Step | |
| Quantitative RT-PCR Kits (with or without ROX) | Invitrogen SuperScript™ III Platinum® | |
| One-Step Quantitative RT-PCR Kit (with | ||
| without ROX) | ||
| OR | ||
| Quanta BioSciences qScript™ One-Step | ||
| qRT-PCR Kit, Low ROX |
:
י
4
:
5
The intended change will add another enzyme kit option for users of the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel. The new enzyme kit option, Quanta BioSciences qScript™ One-Step qRT-PCR Kit, Low ROX functions in the same manner as the current enzyme kit used with the CDC device. A summary of the characteristics of the two enzyme kits is provided in Table 8-2 for comparison.
| | Quanta BioSciences qScript™ One-
Step qRT-PCR Kit, Low ROX | Invitrogen SuperScript™ III Platinum®
One-Step Quantitative RT-PCR Kit (with
or without ROX) |
|-------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| FDA Regulatory Status | RUO | RUO |
| Manufactured Under GMPs | No | No |
| Type of Kit | One-Step RT-PCR | One-Step RT-PCR |
| cDNA synthesis & PCR | Both reactions take place in one tube | Both reactions take place in one tube |
| cDNA Synthesis Temperature | 48°-50°C | 42°-60°C |
| Compatible Real-Time PCR | Multiple, including the ABI 7500 Fast | Multiple, including the ABI 7500 Fast Dx |
| Systems | Dx Real-Time PCR Instrument | Real-Time PCR Instrument |
| Reverse Transcriptase | Optimized 50X formulation of | Recombinant MMLV that has been |
| | recombinant MMLV reverse | engineered to reduce RNase H activity and |
| | transcriptase | provide increased thermal stability |
| Taq polymerase | AccuStart™ Taq DNA polymerase; a
recombinant Taq DNA polymerase
preparation which contains
monoclonal antibodies that bind to the
polymerase and keep it inactive before
PCR thermal cycling. Activated
AccuStart Taq DNA polymerase
possesses 5'→3' DNA polymerase
activity and a double-strand specific
5'→3' exonuclease. The polymerase
does not have 3'-exonuclease activity
and is free of any contaminating endo
or exonuclease activities. | Platinum® Taq DNA polymerase;
Recombinant Taq DNA polymerase that is
complexed with a proprietary antibody that
blocks polymerase activity at ambient
temperatures. Activity is restored during the
PCR denaturation step, providing a "hot start"
PCR that increases sensitivity, specificity, and
yield. |
| Storage & Stability | Stable for 1 year when stored in a | Components must be stored at -20°C. |
| | constant temperature freezer at -20°C. | Manufacturer has not established a shelf life
for the product. |
| Hybridization probe detection | Dual-labeled fluorogenic | Dual-labeled fluorogenic oligonucleotide |
| chemistries | oligonucleotide probes | probes |
Table 8-2: Enzyme Comparison
Each enzyme product name will hereafter be abbreviated; Quanta BioSciences qScript™ One-Step qRT-PCR Kit, Low ROX (Quanta qScript™) and Invitrogen SuperScript™ III Platinum® One-Step Quantitative RT-PCR Kit (with or without ROX) (Invitrogen SuperScript™).
Analytical Performance Evaluation
Analytical Sensitivity - Limit of Detection Study (LOD)
Analytical sensitivity was demonstrated by determining the LOD of each primer and probe set in the CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel using Quanta qScript™ to demonstrate equivalency to the LOD using Invitrogen SuperScript™. Serial dilutions of two different influenza virus strains representing influenza B, A/H1, A/H3, A/H5 and A/H1pdm09 were tested to identify an end-point for detection using both enzymes. RNA was purified from each of the characterized viruses using one of the cleared extraction procedures. The LOD for each primer and probe set was calculated to indicate the range of the lowest detectable concentration of influenza virus (EID50 /mL or TCID30 /mL) at which ≥ 95% of all replicates tested positive. The lowest concentration of influenza virus detected determined the end-point concentration where both the type and subtype primer and probe sets had uniform detection. If the two endpoints differed in concentration, the lowest
6
concentration where the endpoints had uniform detection was reported as the LOD. In all cases, the resulting LOD was either the same or within one 5-fold dilution of the comparator (Invitrogen SuperScript™). The results are summarized in Table 8-3.
