(310 days)
The RAMP® Influenza A/B Assay is a qualitative immunochromatographic assay used to identify the presence of Influenza A and Influenza B nucleoprotein antigens in nasal wash, nasal aspirate, nasopharyngeal aspirate, and nasopharyngeal swab specimens from symptomatic patients. It is an in vitro diagnostic assay that aids in the rapid differential diagnosis of influenza viral infections in symptomatic patients. A negative test is presumptive and it is recommended these results be confirmed by cell culture. Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other management decisions.
The test performance characteristics for Influenza B were established primarily with retrospective, frozen specimens. Users may wish to further evaluate the sensitivity performance of this test for Influenza B using fresh samples.
The RAMP Influenza A/B Assay is a qualitative immunochromatographic test that utilizes the RAMP 200 for the differential determination of Influenza B in nasal wash, nasal aspirate, nasopharyngeal aspirate, and nasopharyngeal swab samples. A wash/aspirate or swab sample is added to the Sample Buffer. The Sample Buffer is optimized to improve binding of the anti-influenza antibodies to the nucleoprotein antigens and reduce non-specific binding and fluorescent signal background. This sample is then mixed using the Assay Tip containing fluorescent-dyed particles conjugated to specific antibodies and applied into the sample well of the Test Cartridge. The sample migrates along the strip. Fluorescent-dyed particles coated with anti-Influenza A and anti-Influenza B antibodies bind to Influenza A or B antigens, respectively, if present in the sample. As the sample migrates along the strip, Influenza-bound particles are captured at either the Influenza A or the Influenza B detection zone, and excess fluorescent- dyed particles are captured at the internal standard zone.
The instrument then measures the amount of fluorescence emitted by the complexes at the two detection zones (Influenza A and Influenza B) and at the internal standard zone. The instrument calculates a ratio (RAMP Ratio) using the fluorescence reading of each detection zone (A or B) and the internal standard zone. The instrument compares these ratios to pre-defined threshold limits to determine a positive or negative result for Influenza B in the tested sample.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state pre-defined acceptance criteria in a dedicated section with target values. However, based on the performance study results, we can infer the observed performance metrics. The primary method of comparison is against cell culture.
| Metric (Inferred Acceptance Criteria based on study results) | Reported Device Performance (RAMP® Influenza A/B Assay) - Prospective Fresh Clinical Specimens | Notes |
|---|---|---|
| Influenza A | ||
| Sensitivity (Nasopharyngeal Swab) | 80.3% (53/66) (95% CI: 68.7-89.1%) | Ranges from 69.6% (age 22-59) to 91.7% (age 0-5) across subgroups. |
| Specificity (Nasopharyngeal Swab) | 96.6% (541/560) (95% CI: 94.8-97.9%) | Ranges from 94.0% (age 0-5) to 99.3% (age 22-59) across subgroups. |
| Sensitivity (Nasal Wash/Aspirate) | 80.0% (36/45) (95% CI: 65.4-90.4%) | Ranges from 0/0 (age 22-59 and >60, due to no positive cases) to 85.7% (age 0-5) across subgroups. |
| Specificity (Nasal Wash/Aspirate) | 93.6% (162/173) (95% CI: 88.9-96.8%) | Ranges from 89.1% (age 6-21) to 100% (age 22-59 and >60) across subgroups. |
| Influenza B | ||
| Sensitivity (Nasopharyngeal Swab) | 58.3% (7/12) (95% CI: 27.7-84.8%) | Ranges from 50.0% (age 6-21, 22-59) to 100% (age 0-5) across subgroups. Lower sensitivity compared to Influenza A. |
| Specificity (Nasopharyngeal Swab) | 98.0% (602/614) (95% CI: 96.6-99.0%) | Ranges from 95.1% (age 6-21) to 99.4% (age 22-59, >60) across subgroups. |
| Sensitivity (Nasal Wash/Aspirate) | 100% (9/9) (95% CI: 66.4-100%) | Due to small numbers, some age groups showed 100% sensitivity but with wide confidence intervals or "NA". Overall 100% sensitivity reported for this collection type. |
| Specificity (Nasal Wash/Aspirate) | 99.0% (207/209) (95% CI: 96.6-99.9%) | Ranges from 98.3% (age 6-21) to 100% (age 22-59 and >60, due to no positive cases). |
| Analytical Precision (Agreement with Expected Results) | 100% (540/540) for Influenza A (High Negative, LoD, 2x LoD positive) and Influenza B (High Negative, LoD, 2x LoD positive) samples across multiple operators, sites, and days. | The overall RAMP Ratio %CV ranged from 9.6% to 15.1%. This demonstrates excellent reproducibility and reliability for quantitative measurements, which supports the qualitative output. |
| Analytical Sensitivity (LoD) | Influenza A: 3.0x10² to 6.4x10² EID50/mL (VTM/PBS) Influenza B: 2.8x10² to 7.1x10⁴ EID50/mL (VTM/PBS) | These indicate the lowest concentration of virus the assay can reliably detect. |
| Analytical Reactivity | 100% Positive for all tested strains of Influenza A (5 strains) and Influenza B (3 strains) at specified concentrations. | Confirms the device's ability to detect various common strains of Influenza A and B. |
| Analytical Specificity (Cross-Reactivity) | Negative for all 15 viruses and 17 bacteria tested. | Shows the device does not cross-react with other common respiratory pathogens or microbes found in the nasal cavity. Note: Chlamydophilia pneumoniae not determined. |
| Interference | 100% agreement with expected results (negative for negative samples, positive for positive samples) in the presence of 23 potentially interfering substances (medications, OTC products, whole blood up to 2% v/v). | Demonstrates robustness against common interfering substances. A warning is included for visibly bloody samples. |
| Transport Media Compatibility | 100% Agreement (Negative for negative, Positive for positive) across 6 commercially available and 2 clinical-site-prepared transport media. | Ensures the device performs reliably with various transport media. |
| Sample Collection Swab Compatibility | 100% Negative for negative swab samples. For LoD positive samples, agreement ranged from 67% to 100% positive for Influenza A and 67% to 100% positive for Influenza B, depending on swab material. | Polyester and Rayon swabs showed 67% detection at LoD for Influenza A and B respectively (compared to 100% for Foam and Nylon). Calcium alginate swabs are noted as not recommended. This indicates slight variability based on swab material, particularly at lower viral loads. |
2. Sample Size and Data Provenance:
-
Test Set (Clinical Performance):
- Prospective Study: 844 fresh specimens (nasal wash/aspirate, nasopharyngeal aspirate, or nasopharyngeal swab samples). This study was conducted in North America during the 2006-2007 influenza season.
