(152 days)
The AVantage™ A/H5N1 Flu Test is intended for the in vitro qualitative detection of influenza A/H5N1 virus directly from symptomatic patient nasal or throat swab specimens or in viral cultures for the presumptive laboratory identification of influenza A/H5N1 virus.
Results from testing with the AVantage™ A/H5N1 Flu Test should be used in conjunction with other laboratory testing and clinical and epidemiological risk factors for the presumptive identification of patients infected with Influenza H5N1 virus. AVantage™ A/H5N1 Flu Test is intended as a Prescription Use device.
Testing 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 either directly from patient specimens or from viral 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.
The AVantage™ A/H5N1 Flu Test is a rapid diagnostic device that detects the presence of the H5N1 subtype from throat swabs or nose swabs collected from patients with flu symptoms, or in viral cultures for the presumptive laboratory identification of influenza H5N1 virus. It is an immunoassay, using a combination of monoclonal antibodies and recombinant proteins containing PDZ domains to capture and detect NS1.
The AVantage™ A/H5N1 Flu Test begins with the extraction of the influenza A H5N1 NS1 viral antigen. The patient sample is prepared by delivering the swab to the transport medium. Sample is then transferred to the lyophilized Lysis Buffer vial (Reagent A) which contains a lysing agent where cells are lysed, releasing intracellular proteins. Next, the Loading Buffer (Reagent B) is added to condition the sample. The sample is then added to the Detector (Reagent C), which contains lyophilized colloidal gold-conjugated monoclonal anti-influenza A antibodies that recognize a broad range of influenza A subtypes and strains. After re-suspension of the antibodies, the solution is added to the sample well of the AVantage™ A/H5N1 Flu Test cassette, where NS1 in the specimen will react with reagents on the membrane of the cassette. The results are read visually by observing the presence or absence of lines on the membrane at the indicated locations.
The Arbor Vita Corporation AVantage™ A/H5N1 Flu Test is a rapid diagnostic device intended for the in vitro qualitative detection of influenza A/H5N1 virus.
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Positive Agreement | High positive agreement with the gold standard. | 100% Positive Agreement with viral culture (95% CI = 86.2%, 100%) for 24 H5N1-positive viral culture samples. |
| Negative Agreement | High negative agreement with the gold standard. | 100% Negative Agreement with viral culture (95% CI = 43.8%, 100%) for 3 H5N1-negative viral culture samples. 100% Specificity (95%CI = 99.57%; 100%) in a prospective clinical study with 895 symptomatic subjects (no true H5N1 positives by gold standard). |
| Cross-Reactivity | No cross-reactivity with common bacterial and viral isolates. | No cross-reactivity observed with 21 bacterial isolates (at ~1.5x10^8 cfu/mL) and 28 viral isolates (at 10^4 - 10^7 TCID50/mL or 10^2 -10^4 CEID50/mL), including seasonal influenza A and B strains. |
| Interference | No inhibitory effect from common substances. | No inhibitory effect on assay performance from whole blood, mucin, mouthwash, dextromethorphan, acetaminophen, throat lozenges, oxymetazoline, erythromycin, nasal corticosteroids, zanamivir, phenylephrine, diphenhydramine, Luffa operculata/Galphimia glauca/Histaminum hydrochloricum/sulfur (Zicam), and rimantadine. |
| Reproducibility | Consistent performance across days, sites, and operators. | Demonstrated reproducible performance across five days, three sites, and two operators for negative, high negative, moderate positive, and high positive recombinant protein H5N1 NS1 samples. |
| Precision (Repeatability) | Consistent results for various analyte concentrations. | Consistent performance over twelve consecutive days, with high negative sample yielding 8% positive, low positive 96% positive, and moderate positive 100% positive results for recombinant H5N1 NS1 protein. |
2. Sample Sizes and Data Provenance
- Test Set (Sensitivity/Positive Agreement): 24 H5N1-positive viral culture specimens and 3 H5N1-negative samples. These were isolates from infected individuals, collected in the course of WHO/NAMRU-3 pandemic surveillance and response activities. All isolates were from Clade 2.2. The study was conducted in BSL-3 labs at NAMRU-3. This data is retrospective regarding the collection of the isolates but prospective for the testing with the AVantage™ device. The country of origin for the isolates is not explicitly stated beyond being "human-derived H5N1 viral culture specimens" from WHO/NAMRU-3 activities.
- Test Set (Specificity/Negative Agreement):
- 3 H5N1-negative viral culture samples (as mentioned above).