| Influenza Virus
| Type/Subtype | LOD (EID50/mL) | |||||
|---|---|---|---|---|---|---|
| Influenza Virus | Invitrogen SuperScript™ | Quanta q Script™ | ||||
| A/H1N1 | A/Brisbane/59/2007 | 1 02.3 | 102.3 | |||
| A/Fujian Gulou/1896/2009 | 1 02.7 | |||||
| 1012 | ||||||
| 102.1 | ||||||
| 1 02.8 | ||||||
| 1 02.8 | ||||||
| 1012 | ||||||
| 1017 | ||||||
| 1 02.1 | ||||||
| 1014 | 1 02.7 | |||||
| A/H1pdm09 | A/California/07/2009 | 1 ()3.0 | ||||
| A/South Carolina/2/2010 | 1 02.8 | |||||
| A/H3N2 | A/Perth/16/2009 | 1 02.8 | ||||
| A/Victoria/361/2011 | 1 02.8 | |||||
| A/H5N1 | A/Vietnam/1203/2004- | |||||
| PR8/CDC-RG | 101.2 | |||||
| A/Anhui/01/2005-PR8-IBCDC- | ||||||
| RG6 | 102.4 | |||||
| B | B/Wisconsin/01/2010 | 1 02.8 | ||||
| B/Nevada/01/2011 | 100.7 |
Table 8-3: LOD Summary Comparison Table
Analytical Sensitivity - Inclusivity Testing
The inclusivity of the CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel using Quanta qScript™ was examined by testing two influenza viruses of each type and subtype against the corresponding target assay within the panel at concentrations at or near the established LOD, Virus RNA was isolated using one of the cleared extraction chemistries and serially diluted to approximately 102 EIDso /mL. The performance of Quanta qScript™ was compared to Invitrogen SuperSprimance testing each virus RNA preparation in triplicate with the CDC Human Influenza Virus RT-PCR Diagnostic Panel.
Table 8-4 summarizes the results of the inclusivity testing of the CDC Human Influenza Virus Realtime RT-PCR Diagnostic Panel with both the investigational (Quanta qScript™) and comparator (Invitrogen SuperScript™) enzyme systems. The average Ct value of the three replicates is aresented for each assay.
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.
| Virus
Type/Subtype | Strain Designation | Titer
(EID50/mL) | InfA (Avg Ct) | | H1 (Avg Ct) | | H3 (Avg Ct) | | pdm InfA (Avg Ct) | | H1pdm (Avg Ct) | | H5a (Avg Ct) | | H5b (Avg Ct) | | B (Avg Ct) | |
|-----------------------|-------------------------------------|---------------------|---------------|------|-------------|------|-------------|------|-------------------|------|----------------|------|--------------|------|--------------|------|------------|------|
| | | | INV2 | QUA2 | INV | QUA | INV | QUA | INV | QUA | INV | QUA | INV | QUA | INV | QUA | INV | QUA |
| A/H1N1 | A/Brisbane/59/07 | 102.4 | 34.3 | 34.1 | 34.5 | 34.9 | | | | | | | | | | | | |
| A/H1N1 | A/Fujian
Gulou/1896/2009 | 102.7 | 33.8 | 32.8 | 33.3 | 33.3 | | | | | | | | | | | | |
| A/H3N2 | A/Perth/16/2009 | 102.8 | 33.7 | 35.0 | | | 35.5 | 35.1 | | | | | | | | | | |
| A/H3N2 | A/Rhode
Island/01/2010 | 102.9 | 30.2 | 29.9 | | | 34.3 | 30.3 | | | | | | | | | | |
| A/H1N1pdm09 | A/California/07/09 | 102.3 | 33.0 | 33.0 | | | | | 31.1 | 35.8 | 34.5 | 36.5 | | | | | | |
| A/H1N1pdm09 | A/South
Carolina/2/2010 | 102.1 | 35.7 | 32.6 | | | | | 34.5 | 33.5 | 34.4 | 36.1 | | | | | | |
| A/H5N1 | A/Anhui/01/2005 -
PR8-IBCDC-RG6 | 102.5 | 34.4 | 32.5 | | | | | | | | | 33.9 | 34.0 | 37.9 | 34.2 | | |
| A/H5N1 | A/Vietnam/1203/2004
- PR8/CDC-RG | 102.0 | 31.3 | 29.7 | | | | | | | | | 34.9 | 33.6 | 34.3 | 35.4 | | |
| B | B/Texas/06/2011 | 102.9 | | | | | | | | | | | | | | | 35.0 | 32.2 |
| B | B/Brisbane/60/2008 | 102.5 | | | | | | | | | | | | | | | 32.9 | 31.9 |
2 INV = Invitrogen SuperScript™; QUA = Quanta qScript™
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8
The results of the inclusivity testing with the CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel using Quanta qScript™ were 100% concordant with the predicate.