- Retrospective Study: 75 retrospective frozen clinical nasopharyngeal swab samples and 130 retrospective frozen clinical wash/aspirate samples. These were compared to original cell culture results performed on fresh specimens.
-
Training Set: The document does not explicitly mention a training set size or methodology for the device's algorithm. The studies described are for analytical (device characteristics) and clinical performance evaluation, not for training a machine learning model. This is a traditional IVD.
3. Number of Experts and Qualifications for Ground Truth (Test Set):
- The ground truth for the clinical performance studies was established using cell culture. The document does not specify the number or qualifications of experts involved in performing or interpreting the cell culture results. It states that "cell culture testing was performed using fresh specimens" and implies these are standard laboratory procedures.
4. Adjudication Method (Test Set):
- The document describes comparison studies where the RAMP® Influenza A/B Assay results were compared directly against cell culture results. The term "adjudication method" typically applies to resolving discrepancies between multiple readers or between a new device and a reference standard where a third, independent assessment is needed. In this case, cell culture acts as the definitive gold standard, and direct comparison is made. There is no mention of a separate adjudication process beyond the cell culture determination.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study:
- No, a multi-reader multi-case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not done. This device is an in-vitro diagnostic (IVD) assay that produces a direct result, not an AI-assisted diagnostic imaging tool that improves human reader performance. The "readers" here are the laboratory personnel performing the assay.
6. Standalone Performance Study:
- Yes, a standalone performance study was done for the device. The "Clinical Performance" section directly compares the RAMP® Influenza A/B Assay (algorithm only, as it generates the result) against the cell culture gold standard. The sensitivity and specificity results presented in the tables are indicative of the algorithm's standalone performance.
7. Type of Ground Truth Used:
- For the clinical performance studies, the ground truth was viral cell culture. This is explicitly stated: "The performance of the RAMP Influenza A/B Assay was compared to cell culture."
8. Sample Size for the Training Set:
- As mentioned in point 2, the document does not describe the training of a machine learning algorithm. Therefore, there is no explicit training set size provided for this device in the context of AI/ML. The analytical studies describe the development and validation of the assay's operational parameters rather than training a model.
9. How the Ground Truth for the Training Set Was Established:
- Not applicable, as there is no mention of an AI/ML training set in the document. For the development of the assay (which could be considered analogous to "training" in a traditional IVD context), the process involves determining optimal reagent concentrations, binding efficiencies, and establishing cut-off values. This is based on internal analytical studies (like LoD, precision, reactivity) using characterized viral strains and clinical samples, rather than a separate ground truth establishment for a training set in the AI sense.
{0}------------------------------------------------
APR 1 6 2008
510(K) SUMMARY OF SAFETY AND EFFECTIVENESS
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: _______________________________________________________________________________________________________________________________________________
Establishment:
Response Biomedical Corporation 100-8900 Glenlyon Parkway Burnaby, British Columbia Canada, V5J 5J8
Tel: (604) 456-6010 Fax: (604) 456-6066
Ken Pilgrim Contact: Director - Quality / Regulatory
Prepared: April 15, 2008
Regulatory Information:
| Trade Name: | RAMP® Influenza A/B Assay |
|---|---|
| Common Name: | Influenza A/B immunological test system |
| Classification Name: | Influenza A/B immunological test system |
| Regulation Number: | 866.3330, Influenza virus serological reagents |
| Classification: | Class I |
| Product Code: | GNX |
| Panel: | Microbiology |
Predicate Device:
lmmunoassay:
BinaxNOW® Influenza A & B Test, (K062109), which is currently marketed by Binax, Inc.
Intended Use:
The RAMP® Influenza A/B Assay is a qualitative immunochromatographic assay used to identify the presence of Influenza A and Influenza B nucleoprotein antigens in nasal wash, nasal aspirate, nasopharyngeal aspirate, and nasopharyngeal swab specimens from symptomatic patients. It is an in vitro diagnostic assay that aids in the rapid differential diagnosis of influenza viral infections in symptomatic patients. A negative test is presumptive and it is recommended these results be confirmed by cell culture. Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other management decisions.
The test performance characteristics for Influenza B were established primarily with retrospective, frozen specimens. Users may wish to further evaluate the sensitivity performance of this test for Influenza B using fresh samples.
{1}------------------------------------------------
Description of the Device:
The RAMP Influenza A/B Assay is a qualitative immunochromatographic test that utilizes the RAMP 200 for the differential determination of Influenza B in nasal wash, nasal aspirate, nasopharyngeal aspirate, and nasopharyngeal swab samples. A wash/aspirate or swab sample is added to the Sample Buffer. The Sample Buffer is optimized to improve binding of the anti-influenza antibodies to the nucleoprotein antigens and reduce non-specific binding and fluorescent signal background. This sample is then mixed using the Assay Tip containing fluorescent-dyed particles conjugated to specific antibodies and applied into the sample well of the Test Cartridge. The sample migrates along the strip. Fluorescent-dyed particles coated with anti-Influenza A and anti-Influenza B antibodies bind to Influenza A or B antigens, respectively, if present in the sample. As the sample migrates along the strip, Influenza-bound particles are captured at either the Influenza A or the Influenza B detection zone, and excess fluorescent- dyed particles are captured at the internal standard zone.