- A prospective clinical study with 464 symptomatic subjects (895 "samples" mentioned in the table combining different influenza types) during the 2007-2008 flu season. Subjects were recruited from four clinics at three sites. The provenance is likely the US, given the reference to the Naval Health Research Center (NHRC) and "U.S. Department of Health and Human Services (DHHS)".
- Test Set (Cross-Reactivity): 21 bacterial isolates and 28 viral isolates. Details on provenance are not provided, but they represent common pathogens.
- Test Set (Interference): Various common substances (e.g., whole blood, mucin, OTC medications). Details on provenance are not provided.
- Test Set (Reproducibility/Precision): Recombinant H5N1 NS1 protein samples (negative, high negative, moderate positive, high positive). Testing was conducted at three sites (intra-laboratory and inter-laboratory).
3. Number of Experts and Qualifications for Ground Truth
- Sensitivity Study (Viral Culture): The true H5N1 status of the viral culture samples was verified by HAI (Hemagglutination Inhibition Assay). The document specifies "Study personnel were blinded to the true H5N1 status" and "The reference method used to verify H5N1-positive status of the viral culture samples was HAI." It does not explicitly state the number or specific qualifications of experts involved in performing or interpreting the HAI, but HAI is a standard laboratory method, implying trained laboratory personnel would have conducted it.
- Specificity Study (Clinical Samples): Sample status was confirmed by IFA (Immunofluorescence Assay) and HAI. Similar to the sensitivity study, the details on the number and qualifications of experts for these reference methods are not provided, but they would be performed by trained laboratory personnel.
4. Adjudication Method for the Test Set
The document does not explicitly describe an adjudication method like 2+1 or 3+1. For the viral culture studies, the "gold standard" (HAI) was used, and for the clinical specificity study, IFA and HAI were used. The results of the AVantage™ test were compared directly against these "gold standard" or reference methods. The study personnel were blinded to the true H5N1 status during device testing. This suggests a direct comparison rather than an adjudication process involving multiple readers interpreting the device results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was done. The document does not mention human readers improving with or without AI assistance, as this is a diagnostic test, not an AI-assisted diagnostic.
6. Standalone Performance Study
Yes, a standalone performance study was conducted. The sensitivity and specificity results presented are for the AVantage™ A/H5N1 Flu Test algorithm only, without human-in-the-loop performance influencing the reported metrics. The results are read visually by observing the presence or absence of lines on the membrane, implying human interpretation of the device's output, but the reported performance metrics are of the device itself against established reference methods.
7. Type of Ground Truth Used
- Sensitivity: Viral culture results confirmed by HAI (Hemagglutination Inhibition Assay).
- Specificity (Clinical): Clinical sample status confirmed by IFA (Immunofluorescence Assay) and HAI.
- Cross-Reactivity and Interference: Established concentrations of bacterial, viral, and chemical substances.
8. Sample Size for the Training Set
The document does not specify a separate "training set" in the context of machine learning model development. This device is an immunoassay (lateral flow test) and does not appear to be an AI/machine learning-based device that would require a distinct training set in that sense. The "training" of the device is inherent in its design and manufacturing.
9. How the Ground Truth for the Training Set Was Established
As this is an immunoassay, not an AI/ML device, the concept of a "training set" and establishing its ground truth in the context of model development is not directly applicable. The device's components (monoclonal antibodies, recombinant proteins) are developed and optimized through laboratory research and development, which would involve internal testing against known positive and negative samples, similar to how the non-clinical studies described (e.g., limit of detection, cross-reactivity) might be conducted during the R&D phase to refine the assay's performance.
{0}------------------------------------------------
.
Arbor Vita Corporation AVantage™ A/H5N1 Flu Test Pre-market Notification
Ko83278
APR - 8 2009
SECTION 7
510(k) SUMMARY
Section 7: 510(k) Summary
Arbor Vita Corporation, Confidential
.
:
{1}------------------------------------------------
Arbor Vita Corporation AVantage™ A/H5N1 Flu Test Pre-market Notification
SECTION 7 510(k) SUMMARY
.
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is K083278.
AVantage™ A/H5N1 Flu Test 807.92 (a)(1): Name:
772 Lucerne Drive Address: Sunnyvale, CA 94085
Phone: 408-585-3909 FAX: 408-585-3901 Dr. Linda McAllister Contact:
807,92 (a)(2): Device name- trade name and common name, and classification
| Trade name: | AVantage™A/H5N1 Flu Test |
|---|---|
| Common Name: | Reagents for the qualitative detection of influenza virus subtype H5N1 |
CFR §21.866.3332 Classification:
807.92 (a)(3); Identification of the legally marketed predicate device
The AVantage™ A/H5N1 Flu Test is substantially equivalent to two previously cleared products, namely the CDC Human Influenza Virus Real-time RT-PCR Detection and Characterization Panel (Centers for Disease Control and Prevention, Atlanta, GA) based on intended use and cleared under K080570, and the QuickVue Influenza A+B Test (Quidel Corporation, San Diego, CA), based on technological characteristics and cleared under K053146.
