The BioSign Flu A+B test is an in vitro rapid qualitative test that detects influenza type A and type B nucleoprotein antigens directly from nasal swab, nasopharyngeal swab, and nasopharyngeal aspirate/wash specimens obtained from patients with signs and symptoms of respiratory infection. It is intended to aid in the rapid differential diagnosis of influenza A and B viral infections. Negative test results are presumptive and it is recommended these results be confirmed by viral culture. 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 test is intended for professional and laboratory use. Performance characteristics for influenza were established during the 2007-2009 influenza seasons when influenza A viruses A/New Caledonia/20/99 (H1N1), A/Solomon Islands/3/2006 (H1N1), A/Brisbane/59/2007 (H1N1), A/California/07/2009 (H1N1), A/Wisconsin/67/2005 (H3N2), A/Brisbane/10/2007 (H3N2), and influenza B viruses B/Ohio/01/2005, B/Florida/4/2006, B/Brisbane/60/2008 were the predominant influenza viruses in circulation according to the Flu Activity & Surveillance report by CDC. Performance characteristics may vary against other emerging influenza viruses. If infection with a novel influenza virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted in these cases unless a BSL+3 facility is available to receive and culture specimens.
Device Story
BioSign Flu A+B is a solid-phase chromatographic immunoassay for qualitative detection of influenza A and B nucleoprotein antigens. Device uses nasal or nasopharyngeal specimens; samples are incubated for 1 minute in extraction reagent. Test utilizes colloidal gold-labeled antibodies; results are read visually after 10 minutes. Internal control (reddish-purple line) confirms proper flow. Intended for professional/laboratory use to aid clinical diagnosis; negative results are presumptive and require confirmation by viral culture. Device does not provide definitive diagnosis; results should be used alongside clinical/epidemiological criteria. Modification adds H5N1 strains (A/Vietnam/1194/2004 and A/Anhui/01/2005) to analytical inclusivity table.
Clinical Evidence
No clinical data provided. Substantial equivalence is supported by analytical testing demonstrating the device's ability to detect the added H5N1 influenza strains.
Technological Characteristics
Solid-phase chromatographic immunoassay; colloidal gold test line; visual readout; internal control line. No software or electronic components.
Indications for Use
Indicated for professional and laboratory use to aid in the rapid differential diagnosis of influenza A and B viral infections in patients with signs and symptoms of respiratory infection, using nasal swab, nasopharyngeal swab, or nasopharyngeal aspirate/wash specimens.
Regulatory Classification
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.
Special Controls
*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.
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SPECIAL 510(k): Device Modification Decision Summary
To: Princeton Biomeditech Corporation
RE: K133474
This 510(k) submission contains information/data on modifications made to the SUBMITTER'S own Class I device requiring a 510(k). The following items are present and acceptable
1. The names and 510(k) number of the SUBMITTER'S previously cleared device:
Trade Names: BioSign® Flu A+B, Status Flu A & B
510(k) number: K132465
2. Submitter's statement that the INDICATION/INTENDED USE of the modified device as described in its labeling HAS NOT CHANGED along with the proposed labeling which includes instructions for use, package labeling, and if available, advertisements or promotional materials.
3. A description of the device MODIFICATION(S):
The modification presented in this 510(k) consisted of expanding the Analytical Inclusivity section of the package insert to include reactivity information for two strains of the H5N1 subtype of influenza A virus, A/Vietnam/1194/2004 and A/Anhui/01/2005.