The instrument then measures the amount of fluorescence emitted by the complexes at the two detection zones (Influenza A and Influenza B) and at the internal standard zone. The instrument calculates a ratio (RAMP Ratio) using the fluorescence reading of each detection zone (A or B) and the internal standard zone. The instrument compares these ratios to pre-defined threshold limits to determine a positive or negative result for Influenza B in the tested sample.
Comparison of Technological Characteristics:
The RAMP Influenza A/B Assay and BinaxNOW Influenza A & B Test are rapid immunochromatographic tests used for the detection of influenza virus antigen utilizing antibodies targeted toward the nucleoprotein (NP) of the virus and thus do not require viable virus particles for detection. The RAMP and BinaxNOW tests provide results in approximately 15 minutes. Viral cell culture relies on the growth of cell lines and their infection with virus contained in the clinical sample. The time required to get a definitive result using these culture methods can be up to 30 days depending on the samples and methods used.
The RAMP Influenza A/B Assay and BinaxNOW Influenza A & B Test are for use in the central laboratory, stat-lab and point-of-care facilities, while viral cell culture is for use in the central laboratories due to its requirement for specialized equipment and highly trained operators.
These methods are indicated for use in the differential determination of Influenza B in nasal wash/aspirate, nasopharyngeal aspirate, and nasopharyngeal swab samples.
Summary of Studies:
ANALYTICAL PERFORMANCE CHARACTERISTICS
Assay Precision
The total intra-assay and inter-assay precision of the RAMP Influenza A/B Assay was evaluated using a panel consisting of high negative Influenza A, Influenza A LoD (Limit of Detection) positive, Influenza A 2x LoD positive, high negative Influenza B, Influenza B LoD positive, and Influenza B 2x LoD positive samples. The influenza strains used to prepare the samples were Influenza A/Hong Kong/8/68 and Influenza B/Lee/40 following viral titer determinations. Multiple operators across multiple sites tested replicates of each sample on 5 different days. There was 100% (540/540) agreement with the expected test results for all specimens tested, with no significant differences within run (same operator on same day), between run, operators, or sites. The RAMP Flu A/B assay is a qualitative assay based on numerical RAMP Ratio values. The overall RAMP Ratio %CV across all sites ranged from 9.6% to 15.1% depending upon analyte type and concentration tested.
{2}------------------------------------------------
| PanelMember ID | Influenza AHighNegative | Influenza ALowPositive | Influenza AMediumPositive | Influenza BHighNegative | Influenza BLowPositive | Influenza BMediumPositive | TotalAgreementAll (%) | |
|---|---|---|---|---|---|---|---|---|
| Viral Titer(EID50/mL) | 50 | 300 | 600 | 60 | 316 | 632 | ||
| Site 1 | AgreementwithExpectedresult | 30/30 | 30/30 | 30/30 | 30/30 | 30/30 | 30/30 | 180/180(100%) |
| % CV | 11.6% | 6.3% | 7.9% | 16.4% | 8.9% | 7.9% | ||
| Site 2 | AgreementwithExpectedresult | 30/30 | 30/30 | 30/30 | 30/30 | 30/30 | 30/30 | 180/180(100%) |
| % CV | 7.7% | 8.1% | 9.3% | 15.6% | 9.5% | 7.0% | ||
| Site 3 | AgreementwithExpectedresult | 30/30 | 30/30 | 30/30 | 30/30 | 30/30 | 30/30 | 180/180(100%) |
| % CV | 14.5% | 9.9% | 13.5% | 11.3% | 9.5% | 10.5% | ||
| TotalAgreementwithExpectedresult | 90/90(100%) | 90/90(100%) | 90/90(100%) | 90/90(100%) | 90/90(100%) | 90/90(100%) | 540/540(100%) | |
| 95% Cl | 96%-100% | 96%-100% | 96%-100% | 96%-100% | 96%-100% | 96%-100% | 99%-100% | |
| Overall% CV | 11.9% | 10.4% | 12.6% | 15.1% | 10.6% | 9.6% |
Analytical Sensitivity
The RAMP Influenza A/B Assay was evaluated for analytical sensitivity after was determined by testing 2 strains of Influenza A (Hong Kong/8/68 and PR/8/34) and 2 strains of Influenza B (Lee/40 and Allen/45) at the Limit of Detection (LoD) concentration, the cut-off concentration, and at a high negative concentration in either VTM (Viral Transport Medium, to simulate a swab sample type) or PBS (Phosphate Buffered Saline, to simulate a wash sample type). Although the specific influenza strains causing infection in humans can vary year to year, all contain the conserved nucleoproteins targeted by the RAMP Influenza A/B Assay. Analytical sensitivity (LoD) ranged from 3.0x102 to 6.4x102 ElDgomL for the Influenza A strains and 2.8x102 to 7.1x104 EID50/mL for the Influenza B strains in VTM and PBS.