.............................................................................................................
Section 7: 510(k) Summary
Arbor Vita Corporation, Confidential
{2}------------------------------------------------
807.92 (a)(4): Device Description
The AVantage™ A/H5N1 Flu Test is a rapid diagnostic device that detects the presence of the H5N1 subtype from throat swabs or nose swabs collected from patients with flu symptoms, or in viral cultures for the presumptive laboratory identification of influenza H5N1 virus. It is an immunoassay, using a combination of monoclonal antibodies and recombinant proteins containing PDZ domains to capture and detect NS1.
The AVantage™ A/H5N1 Flu Test begins with the extraction of the influenza A H5N1 NS1 viral antigen. The patient sample is prepared by delivering the swab to the transport medium. Sample is then transferred to the lyophilized Lysis Buffer vial (Reagent A) which contains a lysing agent where cells are lysed, releasing intracellular proteins. Next, the Loading Buffer (Reagent B) is added to condition the sample. The sample is then added to the Detector (Reagent C), which contains lyophilized colloidal gold-conjugated monoclonal anti-influenza A antibodies that recognize a broad range of influenza A subtypes and strains. After re-suspension of the antibodies, the solution is added to the sample well of the AVantage™ A/H5N1 Flu Test cassette, where NS1 in the specimen will react with reagents on the membrane of the cassette. The results are read visually by observing the presence or absence of lines on the membrane at the indicated locations.
807.92 (a)(5): Intended Use
The AVantage™ A/H5N1 Flu Test is intended for the in vitro qualitative detection of influenza A/H5N1 virus directly from symptomatic patient nasal or throat swab specimens or in viral cultures for the presumptive laboratory identification of influenza A/H5N1 virus.
Results from testing with the AVantage™ A/H5N1 Flu Test should be used in conjunction with other laboratory testing and clinical and epidemiological risk factors for the presumptive identification of patients infected with Influenza H5N1 virus. AVantage™ A/H5N1 Flu Test is intended as a Prescription Use device.
Testing 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 either directly from patient specimens or from viral 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.
{3}------------------------------------------------
April ',
1
Arbor Vita Corporation
AVantage™ A/HSN1 Flu Test
Pre-market Notification
807.92 (a)(6): Technological Similarities and Differences to the Predicat
| CHARACTERISTIC | Arbor Vita AVantageTM A/H5N1Flu Test | CDC Human Influenza Virus Real-timeRT-PCR Detection andCharacterization Pannel(rRT-PCR Flu Panel) K080570 | Quidel QuickVue Influenza A+B Test)K053146 | |
|---|---|---|---|---|
| Intended Use | The AVantageTM A/H5N1 Flu Test isintended for the in vitro qualitativedetection of Influenza H5N1 virusdirectly from symptomatic patient nasalor throat swab specimens or in viralculture for the presumptive laboratoryidentification of Influenza H5N1 virus.Results from testing with theAVantageTM A/H5N1 Flu Test shouldbe used in conjunction with otherlaboratory testing and clinical andepidemiological risk factors for thepresumptive identification of patientsinfected with Influenza H5N1 virus.AVantageTM A/H5N1 Flu Test isintended as a Prescription Use device.Testing should not be performed unlessthe patient meets the most current U.S.Department of Health and HumanServices (DHHS) clinical andepidemiologic criteria for testingsuspect A/H5 specimens. Thedefinitive identification of influenzaA/H5 (Asian lineage) either directlyfrom patient specimens or from viralcultures requires additional laboratorytesting, along with clinical andepidemiological assessment inconsultation with national influenzasurveillance experts.Negative results do not preclude | The test is intended for use in real-time RT-PCR assays on an ABI 7500 Fast Dx Real-Time PCR instrument in conjunction withclinical and epidemiological information:1) for qualitative detection of influenzavirus type A or B in symptomaticpatients from viral RNA innasopharyngeal and/or nasal swabspecimens,2) for determination of the subtype ofseasonal human influenza A virus, asseasonal A/H1 or A/H3, if present, fromviral RNA in nasopharyngeal and/ornasal swab specimens,3) for presumptive identification of virus inpatients who may be infected withinfluenza A/H5 (Asian