(26 days)
The BD Veritor™ System for Rapid Detection of Flu A+B is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral nucleoprotein antigens from nasal and nasopharyngeal swabs of symptomatic patients. The BD Veritor System for Rapid Detection of Flu A+B (also referred to as the BD Veritor System and BD Veritor System Flu A+B) is a differentiated test, such that influenza A viral antigens can be distinguished from influenza B viral antigens from a single processed sample using a single device. The test is to be used as an aid in the diagnosis of influenza A and B viral infections. A negative test is presumptive and it is recommended that these results be confirmed by viral culture or an FDA-cleared influenza A and B molecular assay. Outside the U.S., a negative test is presumptive and it is recommended that these results be confirmed by viral culture or a molecular assay cleared for diagnostic use in the country of use. FDA has not cleared this device for use outside of the U.S. Negative test results do not preclude influenza viral infection and should not be used as the sole basis for treatment or other patient management decisions. The test is not intended to detect influenza C antigens.
The BD Flu A+B test is a chromatographic assay to qualitatively detect influenza A and B viral antigens in respiratory specimens. The patient specimen is mixed in a prefilled unitized tube containing RV Reagent D and added to the test device. RV Reagent D contains mucolytic agents that function to break down mucus in a patient specimen thereby exposing viral antigens and enhancing detection in the assay device. Processed specimens are expressed through a filter tip into a single sample well on the BD Flu A+B test device.
The specimen is mixed and added to the test device where influenza A or influenza B viral antigens bind to anti-influenza antibodies conjugated to detector particles on the BD Flu A+B test strip. The antigen-conjugate complex migrates across the test strip to the reaction area and is captured by an antibody line on the membrane. The assay utilizes a proprietary enhanced colloidal-gold particle at the test lines as the means for identifying the presence of influenza A or B viral antigens. The BD Flu A+B test devices are designed with five spatially-distinct zones including positive and negative control line positions, separate test line positions for the target analytes, and a background zone. The test lines for the target analytes are labeled on the test device as 'A' for Flu A position, and 'B' for Flu B position. The onboard positive control ensures the sample has flowed correctly and is indicated on the test device as 'C'. Two of the five distinct zones on the test device are not labeled. These two zones are an onboard negative control line and an assay background zone. The onboard negative control zone addresses non-specific signal generation and is not labeled on the test device. The remaining zone is used to measure the assay background and is also not labeled.
The BD Flu A+B assay incorporates an active negative control feature in each test to identify and compensate for sample-related, nonspecific signal generation. The BD Veritor™ System Reader uses a proprietary algorithm which subtracts nonspecific signal at the negative control line from the signal present at both the Flu A and Flu B test lines. If the resultant test line signal is above a pre-selected assay cutoff, the specimen is scored as positive. If the resultant test line signal is below the cutoff, the specimen is scored as negative. Use of the active negative control feature allows the BD Veritor™ System reader to correctly interpret test results that cannot be scored visually because the human eye is unable to accurately perform the subtraction of the nonspecific signal.
The BD Veritor™ System Reader measures the amount of light reflected from various zones along the assay strip. The measurement of the assay background zone is an important factor during test interpretation as the reflectance is compared to that of the control and test zones. A background area that is white to light pink indicates the device has performed correctly. The instrument analyzes the reflectance data to provide the proper interpretation.
The provided document describes a Special 510(k) submission for a modification to the BD Veritor™ System for Rapid Detection of Flu A+B. The modification involves updating the product insert with new strain reactivity data, which did not change the intended use or fundamental scientific technology of the device.