| Viral Strain | LoD Concentration |
|---|---|
| Influenza A/Hong Kong/8/68 (H3N2),ATCC VR-544 in VTM | 3.0 X $10^2$ EID50/mL |
| Influenza A/Hong Kong/8/68 (H3N2),ATCC VR-544 in PBS | 5.0 X $10^2$ EID50/mL |
| Influenza A/PR/8/34 (H1N1),ATCC VR-95 in VTM | 2.0 X $10^2$ EID50/mL |
| Influenza A/PR/8/34 (H1N1),ATCC VR-95 in PBS | 6.4 X $10^2$ EID50/mL |
| Influenza B/Lee/40,ATCC VR-101 in VTM | 3.2 X $10^2$ EID50/mL |
| Influenza B/Lee/40,ATCC VR-101 in PBS | 2.8 X $10^2$ EID50/mL |
| Influenza B/Allen/45,ATCC VR-102 in VTM | 5.3 X $10^4$ EID50/mL |
| Influenza B/Allen/45,ATCC VR-102 in PBS | 7.1 X $10^4$ EID50/mL |
{3}------------------------------------------------
Analytical Reactivity
The RAMP Influenza A/B Assay was evaluated for analytical reactivity by testing of Influenza A (FM/1/47, NWS/33, New Jersey/8/76, Aichi/2/68, and Victoria/3/75) and 3 strains of Influenza B (GL/1739/54, Taiwan/2/62, and Hong Kong/5/72) prepared in VTM at concentrations that would consistently give positive results. Five (5) replicates were tested for each viral strain. The viral titers of these influenza strains were determined prior to analytical sensitivity testing. Analytical reactivity was established for the 5 Influenza A and 3 Influenza B strains tested. The concentrations for reactivity ranged from 3.0x102 EIDsy/mL for the Influenza A strains and 1.6x10 to 9.5x10 EID50/mL for the Influenza B strains.
| Strain | ReactivityConcentration | RAMP Result |
|---|---|---|
| Influenza A/FM/1/47 (H1N1)ATCC VR-97 | 3.0 X 103 EID50/mL | 100% Flu A Positive |
| Influenza A/NWS/33 (H1N1)ATCC VR-219 | 3.0 X 102 EID50/mL | 100% Flu A Positive |
| Influenza A/New Jersey/8/76(H1N1), ATCC VR-897 | 3.0 X 102 EID50/mL | 100% Flu A Positive |
| Influenza A/Aichi/2/68 (H3N2)ATCC VR-547 | 9.0 X 102 EID50/mL | 100% Flu A Positive |
| Influenza A/Victoria/3/75(H3N2), ATCC VR-822 | 9.0 X 102 EID50/mL | 100% Flu A Positive |
| Influenza B/GL/1739/54ATCC VR-103 | 9.5 X 103 EID50/mL | 100% Flu B Positive |
| Influenza B/Taiwan/2/62ATCC VR-295 | 1.6 X 101 EID50/mL | 100% Flu B Positive |
| Influenza B/Hong Kong/5/72ATCC VR-823 | 6.3 X 103 EID50/mL | 100% Flu B Positive |
Analytical Specificity (Potential Cross-Reactive Organisms)
The analytical specificity of the RAMP Influenza A/B Assay was determined by testing a panel consisting of 15 viruses and 17 bacteria that may be present in the nasal cavity or nasopharynx. Viral and bacterial isolates were tested at the concentrations listed after titer determination at n=3 replicates each. None of the organisms tested cave a positive result in the RAMP Influenza A/B RAMP Influenza A/B Assay potential cross-reactivity with Chlamydophilia Note: Assay. pneumoniae has not been determined.
| Strain/Isolate | Concentration | RAMP Flu Aresult | RAMP Flu Bresult |
|---|---|---|---|
| Adenovirus, Type 1 | 105 TCID50/mL | Negative | Negative |
| Adenovirus, Type 7a | 105.15 TCID50/mL | Negative | Negative |
| Respiratory Syncytial Virus (RSV) | 105 TCID50/mL | Negative | Negative |
| Human coronavirus, strain OC43 | 105 TCID50/mL | Negative | Negative |
| Human coronavirus Strain 229E | 105.23 TCID50/mL | Negative | Negative |
| Cytomegalovirus | 105.15 TCID50/mL | Negative | Negative |
| Enterovirus, Type 71 | 105.15 TCID50/mL | Negative | Negative |
| Epstein Barr Virus | 105 TCID50/ML | Negative | Negative |
| Measles | 105 TCID50/mL | Negative | Negative |
| Specificity; Potential Cross-Reactive Substances | ||
|---|---|---|
{4}------------------------------------------------
| Strain/Isolate | Concentration | RAMP Flu Aresult | RAMP Flu Bresult |
|---|---|---|---|
| Mumps virus | 105 TCID50/mL | Negative | Negative |
| Human Parainfluenza, Type 1 | 104.75 TCID50/mL | Negative | Negative |
| Human Parainfluenza, Type 2 | 105 TCID50/mL | Negative | Negative |
| Human Parainfluenza, Type 3 | 105 TCID50/mL | Negative | Negative |
| Human metapneumovirus | 105 TCID50/mL | Negative | Negative |
| Human Rhinovirus, Strain 1A | 105 TCID50/mL | Negative | Negative |
| Bordetella pertussis | 106 cfu/mL | Negative | Negative |
| Corynebacterium Sp. | 106 cfu/mL | Negative | Negative |
| Escherichia coli | 106 cfu/mL | Negative | Negative |
| Haemophilus influenzae | 106 cfu/mL | Negative | Negative |
| Lactobacillus casei | 106 cfu/mL | Negative | Negative |
| Legionella pneumophila | 106 cfu/mL | Negative | Negative |
| Moraxella catarrhalis | 106 cfu/mL | Negative | Negative |
| Mycobacterium tuberculosis avirulent | 106 cfu/mL | Negative | Negative |
| Mycoplasma pneumoniae | 106 cfu/mL | Negative | Negative |
| Neisseria menigitidis | 106 cfu/mL | Negative | Negative |
| Neisseria sicca | 106 cfu/mL | Negative | Negative |
| Pseudomonas aeruginosa | 106 cfu/mL | Negative | Negative |
| Streptococcus pneumoniae | 106 cfu/mL | Negative | Negative |
| Streptococcus pyogenes (Group A) | 106 cfu/mL | Negative | Negative |
| Streptococcus salivarius | 106 cfu/mL | Negative | Negative |
| Staphylococcus epidermidis | 106 cfu/mL | Negative | Negative |
| Staphylococcus aureus (Protein Aproducer) | 106 cfu/mL | Negative | Negative |
Interference
Whole blood and a number of other potentially interfering substances (medications and over the counter (OTC) products) that may be present naturally or artificially introduced in the nasal cavity or nasopharynx were evaluated in the RAMP Influenza A/B Assay. The substances were added to a negative sample (viral transport media), an Influenza A LoD positive sample, an Influenza A to a nogative sample, an Influenza B LoD positive sample and an Influenza B 2x LoD positive sample and tested in the RAMP Influenza A/B Assay. The influenza strains used to prepare the samples were Influenza A/Hong Kong/8/68 and Influenza B/Lee/40 following titer determination. There was 100% agreement with expected results for all replicates (for n=3 replicates tested). None of the substances tested at the concentrations indicated interfered with the test results of None of the oubsitive influenza samples in the RAMP Influenza A/B Assay. The RAMP Flu A/B negative and positive assay based on numerical RAMP Ratio values. The Percent of Mean Control Ratio values were calculated using these RAMP Ratios.