lineage) fromviral RNA in human respiratoryspecimens and viral culture inconjunction with clinical andepidemiological risk factors4) to provide epidemiologic information forsurveillance for influenza viruses.The definitive identification of influenza A/H5(Asian lineage) either directly from patientspecimens or from virus cultures requiresadditional laboratory testing, along withclinical and epidemiological assessment inconsultation with national influenzasurveillance experts. Negative results do notpreclude influenza virus infection and shouldnot be used as the sole basis for treatment orother management decisions.All users, analysts and any person reporting | Rapid qualitative detection of influenza type Aand type B antigens directly from nasal swab,nasal wash and/or nasal aspirate specimens.Intended for uses as an aid in the rapid diagnosisof acute influenza virus infections. Negativeresults should be confirmed by culture. |
Section 7: 510(k) Summary
Arbor Vita Corporation, Confidentia
{4}------------------------------------------------
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ |
|---|
| pri |
| ಳ |
Arbor Vita Corporation
AVantage™ AVHSNI Flu Test
| CHARACTERISTIC | Pre-market Notification | ||
|---|---|---|---|
| Arbor Vita AVantage™ A/H5N1Flu Test | CDC Human Influenza Virus Real-timeRT-PCR Detection andCharacterization Pannel(rRT-PCR Flu Panel) K080570 | Quidel QuickVue Influenza A+B Test)K053146 | |
| Indications forUse/Limitations | influenza virus infection and should notbe used as the sole basis for treatmentor other patient management decisions. | trained to perform and interpret the resultsfrom this procedure by a CDC instructor ordesignee prior to use. | For In Vitro diagnostic use |
| For prescription use onlyThe AVantage™ A/H5N1 Flu Test isindicated for use only in highcomplexity laboratories. | (Same as Intended Use)Special instrument required is the ABI 7500Fast Dx Real-Time PCR instrument. Thespecial condition for use is for prescription useonly. | ||
| Sample | Throat or nasal swab, or virus culture. | Nasopharyngeal or nasal swab respiratoryspecimens, or virus culture | Nasal swab, nasal wash and/or nasal aspirate |
| Sample Preparation | M4 viral transport media and swabssupplied by REMEL should be used forsample collection. Swabs are applied tothe throat or nose, and rotation andslight pressure are applied to collectspecimen. The specimen in the swab isthen placed in 3 mL M4 Viral TransportMedia (REMEL). | Using reagents and specific lots recommendedby CDC, RNA is extracted and purified fromthe cellular specimen matrix. cDNA isproduced from RNA with RT-PCR reaction.Fluorescently labeled probes anneal toamplified DNA fragments and the fluorescentsignal is monitored by the ABI 7500 Fast Dxinstrument during each PCR cycle.Amplification of target is recorded as increaseof fluorescence over time in comparison of abackground signal. | Nasal swabs are applied to nostril with mostsecretion, and pressed against the nasal wall withrotation. The material from the swab is thenextracted with reagents supplied in the kit.Nasal aspirates/wash are collected by instillingwith a syringe 2.5 ml sterile normal saline intoone nostril of the patient. Collect fluid into a dryspecimen container. Swabs are supplied in thekit. |
| Methodology | Two step test (gold-mAb detector driedin a tube). Test is based onimmunochromatographic principles. | RNA is extracted and purified from thecellular specimen matrix. Using reversetranscription, cDNA is made from the RNA.The cDNA is amplified, and an increasingfluorescent signal is produced through eachPCR cycle by fluorescently labeled probes thatanneal to amplified DNA fragments. Thefluorescence intensity is monitored by the ABI7500 Fast Dx instrument during each cycle. | One step test (latex-mAb detector dried in a padwithin a dipstick). Test is based onimmunochromatographic principles. |
| Quality Control | Each kit contains a positive control(external quality control) that must besuccessfully run before using the kit.Testing with the negative control (M4Viral Transport Media (not included inthe kit) must also be performed beforeusing the kit. When running the test, theappearance of a red Control Line ineach test indicates proper function of | The kit contains several controls:The Internal positive control, the humanRNASE P (RP) primer and probe set detectshuman RP and ensures that adequate isolationof nucleic acid resulted from extraction fromthe specimen as well as overall instrumentperformance.The Human Specimen Control (HSC) is a | Each kit contains external positive and negativecontrol swabs supplied in the kit. Controlsshould be tested with each new lot or shipmentof materials. The test also contains built-inprocedural control features. The appearance of ablue procedural Control Line provides threeforms of positive internal control bydemonstrating:, 2) capillary flow occurred, 3)functional integrity of the Test Strip was |