The ability of the BioSign Flu A+B Test to detect H5N1 was tested using the aforementioned influenza virus strains. These strains were obtained from the Influenza Reagent Resource (established by the Centers for Disease Control and Prevention and managed by the American Type Culture Collection) as non-infectious beta-propiolactone inactivated virus. An analytical inclusivity study was performed with each of the viruses using the same procedure employed in the original submission. Each titered virus was diluted until the minimal visual signal intensity appeared on the test line. This was defined as the lowest reacting level of the virus. Each virus was then tested in triplicate at that dilution. All virus strains tested were detected in 3 out of 3 tests at the lowest reacting level. The lowest reactivity level for each virus is listed below:
- A/Anhui/01/2005 (H5N1) – 1.6 x 10⁷ EID₅₀/mL
- A/Vietnam/1194/2004 (H5N1) – 1.6 x 10⁶ EID₅₀/mL
The package inserts for the BioSign Flu A+B Test and the Status Flu A&B Test have been updated to include the additional analytical reactivity information. Status Flu A&B is the name of the same device being sold by LifeSign LLC under agreement with Princeton BioMeditech Corporation.
4. The FUNDAMENTAL SCIENTIFIC TECHNOLOGY of the modified devices has not changed.
5. Comparison Information (similarities and differences) to applicant's legally marketed predicate devices including, labeling, intended use, and physical characteristics:
Similarities
| | Modified Device | Predicate Device |
| --- | --- | --- |
| Features | BioSign Flu A+B | BioSign Flu A+B |
| Intended Use | The BioSign Flu A+B test is an in vitro rapid qualitative test that detects influenza type A and type B nucleoprotein antigens directly from nasal swab, nasopharyngeal swab, and nasopharyngeal aspirate/wash specimens obtained from patients with signs and symptoms of respiratory infection. It is intended to aid in the | The BioSign Flu A+B test is an in vitro rapid qualitative test that detects influenza type A and type B nucleoprotein antigens directly from nasal swab, nasopharyngeal swab, and nasopharyngeal aspirate/wash specimens obtained from patients with signs and symptoms of respiratory infection. It is intended to aid in the |
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| | to aid in the rapid differential diagnosis of influenza A and B viral infections. Negative test results are presumptive and it is recommended these results be confirmed by viral culture. 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 test is intended for professional and laboratory use. Performance characteristics for influenza were established during the 2007-2009 influenza seasons when influenza A viruses A/New Caledonia/20/99 (H1N1), A/Solomon Islands/3/2006 (H1N1), A/Brisbane/59/2007 (H1N1), A/California/07/2009 (H1N1), A/Wisconsin/67/2005 (H3N2), A/Brisbane/10/2007 (H3N2), and influenza B viruses B/Ohio/01/2005, B/Florida/4/2006, B/Brisbane/60/2008 were the predominant influenza viruses in circulation according to the Flu Activity & Surveillance report by CDC. Performance characteristics may vary against other emerging influenza viruses. If infection with a novel influenza virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted in these cases unless a BSL+3 facility is available to receive and culture specimens. | rapid differential diagnosis of influenza A and B viral infections. Negative test results are presumptive and it is recommended these results be confirmed by viral culture. 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 test is intended for professional and laboratory use. Performance characteristics for influenza were established during the 2007-2009 influenza seasons when influenza A viruses A/New Caledonia/20/99 (H1N1), A/Solomon Islands/3/2006 (H1N1), A/Brisbane/59/2007 (H1N1), A/California/07/2009 (H1N1), A/Wisconsin/67/2005 (H3N2), A/Brisbane/10/2007 (H3N2), and influenza B viruses B/Ohio/01/2005, B/Florida/4/2006, B/Brisbane/60/2008 were the predominant influenza viruses in circulation according to the Flu Activity & Surveillance report by CDC. Performance characteristics may vary against other emerging influenza viruses. If infection with a novel influenza virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted in these cases unless a BSL+3 facility is available to receive and culture specimens. |
| --- | --- | --- |
| Specimen Type | Same as predicate device | Nasal swab, nasopharyngeal swab, nasopharyngeal aspirate/wash |
| Analytical Principle | Same as predicate device | Solid phase chromatographic immunoassay |
| Extraction | Same as predicate device | Incubated 1 minute in extraction reagent |
| Read Result Time | Same as predicate device | 10 minutes |