Here's a breakdown of the requested information based on the provided text:
1. A table of acceptance criteria and the reported device performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Ability to detect additional Flu strains. | Veritor was successful in detecting all strains tested. (From "RESULTS OF THE ANALYSIS" section) |
| A positive instrumented read with samples of subject flu viruses. | The study listed specific LODs (Limit of Detection) for each of the 14 tested influenza A and B strains, indicating that the device provided a positive instrumented read at these concentrations. For example, A/Fujian-Gulou/1896/2009 H1N1 was detected at $4.5 \times 10^5$ CEID50/mL. |
| No cross-reactivity between Flu A and Flu B lines. | For Flu A strains, "none cross react with the Flu B line." For Flu B strains, "none cross react with the Flu A line." (From "Conclusions" section) |
| Reduce the probability of occurrence for the hazard of "False Negative". | The study results reduced the probability of occurrence from P-3 ("Occasional") to P-1 ("Improbable"), thereby reducing the risk to the "negligible" category (GR). (From "RESULTS OF THE ANALYSIS" section) |
2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
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Test Set Sample Size:
- Viruses: 9 Flu A strains and 5 Flu B strains (total of 14 strains).
- Replicates: 10-fold dilutions from the stock were tested in triplicate. This means 14 strains * an unspecified number of 10-fold dilutions * 3 replicates. The exact number of dilutions isn't specified, but it's more than just 14 individual tests.
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Data Provenance:
- Country of Origin of Data: The study was conducted at the R/D laboratories in San Diego, CA, USA.
- Retrospective or Prospective: Not explicitly stated, but the study was conducted to confirm reactivity to new strains forecasted for the 2015/2016 Influenza Season and other available strains (CDC and WHO). This suggests a prospective testing approach for these specific strains. The primary clinical performance for the original device was established "during January through March of 2011" (mentioned in the "Indications for Use" section), but this specific submission focuses on new strain reactivity, which implies a prospective evaluation of freshly acquired or newly relevant strains.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
The ground truth for the test set was established by viral culture and titration, not clinical expert consensus. The viral material was obtained from the WHO Collaborating Centre for Surveillance, Epidemiology and Control of Influenza and the US Centres for Disease Control, and some were amplified and titred following procedures outlined in the WHO Manual on Animal Influenza Diagnosis and Surveillance (2002). The study was conducted "under the direction of Richard Anderson Ph.D. at the R/D laboratories." The expertise involved is in virology and laboratory methods for viral quantification (TCID50, EID50, HA), not clinical diagnosis by medical experts.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. The ground truth was established by laboratory methods (viral culture and titration) and objective instrument readings, not by human interpretation or adjudication processes involving multiple experts making subjective judgments. The device itself uses a "proprietary algorithm which subtracts nonspecific signal at the negative control line from the signal present at both the Flu A and Flu B test lines" to score results.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
No MRMC comparative effectiveness study was done. This device is a rapid chromatographic immunoassay read by an instrument (BD Veritor™ System Reader), not by human readers interpreting images or complex data that would typically involve an MRMC study. The focus is on the device's ability to detect different viral strains, not on human interpretive performance.
6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done
Yes, a standalone study was performed. The BD Veritor™ System Reader automatically interprets the test strip signals using its proprietary algorithm without human-in-the-loop decision-making for the result itself. The study focused on the device's ability to objectively detect the viral antigens at specific concentrations.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth used was based on laboratory-confirmed viral presence and quantification via methods like TCID50 (Tissue Culture Infectious Dose 50%), CEID50 (Chicken Embryo Infectious Dose 50%), EID50 (Egg Infectious Dose 50%), and HA (Hemagglutination assay) titers. This is a form of highly objective, laboratory-based "pathology" in the context of infectious disease diagnostics.
8. The sample size for the training set
The document does not explicitly state a sample size for a training set. This submission is for a modification to an already cleared device, focusing on analytical reactivity to new strains. The device's core algorithm and performance characteristics (established in previous 510(k) clearances, K112277, K132259, K132692) would have been based on extensive development and potentially training data, but those details are not provided in this document for this modification. The current study is an analytical verification rather than a de novo development or clinical training study.
9. How the ground truth for the training set was established
As no training set is explicitly discussed in this document, the method for establishing its ground truth is also not detailed. For the analytical study described, the "ground truth" (i.e., the known presence and concentration of specific viral strains) was established through laboratory methods of viral culture, amplification, and titration, as detailed in point 3 above.
§ 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.