| Arbor Vita CorporationAVantage™ A/H5N1 Flu TestPre-market Notification | |||
| Arbor Vita AVantage™ A/H5N1 CDC Human Influenza Virus Real-timeFlu Test | Quidel QuickVue Influenza A+B Test)K053146 | ||
| the buffer reagents, capillary flow, andfunctional integrity. If the control linedoes not appear, the test is consideredInvalid. | maintained. If the Control Line does not showup, the test is considered invalid. | ||
| (rRT-PCR Flu Panel) K080570noninfectious cultured human cell materialthat demonstrates successful recovery of RNAas well as extraction reagent integrity.The Seasonal Influenza Virus Control (SIVC)consists of three different influenza virusesrepresenting A/H1, A/H3 and Influenza Bviruses and cultured human cells. The SIVCcontrol demonstrates that the master mix andprimer probe sets are functioning properly.The influenza Virus A/H5N1 Positive Control(H5VC) is a genetically modified reassortanthuman influenza virus (BSL2 category) andcultured human cells. This controldemonstrates that the master mix and primerand probe sets for Influenza A, InfluenzaA/H5 (H5a, H5b), and RP are functioningproperly. | |||
| Visual | Real Time Fluorescence which is monitoredby fluorimeter | Visual | |
| Professional use | CDC Influenza Division will limit thedistribution of this device to only those userswho have successfully completed trainingprovided by CDC instructors or designees. | Professional use | |
| Detection levels were: | Limit of Detection levels were reported forinfluenza A/H1N1, A/H3N2, A/H5N1 and B.The following are the LoD's reported forA/H5N1: | Detection levels range from 6.6x106 pfu/ml to1.6x107 pfu/ml for influenza A viruses | |
| 36 TCID50/ml for H5N1 isolate2006914724 (Influenza A virus)(A/Egypt/14724-NAMRU3/2006(H5N1) (CDC Genbank#200512) | LoD of 1010 EID50/ml forA/Vietnam/1203/2004xA/Puerto Rico/8/34reassortant. | ||
| 134 TCID50/ml for H5N1 isolate2008903158 (Influenza A virus)(A/Egypt/3158-NAMRU3/2008(H5N1)(CDC Genbank # FJ226060) | LoD of 1010 EID50/ml forA/Anhui/01/2005xA/Puerto Rico/8/34reassortant | ||
| CHARACTERISTIC | Arbor Vita AVantage™ A/H5N1 Flu Test | CDC Human Influenza Virus Real-time RT-PCR Detection and Characterization Pannel(rRT-PCR Flu Panel) K080570 | Quidel QuickVue Influenza A+B Test)K053146 |
| cultured specimens (total of 24) were tested, with 100 % positive agreement with viral culture. All samples were of Clade 2.2 | Positive Agreement with viral culture (56.6%-100%) 95% CI. A total of 19 H5N1-positive cultured specimens were also tested, with 100 % positive agreement (83.2-100%) 95% CI with viral culture. Samples tested were from Clades 2.2.1, 2.2, and 2.3. | The QuickVue Influenza Test was evaluated with a total of 62 bacterial and viral isolates. Bacterial isolates were evaluated at a concentration between $10^7$ and $10^9$ org/ml. Viral isolates were evaluated at a concentration of at least $10^4$ - $10^8$ TCID50/ml. None of the organisms tested gave a positive result in the QuickVue Influenza Test. | |
| Cross-Reactivity | The AVantage™ A/H5N1 Flu Test did not cross-react with 21 bacterial isolates and 28 viral isolates (including seasonal influenza A and B). Bacterial isolates were evaluated at a concentration of:$1.5x10^8$ cfu/ml. Viral isolates were evaluated at a concentration of at least $8.89x10^3$ TCID50/ml | The H5N1 component of the rRT-PCR Flu Panel test did not cross-react with ten (10) influenza virus strains of A/H1N1, A/H3N2 and Influenza B at low virus concentrations at $10^2$ TCID50/ml.The rRT-PCR Flu Panel test did not cross-react with nucleic acids extracted from 27 organisms (9 non-influenza A/B viruses, 17 bacteria, and 1 yeast) representing common respiratory pathogens or flora commonly present in specimens from the nasopharynx region. Bacteria and yeast were tested at concentrations greater than or equal to $10^6$ cfu/ml. Non-influenza respiratory viruses were tested at concentrations greater than $10^6$ TCID50/ml with the exception of human parainfluenza type 2 which was tested at $10^{3.1}$ TCID50/ml and Human Corona viruses OC43 (50.4 ng/ul of total RNA from culture) and 299E (31.6 ng/ul total RNA from culture). | |