Clinical Performance Evaluation
A prospective clinical study was conducted during the 2011-2012 influenza season to compare the performance of the CDC Human Influenza rRT-PCR Diagnostic Panel using Quanta qScript™ and Invitrogen Superscript™. Residual material from a total of 1,002 respiratory specimens from patients who were symptomatic for influenza-like illness (IL)) was collected and tested at 6 clinical sites. Nine hundred thirty-one specimens were included in the data analysis after exclusion of samples with inconclusive results (42), technician or instrument error (25), or unspecified specimen type (4).
The study population and specimen types are summarized by age range and specimen type in Table 8-5.
| Number of Clinical Specimens by Type | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age Range | NA | NW | NS | NPS | NPS/TS | TS | LR | Unknown |
| 0-16 | 10 | 15 | 51 | 337 | 14 | 2 | 3 | 2 |
| 17-54 | 2 | 6 | 37 | 263 | 14 | 2 | 2 | 2 |
| ≥ 55 | 1 | 2 | 25 | 175 | 9 | 4 | 0 | 0 |
| Unknown | 0 | 1 | 0 | 23 | 0 | 0 | 0 | 0 |
| Totals | 13 | 24 | 113 | 798 | 37 | 8 | 5 | 4 |
Table 8-5: Study Population and Specimen Type Summary
NA=nasal aspirate, NW=nasal wash, NS=nasal swab, NPS=nasopharyngeal swab, NPS/TS=dual nasopharyngeal and throat swab, TS=throat swab, LR=lower respiratory specimens including bronchoalveolar lavage, bronchial wash, tracheal aspirate, sputum, or lung tissue,
Expected Values
During February 25, 2012 to May 19, 2012, World Health Organization and National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories in the United States tested 47,281 respiratory specimens for influenza viruses. Of these. 9,415 (19.9%) were positive: 85% of the positive specimens were positive for influenza A viruses and 15% were positive for influenza B viruses. Among the 5,071 influenza A viruses for which subtyping was performed, 3,680 (72.6%) were influenza A/H3 viruses and 1,391 (27.4%) were 2009 H1N1 influenza viruses.
Prospective Study Comparison
The performance of each assay within the panel, with the exception of the H5a and H5b assays, was demonstrated at each clinical site using both enzymes. The results from the prospective study are summarized in Table 8-6 showing the percent sensitivity or specificity with the two-sided 95% confidence interval.
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| Assay Result | # of Positives1 | % Positive
Agreement (95% CI) | # of
Negatives1 | % Negative
Agreement (95% CI) |
|--------------|-----------------|----------------------------------|--------------------|----------------------------------|
| InfB | 77/80 | 96.3 (89.5 – 98.7) | 851/851 | 100.0 (99.6 – 100.0) |
| A/H1 | 0 | NA2 | 931/931 | 100.0 (99.6 – 100.0) |
| A/H3 | 331/335 | 98.8 (97.0 – 99.5) | 595/596 | 99.8 (99.1 – 100.0) |
| A/H1pdm09 | 43/43 | 100.0 (91.8 – 100.0) | 888/888 | 100.0 (99.6 – 100.0) |
Table 8-6: Summary Comparison
Proportion of true positives or true negatives correctly identified versus the comparator 2NA = not applicable
Retrospective Study Comparison
Due to the absence of seasonal influenza A/H1N1, retrospective specimens from a previous clinical study conducted during the 2006-2007 influenza season were used to supplement the clinical evaluation. The study director used historical study results to select specimens containing varying concentrations of seasonal influenza A/H1N1. No negative specimens were selected since the prospective study provided sufficient numbers of negative specimens for comparing the specificity of the investigational enzyme with the A/H1 marker assay. The results of the retrospective specimen testing are summarized in Table 8-7.
Table 8-7: A/H1 Comparison
| Assay Result | # of Positives¹ | % Positive Agreement
(95% CI) | # of Negatives¹ | % Negative Agreement
(95% CI) |
|--------------|-----------------|----------------------------------|-----------------|----------------------------------|
| A/H1 | 30/30 | 100.0 (88.7 – 100.0) | 0 | NA² |
1Proportion of true positives or true negatives correctly identified versus the comparator 2NA = not applicable
Due to the lack of available clinical specimens containing influenza A/H5N1, evaluation of the performance of the H5a and H5b primer and probe sets was addressed with an alternative approach. Samples for the retrospective study were prepared according to a method using a characterized and titered stock of influenza A/H5N1 virus and human A549 cells (Lednicky et al.). The stock virus was added to the A549 cell suspension in high, moderate, and low concentrations with 12 samples at each concentration. The low virus concentration was prepared to approximate the LOD of the A/H5 assay. Test results of simulated A/H5N1 samples are summarized in Tables 8-8 to 8-10.