Interfering Substances Study Results
| Substance Tested | Conc.Tested | RAMP Results: Percent of Mean Control Ratio | ||||
|---|---|---|---|---|---|---|
| NegativeFluA / Flu B | Influenza ALoD | Influenza A2x LoD | Influenza BLoD | Influenza B2x LoD | ||
| Control(No interferingsubstance) | NotApplicable | 100% / 100% | 100% | 100% | 100% | 100% |
| Substance Tested | Conc.Tested | RAMP Results: Percent of Mean Control Ratio | ||||
| NegativeFluA / Flu B | Influenza ALoD | Influenza A2x LoD | Influenza BLoD | Influenza B2x LoD | ||
| Fisherman's FriendThroat Drop | 15% w/v | 120% / 105% | 101% | 103% | 99% | 120% |
| Halls Throat Drop | 15% w/v | 96% / 104% | 101% | 111% | 91% | 111% |
| Cepacol Throat Drop | 15% w/v | 91% / 101% | 98% | 101% | 105% | 118% |
| 4-Acetamidophenol | 10 mg/mL | 110% / 117% | 99% | 100% | 104% | 117% |
| Acetylsalicylic Acid | 15 mg/mL | 89% / 106% | 98% | 97% | 110% | 118% |
| Chloropheniramine | 5 mg/mL | 107% / 110% | 101% | 95% | 112% | 118% |
| Diphenylhydramine | 5 mg/mL | 109% / 126% | 99% | 100% | 115% | 116% |
| PhenylpropanolamineHCl | 20 mg/mL | 126% / 100% | 91% | 96% | 113% | 113% |
| Oseltamivir Phosphate(Tamiflu) | 50 mg/mL | 106% / 101% | 105% | 105% | 106% | 111% |
| Rimantadine HCl | 500 ng/mL | 103% / 103% | 105% | 94% | 111% | 113% |
| Ribavirin (Rebetol) | 100 mg/mL | 137% / 136% | 111% | 106% | 118% | 120% |
| Good and KindMouthwash | 20% v/v | 97% / 118% | 97% | 106% | 99% | 125% |
| Cepacol Mouth Wash | 20% v/v | 88% / 85% | 103% | 104% | 98% | 118% |
| Scope Mouthwash | 20% v/v | 88% / 99% | 96% | 94% | 98% | 112% |
| Rhinocort Nasal Spray | 15% v/v | 85% / 88% | 109% | 101% | 90% | 122% |
| Nasonex Nasal Spray | 15% v/v | 104% / 90% | 103% | 106% | 92% | 113% |
| Flonase Nasal Spray | 15% v/v | 103% / 104% | 109% | 100% | 95% | 113% |
| Oxymetazoline HCl | 0.05% v/v | 116% / 95% | 101% | 103% | 97% | 108% |
| Phenylephrine HCl | 10 mg/mL | 126% / 119% | 101% | 99% | 106% | 117% |
| Guaiacol Glycerol Ether(Benylin) | 20 mg/mL | 166% / 153% | 118% | 113% | 118% | 124% |
| Dextromethorphan | 2 mg/mL | 95% / 101% | 115% | 115% | 126% | 134% |
| Salbutamol Sulfate | 400 ng/mL | 102% / 92% | 98% | 99% | 111% | 116% |
| Substance Tested | Conc.Tested | RAMP Results: Percent of Mean Control Ratio | ||||
| NegativeFluA / Flu B | Influenza ALoD | Influenza A2x LoD | Influenza BLoD | Influenza B2x LoD | ||
| Whole Blood* | 2% v/v | 126%/91% | 75% | 90% | 106% | 98% |
{5}------------------------------------------------
{6}------------------------------------------------
*A warning is added to the package insert to reflect that samples contaminated with whole blood in greater concentrations (visibly bloody samples) may interfere in the interpretation of the assay.