| Clinical Specificity | A total of 415 prospective seasonal specimens collected for routine influenza testing from nasal and nasopharyngeal swabs were used in this study. The H5N1 component of the rRT-PCR Flu Panel test had 100% Percent Negative Agreement with viral culture (99.1%-100%) 95% CI. | Nasal Swabs: 96 % [95% C.I. 91%-98%]160/167Nasal Wash or Aspirates: 99% [95% C.I. 91%-100%] 68/69 | |
| Interference | Whole blood, Mucin and 19 over-the-counter (OTC) products were tested in excess of | ||
| 100% negative agreement with 440 throat and 447 nasal swab samples (95% CI::99.1% - 100%) | |||
| CHARACTERISTIC | Arbor Vita AVantage™ A/H5N1 Flu Test | CDC Human Influenza Virus Real-timeRT-PCR Detection andCharacterization Pannel(rRT-PCR Flu Panel) K080570 | Quidel QuickVue Influenza A+B Test)K053146 |
| did not interfere with the AVC AvianFlu Test. | physiological levels and did not interfere withthe QuickVue Influenza Test. | ||
| Testing of AVantage™ A/H5N1 FluTest was conducted at three sites usinga panel of coded specimens containingrecombinant H5N1 NS1 protein. Twooperators at each site performed threereplicates/sample, for a total of 24 testsper day for five days. Panel containednegative, high negative, moderatepositive and high positive specimens.The fifth day contained an extrachallenge sample for an additional 6measurements. No significantdifferences were observed between runs(5 days), between operators (2operators) or between sites (3 sites). | Reproducibility and precision studies weredone at 3 sites, using a panel of 9 simulatedsamples (two viral concentrations: low viralRNA titer range concentration and 1:10dilution of the previous sample) for influenzaA/H1N1, A/H3N2, A/H5N1 (reassortant) andB. The panels and assay controls were testedat each site by two operators on five (5)different days within a 10-day period. The"low viral RNA titer" concentration wasgenerally one log above the assay cutoff for allanalytes, whereas the 1:10 dilution of the samesample approximated a sample at the assaycutoff. Each participating clinical site testedone of four RNA purification methods toevaluate reproducibility of the CDC rRT-PCRFlu Panel on the validated ABI 7500 Fast DxReal-Time PCR instruments. | Evaluation of QuickVue Influenza Test wasconducted at three Physicians Offices using apanel of coded specimens. Personnel withdiverse backgrounds performed the test. Panelcontained neg., low positive and moderatepositive specimens. Each specimen level wastested in each site in replicates of at least sixover a period of three days. The results at eachsite agreed 99% with the expected results. Nosignificant differences were observed within run(6 replicates), between runs (3 different days), orbetween the three sites. | |
| Reproducibility | |||
| For H5N1 studies, the total agreement withexpected results was as follows:H5a (low viral titer): 40/40 (95% CI: 91.2-100 %H5b (low viral titer): 39/40 (95% CI: 86.8-99.9 %)H5a (1/10 of low viral titer): 31/40 (95% CI:61.6-89.2)H5b (1/10 of low viral titer): 27/40 (95% CI:50.9-81.4 %) |
・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・
ייר
ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘ
:
.
ection 7: 510(k) Summary
・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・
Page 5 of 12 Arbor Vita Corporation, Confidential
{5}------------------------------------------------
Arbor Vita Corporation, Confidential
Page 6 of 12
Section 7: 510(k) Summary
April
{6}------------------------------------------------
April 1
Arbor Vita Corporation
AVantage™ A/H5NI Flu Test
Pre-market Notification
Section 7: 510(k) Summary
{7}------------------------------------------------
April ↑
Arbor Vita Corporation
AVantage™ A/H5N1 Flu Test
Pre-market Notification
-: 2
. .
. . ..
Section 7: 510(k) Summary
{8}------------------------------------------------
. . . . . . .
807.92 (b)(1) and 807.92 (b)(2):
Brief Description of Nonclinical and Clinical Data
The precision/repeatability of the AVantage™ A/H5N1 Flu Test was demonstrated by conducting within-laboratory tests at a range of recombinant H5N1 NS1 protein analyte concentrations over twelve consecutive days. Performance of the assay was consistent, with the high negative sample vielding 8% positive results while the low positive and moderate positive samples vielding respectively 96% and 100% positive results.