| Test Line | Same as predicate device | Colloidal gold |
| Internal Control | Same as predicate device | Reddish-purple line |
| Control Samples | Same as predicate device | Positive control swab: Influenza A and B antigens (non-infective recombinant nucleoprotein)
Negative control swab: Inactivated group B Streptococcus antigen (non-infective) |
## Differences
1) The package insert for the BioSign Flu A+B (K083746) has been updated to include detection of the A/Vietnam/1194/2004 and A/Anhui/01/2005 viruses in the analytical inclusivity section at the following reactivity levels:
- A/Anhui/01/2005 (H5N1)** – 1.6 x 10⁷ EID₅₀/mL
- A/Vietnam/1194/2004 (H5N1)** – 1.6 x 10⁶ EID₅₀/mL
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2) The following language is included in the package insert on page 7 in the analytical inclusivity section (below the analytical inclusivity table):
**Although this test has been shown to detect these viral strains cultured from positive human respiratory specimens, the performance characteristics of this device with clinical specimens that are positive for these viruses have not been established.**
3) The following language was removed from the package insert on page 7 in the analytical inclusivity section (below the analytical inclusivity table) as the results of the testing provided in K133474 make this language unnecessary.
NOTE: The performance characteristics of the test with cultured avian influenza A subtype H5N1 virus, or with specimens from humans infected with H5N1 or other avian influenza viruses have not been established.
## 6. Design Control Activities Summary:
1) Analytical reactivity testing was conducted for the H5N1 virus using identical methods employed in the original submission for the unmodified device.
2) Risk Analysis
The risk analysis method used to assess the impact of the modification (adding additional viruses to the analytical sensitivity section of the package insert) was a Failure Modes and Effects Analysis (FMEA). Based on the result of the risk analysis, the verification activities required and acceptance criteria were identified. Because the change is adding detection levels of additional virus strains without changing any other characteristics of the test device (including the fundamental scientific technology or indications for use), no risk is involved for this change except as listed below:
| Change | Hazard | Resolution of Risk | Testing Performed | Test Method | Acceptance Criteria | Acceptance Criteria Met |
| --- | --- | --- | --- | --- | --- | --- |
| Addition of new virus strains to package insert | Non-detection of any of the adding virus strains | Confirm Analytical Sensitivity for all additional strains | Analytical Sensitivity Testing conducted for each of the added strains | Tested in triplicate for each dilution of each additional strain | Positive Results at 10 minutes for each virus at the determined analytical sensitivity level. | *Yes |
| | Misinterpretation of test use: test used for detection of the additional strains from human specimen | Labeling: Limitation of test provided in the below of inclusivity table | N/A | N/A | N/A | N/A |
*This was indicated after all experiments were completed.
## 2) Declaration of Conformity
A "Declaration of Conformity" statement was submitted for the manufacturing facility and validation activities and signed by the Regulatory Affairs Manager and the Quality Assurance Manager. The statements indicate that:
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a) As required by the risk analysis, all verification and validation activities were performed by the designated individuals and the results demonstrated that the predetermined acceptance criteria were met.
b) The manufacturing facility is in conformance with the design control procedure requirements as specified in 21 CFR 820.30 and the records are available for review.
In conclusion, based on the results of the analytical reactivity testing the modified labeling is truthful and accurate. The changes do not affect the performance of the BioSign Flu A+B Test therefore the modified test is substantially equivalent to the currently cleared test.
7. A Truthful and Accurate Statement, a 510(k) Summary, and the Indications for Use Enclosure.
The labeling for the modified subject device has been reviewed to verify that the indication/intended use for the device is unaffected by the modification. In addition, the submitter's description of the particular modification and the comparative information between the modified and unmodified devices demonstrate that the fundamental scientific technology has not changed. On this basis, I recommend that the device is determined to be substantially equivalent to the previously cleared device.