Transport Media
Six commercially available and two clinical-site-prepared transport media were evaluated for compatibility in the RAMP Influenza A/B Assay by testing a negative sample (transport media only), an Influenza A LoD positive sample, an Influenza A 2x LoD positive sample, an Influenza B LoD positive sample, and an Influenza B 2x LoD positive sample in the RAMP Influenza A/B Assay. The influenza strains used to prepare the samples were Influenza A/Hong Kong/8/68 and Influenza B/Lee/40 following titer determination. The RAMP Flu A/B assay is a qualitative assay based on numerical RAMP Ratio values. The %CVs were calculated for the RAMP Ratios. None of the tested transport media interfered with the performance of the RAMP Influenza A/B Assay.
| Transport MediaTested | RAMP Results | ||||
|---|---|---|---|---|---|
| Negative | Influenza ALoD | Influenza A2x LoD | Influenza BLoD | Influenza B2x LoD | |
| Copan UniversalTransport Media(UTM) | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Remel M4 Media | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Remel M4-RTMedia | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Remel M5 Media | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Starplex TransportMedia | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| PhosphateBuffered Saline(PBS) Solution | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Site B In-houseMedia | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Site A In-houseMedia | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| RAMP Ratio % CV | Flu A 19%Flu B 13% | 4% | 9% | 7% | 11% |
Sample Collection Swabs
Four swab materials were evaluated for compatibility in the RAMP Influenza A/B Assay by testing a negative sample (swab alone with no virus present), an Influenza A low positive sample (LoD), an Influenza A positive sample (2x LoD), an Influenza B low positive sample (LoD), and an Influenza B positive sample (2x LoD) in the RAMP Influenza A/B Assay. The Flu strains used to prepare the samples were Influenza A/Hong Kong/8/68 and Influenza B/Lee/40 following titer
{7}------------------------------------------------
Each swab was dosed with the appropriate sample and extracted into Copan determination. Universal Transport media prior to testing in the RAMP Influenza A/B Assay. The RAMP Flu A/B assay is a qualitative assay based on numerical RAMP Ratio values. The %CVs were calculated based on the RAMP Ratios for the testing. The negative sample (swab alone) tested negative. At least 67% of each swab type inoculated with Influenza B at the LoD tested positive for the virus.
Note: In general, calcium alginate swabs are not recommended because they may be cytotoxic to cells and cause viral culture assay inhibition.2.
| RAMP Results | |||||
|---|---|---|---|---|---|
| Swab Material Tested | Negative | Influenza ALoD | Influenza A2x LoD | Influenza BLoD | Influenza B2x LoD |
| Foam | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| Polyester | 100% Neg | 67%Flu A Pos | 100%Flu A Pos | 67 %Flu B Pos | 100%Flu B Pos |
| Rayon | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 67 %Flu B Pos | 100%Flu B Pos |
| Nylon | 100% Neg | 100%Flu A Pos | 100%Flu A Pos | 100%Flu B Pos | 100%Flu B Pos |
| RAMP Ratio % CV | Flu A 17%Flu B 22% | 15% | 8% | 29% | 24% |
CLINICAL PERFORMANCE
Method Comparison
The performance of the RAMP Influenza A/B Assay was compared to cell culture in a prospective study conducted as part of a multi-center trial in North America during the 2006-2007 influenza season when influenza A/H3 (36.5%) and A/H1 (63.5%) were the predominant Influenza A viruses in circulation. Four independent laboratories (located in distinct geographic regions) evaluated the RAMP Influenza A/B Assay in parallel with cell culture. Eight hundred forty-four (844) fresh specimens (nasal wash/aspirate, nasopharyngeal aspirate, or nasopharyngeal swab samples) prospectively collected during the 2006-2007 influenza season were tested. Across the sites these samples were drawn from an approximately equal mix of pediatric (0 – 21 years) and adult patients (21+ years) with approximately equal numbers of male and female patients. The mean (standard deviation) age of the patients was 28.6 (30.7) years. In order to supplement the prospective study, performance of the RAMP Influenza A/B Test was also evaluated by two independent laboratories comparing to the original cell culture testing results (cell culture testing was performed using fresh specimens) on 75 retrospective frozen clinical nasopharyngeal swab samples and 130 retrospective frozen clinical wash/aspirate samples.
{8}------------------------------------------------
Prospective Testing
Sensitivity and Specificity by Age Relative to Culture – Fresh Nasopharyngeal Swab; Age 0-5
| Prospective FreshNasopharyngealSwab(Age 0-5) | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total |
| Positive | 11 | 1 | 12 | 1 | 0 | 1 |
| Negative | 12 | 187 | 199 | 6 | 204 | 210 |
| Total | 23 | 188 | 211 | 7 | 204 | 211 |
| 95% CI | 95% CI | |||||
| Sensitivity | 11/12 | 91.7% | 61.5-99.8% | 1/1 | 100% | NA |
| Specificity | 187/199 | 94.0% | 89.7-96.8% | 204/210 | 97.1% | 93.9-98.9% |
Sensitivity and Specificity by Age Relative to Culture - Fresh Nasopharyngeal Swab; Age 6-21
| Prospective FreshNasopharyngealSwab(Age 6-21) | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total |
| Positive | 12 | 3 | 15 | 2 | 2 | 4 |
| Negative | 4 | 66 | 70 | 4 | 77 | 81 |
| Total | 16 | 69 | 85 | 6 | 79 | 85 |
| 95% CI | 95% CI | |||||
| Sensitivity | 12/15 | 80.0% | 51.9-95.7% | 2/4 | 50.0% | 6.8-93.2% |
| Specificity | 66/70 | 94.3% | 86.0-98.4% | 77/81 | 95.1% | 87.8-98.6% |
Sensitivity and Specificity by Age Relative to Culture - Fresh Nasopharyngeal Swab; Age 22-59