The reproducibility of the AVantage™ A/H5N1 Flu Test was determined by measuring the consistency of assay performance using negative control, and high negative, moderate positive, and high positive recombinant protein H5N1 NS1 samples over five days at three sites with two operators at each site. The results showed reproducible performance across days, sites and operators.
Due to the rare occurrence of H5N1 infection and the absence of infection in the United States, sensitivity studies of the AVantage™ A/H5N1 Flu Test were performed using H5N1 isolates from infected individuals, collected in the course of WHO/NAMRU-3 pandemic surveillance and response activities. All isolates studied herein were classified as Clade 2.2 and are part of the CDC global H5N1 repository.
The 24 human-derived H5N1 viral culture specimens were grown in MDCK cells or eggs. Included in the study were three HSNI negative samples. Study personnel were blinded to the true H5N1 status. The reference method used to verify H5N1-positive status of the viral culture samples was HAI. Eleven of these specimens were from first passage cultures, and 13 of the specimens were from second passage cultures. The study was conducted in BSL-3 labs at NAMRU-3 by NAMRU-3 personnel. The AVantage™ A/H5N1 Flu Test used in this study was performed according to the AVC Test Instructions for Use.
A Vantage™ A/H5N1 Flu Test results showed 100% positive agreement for all 24 H5N1-postive in the AVantage™ A/H5N1 Flu Test.
| NAMRU-3ComparisonResults | Virus Culture (Gold Standard) Results | Performance | |
|---|---|---|---|
| H5N1 (+) | H5N1 (-) | ||
| AVantage™ A/H5N1Flu Test Positive | 24 | 0 | 100% Positive Agreement*95% CI = (86.2%, 100% ) |
| AVantage™ A/H5N1Flu Test Negative | 0 | 3 | 100% Negative Agreement95% CI = ( 43.8%, 100% ) |
| Total | 24 | 3 |
Performance Summary - AVantage™ A/H5N1 testing with viral culture samples
Twenty four H5N1+ viral culture specimens; eleven were from first passage cultures, and thirteen were from second passage cultures. Sample status was confirmed by HAI.
Section 7: 510(k) Summary
:
. .
| : : ヽ : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : :
Arbor Vita Corporation, Confidential
{9}------------------------------------------------
The specificity of the AVantage™ A/H5N1Flu Test was assessed in a prospective clinical study during the 2007-2008 flu season. Symptomatic subjects were recruited from four clinics at three sites into a broader surveillance study conducted by the Naval Health Research Center (NHC). A portion of subjects (464) was recruited into the AVC study. Of these 464 symptomatic subjects, 110 had influenza infection (73, Influenza A and 37 Influenza B). AVC testing was performed in two laboratories and yielded no false positive results.
| NHRCComparisonResults | Virus Culture (Gold Standard) Results | Performance | |||
|---|---|---|---|---|---|
| H5N1 (+) | Influenza A (+)H5N1 (-) | Influenza B (+)H5N1 (-) | Influenza A&B (-)H5N1 (-) | ||
| AVantage™A/H5N1Flu Test Positive | 0 | 0 | 0 | 0 | N/A* |
| AVantage™A/H5N1Flu Test Negative | 0 | 113 | 55 | 727 | 100%Specificity95%CI =(99.57%;100%) |
| Total | 0 | 113 | 55 | 727 |
Performance Summary - AVantage™ A/H5N1 testing prospective clinical samples
Sample status was confirmed by IFA and haemagglutination-inhibition test (HAI).
- No true positive samples were identified by Gold Standard methods.
** 8 samples were not subtyped by IFA or HAI, but were determined to be H3 by Lightcycler RT-PCR using primers developed by the Air Force Institute of Operational Health.
The AVantage™ A/H5N1 Flu Test was evaluated for potential cross-reactivity with a total of 49 bacterial and viral isolates. The bacterial isolates were tested at concentrations of approximately 1.5x108 cfu/mL. The viral isolates were used at concentrations of 104 - 10 TCID50 mL, or 102 -104 CEID50/mL.
None of the pathogens tested showed cross-reactivity with the assay.