Table 8-8: A/H5 Comparison High Virus Concentration
| Invitrogen SuperScript™ | |||||
|---|---|---|---|---|---|
| Positive | Negative | Inconclusive | Total | ||
| Quanta | |||||
| qScript™ | Positive | 12 | 0 | 0 | 12 |
| Negative | 0 | 0 | 0 | 0 | |
| Inconclusive | 0 | 0 | 0 | 0 | |
| Total | 12 | 0 | 0 | 12 |
10
| Invitrogen SuperScript™ | |||||
|---|---|---|---|---|---|
| Positive | Negative | Inconclusive | Total | ||
| Quanta | |||||
| qScript™ | Positive | 12 | 0 | 0 | 12 |
| Negative | 0 | 0 | 0 | 0 | |
| Inconclusive | 0 | 0 | 0 | 0 | |
| Total | 12 | 0 | 0 | 12 |
Table 8-9: A/H5 Comparison Moderate Virus Concentration
Table 8-10: A/H5 Comparison Low Virus Concentration
| Invitrogen SuperScript™ | |||||
|---|---|---|---|---|---|
| Positive | Negative | Inconclusive | Total | ||
| Quanta | |||||
| qScript™ | Positive | 1 | 0 | 1 | 2 |
| Negative | 0 | 0 | 0 | 0 | |
| Inconclusive | 2 | 0 | 8 | 10 | |
| Total | 3 | 0 | 9 | 12 |
Fifty negative specimens were obtained from a previous clinical study conducted during the 2006-2007 influenza season wherein respiratory specimens were collected and stored under the same conditions and acceptance criteria as the prospective study. The results with the negative specimens showed 100% agreement with a 95% confidence interval of 92.9-100.0.
Conclusion
Analytical and clinical data demonstrate that the performance of the CDC Human Influenza Virus rRT-PCR Diagnostic Panel with Quanta qScript™ is substantially equivalent to that with Invitrogen SuperscriptTM.
References
Lednicky JA, Villanueva JM, Burke SA, Shively R, Shaw MW, Daniels DE, Hamilton SB, Donis RO. 2010. Validation of a method for preparing influenza H5N1 simulated samples, J Virol Methods. 2010 Aug;167(2):125-31.
11
DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/11/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo is circular and contains the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - (USA)" around the top half of the circle. Inside the circle is an abstract symbol that resembles an eagle or bird-like figure.
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
May 22,2013
HYE-JOO KIM ASSOCIATE DIRECTOR FOR REGULATORY AFFAIRS CENTERS FOR DISEASE CONTROL AND PREVENTION 1600 CLIFTON RD. N.E. MS-C18 ATLANTA GA 30333
Re: K130551
Trade/Device Name: CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel Regulation Number: 21 CFR 866.3332
Regulation Name: Reagents for detection of specific novel influenza A viruses Regulatory Class: II Product Code: OQW, NSU, NXD, OEP Dated: March 01, 2013 Received: March 04, 2013
Dear Dr. Kim:
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, de nees mat have boon require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The r ou may, aterer, many 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 i lease of derised that i Drivination that your device complies with other requirements of the Act that i Drederal statutes and regulations administered by other Federal agencies. You must or any I with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements modified the reality systems (QS) regulation (21 CFR Part 820); and if applicable, the as section noduct radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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Page 2-Dr. Kim
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm.
Sincerely vours.
Sally A.Hojvat -S
Sally Hoivat Director, Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
13
Intended Use
510(k) Number (if known): K130551
Device Name: CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel
Intended Use:
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is intended for use in real-time RT-PCR (rRT-PCR) assays on an Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument in conjunction with clinical and epidemiological information:
- For qualitative detection of influenza virus type A or B 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:
- For determination of the subtype of seasonal human influenza A viruses as seasonal . A/H1, A/H3, and/or A/H1pdm09 from viral RNA in upper respiratory tract clinical specimens (including NPS, NS, TS, NA, NW and NPS/TS) and lower respiratory tract specimens (including BAL, BW, TA, sputum and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
- 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 season when seasonal influenza viruses A/H1 and A/H3 were the predominant influenza A viruses in circulation and during a season when the A/H I 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 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 or co-infection with other viruses. The agent detected may not be the definite cause of disease.
Page 1 of 2
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If infection with a novel influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted unless a BSL 3+ 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.
Prescription Use x (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 807 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH; Office of In Vitro Diagnostics and Radiological Health (OIR)
Tamara V. Feldblyum -S 2013.05.21 14:36:39 -04'00'