| Prospective FreshNasopharyngealSwab(Age 22-59) | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total |
| Positive | 16 | 7 | 23 | 2 | 2 | 4 |
| Negative | 1 | 136 | 137 | 1 | 155 | 156 |
| Total | 17 | 143 | 160 | 3 | 157 | 160 |
| 95% CI | 95% CI | |||||
| Sensitivity | 16/23 | 69.6% | 47.1-86.8% | 2/4 | 50.0% | 6.8-93.2% |
| Specificity | 136/137 | 99.3% | 96.0-100% | 155/156 | 99.4% | 96.5-100% |
Sensitivity and Specificity by Age Relative to Culture – Fresh Nasopharyngeal Swab; Age ≥60
| Prospective FreshNasopharyngealSwab(Age ≥60) | RAMP Influenza A | RAMP Influenza B | |||||
|---|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total | |
| Positive | 14 | 2 | 16 | 2 | 1 | 3 | |
| Negative | 2 | 152 | 154 | 1 | 166 | 167 | |
| Total | 16 | 154 | 170 | 3 | 167 | 170 | |
| 95% CI | 95% CI | ||||||
| Sensitivity | 14/16 | 87.5% | 61.7-98.4% | 2/3 | 66.7% | 9.4-99.2% | |
| Specificity | 152/154 | 98.7% | 95.4-99.8% | 166/167 | 99.4% | 96.7-100% |
{9}------------------------------------------------
| Prospective FreshNasalWash/Aspirate(Age 0-5) | Tissue Culture | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|---|
| Positive | Negative | Total | Positive | Negative | Total | ||
| Positive | 24 | 4 | 28 | 6 | 0 | 6 | |
| Negative | 6 | 117 | 123 | 1 | 144 | 145 | |
| Total | 30 | 121 | 151 | 7 | 144 | 151 | |
| 95% CI | 95% CI | ||||||
| Sensitivity | 24/28 | 85.7% | 67.3-96.0% | 6/6 | 100% | 54.1-100% | |
| Specificity | 117/123 | 95.1% | 89.7-98.2% | 144/145 | 99.3% | 96.2-100% |
Sensitivity and Specificity by Age Relative to Culture - Fresh Wash/Aspirate; Age 0-5
Sensitivity and Specificity by Age Relative to Culture - Fresh Wash/Aspirate; Age 6-21
| Prospective FreshNasalWash/Aspirate(Age 6-21) | Tissue Culture | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|---|
| Positive | Negative | Total | Positive | Negative | Total | ||
| Positive | 12 | 5 | 17 | 3 | 0 | 3 | |
| Negative | 5 | 41 | 46 | 1 | 59 | 60 | |
| Total | 17 | 46 | 63 | 4 | 59 | 63 | |
| 95% CI | 95% CI | ||||||
| Sensitivity | 12/17 | 70.6% | 44.0-89.7% | 3/3 | 100% | 29.2-100% | |
| Specificity | 41/46 | 89.1% | 76.4-96.4% | 59/60 | 98.3% | 91.1-100% |
Sensitivity and Specificity by Age Relative to Culture - Fresh Wash/Aspirate; Age 22-59
| Prospective FreshNasalWash/Aspirate(Age 22-59) | Tissue Culture | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|---|
| Positive | Negative | Total | Positive | Negative | Total | ||
| Positive | 0 | 0 | 0 | 0 | 0 | 0 | |
| Negative | 0 | 3 | 3 | 0 | 3 | 3 | |
| Total | 0 | 3 | 3 | 0 | 3 | 3 | |
| 95% CI | 95% CI | ||||||
| Sensitivity | 0/0 | NA | NA | 0/0 | NA | NA | |
| Specificity | 3/3 | 100% | 29.2-100% | 3/3 | 100% | 29.2-100% |
Sensitivity and Specificity by Age Relative to Culture - Fresh Wash/Aspirate; Age ≥60
| Prospective FreshNasalWash/Aspirate(Age ≥60) | RAMP Influenza A | RAMP Influenza B | |||||
|---|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total | |
| Positive | 0 | 0 | 0 | 0 | 0 | 0 | |
| Negative | 0 | 1 | 1 | 0 | 1 | 1 | |
| Total | 0 | 1 | 1 | 0 | 1 | 1 | |
| 95% CI | 95% CI | ||||||
| Sensitivity | 0/0 | NA | NA | 0/0 | NA | NA | |
| Specificity | 1/1 | 100% | NA | 1/1 | 100% | NA |
{10}------------------------------------------------
| Prospective FreshNasopharyngealSwab | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total |
| Positive | 53 | 13 | 66 | 7 | 5 | 12 |
| Negative | 19 | 541 | 560 | 12 | 602 | 614 |
| Total | 72 | 554 | 626 | 19 | 607 | 626 |
| 95% CI | 95% CI | |||||
| Sensitivity | 53/66 | 80.3% | 68.7-89.1% | 7/12 | 58.3% | 27.7-84.8% |
| Specificity | 541/560 | 96.6% | 94.8-97.9% | 602/614 | 98.0% | 96.6-99.0% |
Sensitivity and Specificity by Collection Type Relative to Culture - Fresh Nasopharyngeal Swab
Sensitivity and Specificity by Collection Type Relative to Culture - Fresh Wash/Aspirate
| Prospective FreshNasalWash/Aspirate | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total |
| Positive | 36 | 9 | 45 | 9 | 0 | 9 |
| Negative | 11 | 162 | 173 | 2 | 207 | 209 |
| Total | 47 | 171 | 218 | 11 | 207 | 218 |
| 95% CI | 95% CI | |||||
| Sensitivity | 36/45 | 80.0% | 65.4-90.4% | 9/9 | 100% | 66.4-100% |
| Specificity | 162/173 | 93.6% | 88.9-96.8% | 207/209 | 99.0% | 96.6-99.9% |
Retrospective Testing
In order to supplement the prospective study, performance of the RAMP Influenza A/B Test was also evaluated by two independent laboratories comparing to the original cell culture that alle sythally by by here performed originally using fresh specimens) on 75 retrospective frozen clinical nasopharyngeal swab samples and 130 retrospective frozen clinical wash/aspirate samples. The results of the retrospective clinical trials based on sample type are given in the following tables:
Retrospective Positive and Negative Percent Agreements by Collection Type Relative to Culture; Nasopharyngeal Swab
| RetrospectiveFrozenNasopharyngealSwab | RAMP Influenza A | RAMP Influenza B | ||||||
|---|---|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total | ||
| Positive | 11 | 2 | 13 | 23 | 7 | 30 | ||
| Negative | 0 | 62 | 62 | 0 | 45 | 45 | ||
| Total | 11 | 64 | 75 | 23 | 52 | 75 | ||
| 95% CI | 95% CI | |||||||
| Positive PercentAgreement | 11/13 | 84.6% | 54.5-98.1 % | 23/30 | 76.7% | 57.7-90.1% | ||
| Negative PercentAgreement | 62/62 | 100% | 94.2-100% | 45/45 | 100% | 92.1-100% |
{11}------------------------------------------------
| RetrospectiveFrozen NasalWash/Aspirate | RAMP Influenza A | RAMP Influenza B | ||||
|---|---|---|---|---|---|---|
| Tissue Culture | Positive | Negative | Total | Positive | Negative | Total |
| Positive | 35 | 10 | 45 | 33 | 6 | 39 |
| Negative | 2 | 83 | 85 | 2 | 89 | 91 |
| Total | 37 | 93 | 130 | 35 | 95 | 130 |
| 95% CI | 95% CI | |||||
| Positive PercentAgreement | 35/45 | 77.8% | 62.9-88.8% | 33/39 | 84.6% | 69.5-94.1% |