Bacterial Panel: Bacteroides fragilis Bordetella pertussis Corynebacterium xerosis Escherichia coli Haemophilus influenzae Lactobacillus casei Legionella pneumonphila Moraxella catarrhalis Mvcoplasma pneumoniae Neisseria meningitidis... ...... ... ... ... ... .... .... ................................................................................................................... Neisseria mucosa Peptostreptococcus anaerobius Porphyromonas asaccharolyticus Section 7: 510(k) Summary
Arbor Vita Corporation, Confidential
{10}------------------------------------------------
Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Group.A Streptococcus salivarius Streptococcus sp. Group B Streptococcus sp. Group C
Viral Panel
Adenovirus, Type 2 Adenovirus Type 3 Adenovirus Type 7 Adenovirus Type 14 Coronavirus OC 43 Coronavirus 299E Coxsackievirus Type A9 Coxsackievirus Type B5 Cytomegalovirus Echovirus Type 2 Echovirus Type 3 Echovirus Type 6 Enterovirus Herpes simplex virus Type 1 Measles virus Mumps virus Parainfluenza virus Type 1 Parainfluenza virus Type 2 Parainfluenza virus Type 3 Rhinovirus Type 1A Respiratory Syncytial virus Type A Respiratory Syncytial virus Type B A2/Wisconsin/67/2005 (H3N2-like) A/Hiroshima/52/2005 (H3N2-like) A/Port Chalmers/1/73 (H3N2) A/PR8/34 (H1N1) A1/Denver/1/57 B/Hong Kong/5/72
Substances commonly encountered in nasal and throat specimens were tested for their potential inhibitory effect on the performance of the AVantage™ A/H5N1 Flu Test. Listed below are the substances and concentrations at which they were tested. None of the substances tested had an inhibitory effect on assay performance.
Whole blood (2%) Mucin (500 ug/ml) Section 7: 510(k) Summary
{11}------------------------------------------------
Mouthwash (Scope®) (25%) Dextromethoraphan (Robitussin®) (5 mg/ml) Acetaminophen (Tyelenol®) (10 mg/ml) Throat losange (Cepacol® - cetypyridium chloride, benzocaine and menthol) (25%) Oxymetazoline (Afrin®) (10%) Erythromcyin (20 µg/ml) Nasal corticosteroids (triamcinolone) (25 mg/ml) Zanamivir (Relenza®) (1 mg/ml) Phenyephrine (Neosynephrine®) (100 mg/ml) Diphenhydramine (Benadryl®) (1 mg/ml) Luffa operculata, Galphimia glauca, Histaminum hydrochloricum and sulfur (Zicam®) (1%) Rimantadine (250 ng/ml)
807.92 (b)(3): Conclusions from Nonclinical and Clinical Testing
.. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nonclinical and clinical testing was performed for the AVantage™ A/H5N1 Flu Test. The test system was shown to be safe and effective for its intended use.
Section 7: 510(k) Summary
{12}------------------------------------------------
DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/12/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized depiction of an eagle or bird-like figure. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES. USA" are arranged in a circular pattern around the bird symbol.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Linda McAllister, MD, PhD Executive Vice President of Diagnostics Chief Medical Officer Regulatory Affairs Arbor Vita Corporation 772 Lucerne Drive Sunnyvale, CA 94087
APR - 8 2009
Re: K083278
Trade/Device Name: AVantage™A/H5N1 Flu Test Regulation Number: 21 CFR 866.3332 Regulation Name: Reagent for detection of specific novel influenza A viruses Regulatory Class: Class II Product Code: OMS Dated: April 7, 2009 Received: April 7, 2009
Dear Dr. McAllister:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
{13}------------------------------------------------
This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Your device is classified (see above) into class II (Special Controls) and is subject to additional controls as outlined in the Class II Special Controls Guidance Document: Reagents for Detection of Specific Novel Influenza A Viruses including the post market measures described in Section 8 "Postmarket Measures".
Sincerely vours.
Sallastm
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{14}------------------------------------------------
Indication for Use
510(k) Number (if known): K083278
Device Name: AVantage™ A/H5N1 Flu Test
Indication For Use:
The AVantage™ A/H5N1 Flu Test is intended for the in vitro qualitative detection of influenza A/H5N1 virus directly from symptomatic patient nasal or throat swab specimens or in viral cultures for the presumptive laboratory identification of influenza A/H5N1 virus.
Results from testing with the AVantage™ A/H5N1 Flu Test should be used in conjunction with other laboratory testing and clinical and epidemiological risk factors for the presumptive identification of patients infected with Influenza H5N1 virus. A Vantage™ A/H5N1 Flu Test is intended as a Prescription Use device.
Testing 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 either directly from patient specimens or from viral 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.
Prescription Use X X (21 CFR Part 801 Subpart D) . . ..............................................................................................................................................
And/Or
Over the Counter Use
(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OVD)
Jay ath
Office of In Vitto Diagnostic Device increase of the more of the more of the security of the Evaluation and Safety
510(k)
§ 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.