| Negative PercentAgreement | 83/85 | 97.6% | 91.8-99.7% | 89/91 | 97.8% | 92.3-99.7% |
Retrospective Positive and Negative Percent Agreements by Collection Type Relative to Culture; Wash / Aspirate
REFERENCES
·
1 Storch GA, Rapid diagnostic tests for influenza. Current Opinion in Pediatrics 2003, 15:77-84.
2 Lauer and Masters, Journal Clinical Microbiology, 1988 January; 26(1): 54–56
:
:
- 3 Centers for Disease Control, Weekly Report: Influenza Summary Update, Week ending May 19, 2007 - Week 20
{12}------------------------------------------------
DEPARTMENT OF HEALTH & HUMAN SERVICES
DEPARTMENT OF HEALTH & HUMAN SERVICES (USA)
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Mr. Ken Pilgrim Director - Quality/Regulatory Response Biomedical Corporation 100-8900 Glenlyon Parkway Burnaby, B.C. Canada V5J 5J8
APR 1 6 2008
Re: K071591
Trade/Device Name: RAMP® Influenza A/B Assay Regulation Number: 21 CFR § 866.3330 Regulation Name: Influenza virus serological reagents Regulatory Class: I Product Code: GNX Dated: April 3rd, 2008 Received: April 7th, 2008
Dear Mr. Pilgrim:
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 indicons 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 Amendmonts, 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, l'isting 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}------------------------------------------------
Page 2 -
This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at 240-276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at 240-276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at 240-276-3464. You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Sally attayna
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}------------------------------------------------
Statement of Indications for Use
Indications for Use
510(k) Number (if known): K071591 Device Name: RAMP® Influenza A/B Assay Indications for Use:
The RAMP® Influenza A/B Assay is a qualitative immunochromatographic assay used to identify the presence of Influenza A and Influenza B nucleoprotein antigens in nasal wash, nasal aspirate, nasopharyngeal aspirate, and nasopharyngeal swab specimens from symptomatic patients. It is an in vitro diagnostic assay that aids in the rapid differential diagnosis of influenza viral infections in symptomatic patients. A negative test is presumptive and it is recommended these results be confirmed by cell culture. Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other management decisions.
The test performance characteristics for Influenza B were established primarily with retrospective, frozen specimens. Users may wish to further evaluate the sensitivity performance of this test for Influenza B using fresh samples.
Prescription Use × (21 CFR Part 801 Subpart D) And/Or
Over the Counter Use (21 CFR Part 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Uve Schef
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K071591
§ 866.3328 Influenza virus antigen detection test system.
(a)
Identification. An influenza virus antigen detection test system is a device intended for the qualitative detection of influenza viral antigens directly from clinical specimens in patients with signs and symptoms of respiratory infection. The test aids in the diagnosis of influenza infection and provides epidemiological information on influenza. Due to the propensity of the virus to mutate, new strains emerge over time which may potentially affect the performance of these devices. Because influenza is highly contagious and may lead to an acute respiratory tract infection causing severe illness and even death, the accuracy of these devices has serious public health implications.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The device's sensitivity and specificity performance characteristics or positive percent agreement and negative percent agreement, for each specimen type claimed in the intended use of the device, must meet one of the following two minimum clinical performance criteria:
(i) For devices evaluated as compared to an FDA-cleared nucleic acid based-test or other currently appropriate and FDA accepted comparator method other than correctly performed viral culture method:
(A) The positive percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.
(B) The negative percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.
(ii) For devices evaluated as compared to correctly performed viral culture method as the comparator method:
(A) The sensitivity estimate for the device when testing for influenza A must be at the point estimate of at least 90 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 80 percent. The sensitivity estimate for the device when testing for influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.
(B) The specificity estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.
(2) When performing testing to demonstrate the device meets the requirements in paragraph (b)(1) of this section, a currently appropriate and FDA accepted comparator method must be used to establish assay performance in clinical studies.
(3) Annual analytical reactivity testing of the device must be performed with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:
(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA-designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.
(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:
(A) Placing the results directly in the device's § 809.10(b) of this chapter compliant labeling that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or
(B) In the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.
(4) If one of the actions listed at section 564(b)(1)(A)-(D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's § 809.10(b) of this chapter compliant labeling that physically accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.