(28 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 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 antigens from nasopharyngeal and nasal swabs of symptomatic patients. The test is to be used as an aid in the diagnosis of influenza A and B viral infections. It 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 test device. Negative test results do not preclude influenza viral infection and should not be used as the sole basis for treatment or other management decisions. All negative test results should be confirmed by another methodology, such as a nucleic acid based method. All BD Veritor System Flu A+B test devices are interpreted by a BD Veritor System Instrument, either a BD Veritor Reader or BD Veritor Plus Analyzer.
The BD Veritor Flu A+B test is an immuno-chromatographic assay for detection of influenza A and B viral antigens in samples processed from respiratory specimens. The viral antigens detected by the BD Flu A+B test are nucleoprotein, not hemagglutinin (HA) or neuraminidase (NA) proteins. Flu viruses are prone to minor point mutations (i.e., antigenic drift) in either one or both of the surface proteins (i.e., HA or NA). The BD Flu A+B test is not affected by antigenic drift or shift because it detects the highly conserved nucleoprotein of the influenza viruses 12. To perform the test, the patient specimen swab is treated in a supplied reaction tube prefilled with a lysing agent that serves to expose the target viral antigens, and then expressed through a filter tip into the sample well on a BD Veritor Flu A+B test device. Any influenza A or influenza B viral antigens present in the specimen bind to anti-influenza antibodies conjugated to colloidal gold micro-particles on the Veritor Flu A+B test strip. The antigen-coniugate complex then migrates across the test strip to the capture zone and reacts with either Anti-Flu A or Anti-Flu B antibodies that are immobilized on the two test lines on the membrane.
The BD Flu A+B test device shown in Figure 1 is 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 active negative control feature in each test identifies and compensates for specimen-related, nonspecific signal generation. The remaining zone is used to measure the assay background.
The Veritor System is made up of assay kits with analyte specific reagents and an optoelectronic interpretation instrument.
The BD Veritor System instruments use a reflectance-based measurement method and apply assay specific algorithms to determine the presence or absence of the target analyte. In the case of the Flu A + B test. the BD Veritor System instruments subtract nonspecific signal at the negative control line from the signal present at both the Flu A and Flu B test lines. If the resultant line signal is above a pre-selected assay cutoff, the specimen scores as positive. If the resultant line signal is below the cutoff, the specimen scores as negative. Use of the active negative control feature allows the BD Veritor System instruments 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 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. Sample preparation is the same for use with both instruments, and both can utilize the same kit components. Neither instrument requires calibration.
The Veritor Reader and the Veritor Plus Analyzer use the functional components and decision algorithm in the firmware. The BD Veritor Plus Analyzer has the flexibility of an optional bar code scanning module and cellular connectivity designed to facilitate record keeping as well as the addition of a "Walk Away" work flow mode. Depending on the configuration chosen by the operator, the Veritor Plus Analyzer communicates status and results to the operator via a liquid crystal display (LCD) on the instrument, a connected printer, or through a secure connection to the facility's information system.
Here's a breakdown of the acceptance criteria and study information for the BD Veritor System for Rapid Detection of Flu A + B CLIA Waived Kit, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" numerical targets. Instead, it presents performance data compared to a reference method (PCR) which implies these are the achieved performance metrics considered acceptable for substantial equivalence. The key performance indicators are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) for influenza A and B.
| Performance Metric | Acceptance Criteria (Implied) | Reported Performance (All Swabs - All Sites) |
|---|---|---|
| Influenza A | ||
| PPA | Not explicitly stated | 83.6% (95% CI: 76.1%, 89.1%) |
| NPA | Not explicitly stated | 97.5% (95% CI: 95.7%, 98.5%) |
| Influenza B | ||
| PPA | Not explicitly stated | 81.3% (95% CI: 71.1%, 88.5%) |
| NPA | Not explicitly stated | 98.2% (95% CI: 95.7%, 99.3%) |
2. Sample Size and Data Provenance for the Test Set
The reported performance data in the table (PPA and NPA) are derived from a test set with the following characteristics:
- Sample Size for Influenza A: 736 total samples (226 PCR positive, 510 PCR negative).
- Sample Size for Influenza B: 736 total samples (171 PCR positive, 565 PCR negative).
- Data Provenance: The document states the performance characteristics were established "during January through March of 2011" and summarizes data "across all age groups, clinical testing sites and sample types." This indicates a prospective clinical study involving collection of symptomatic patient samples. The country of origin is not explicitly stated for the "All Sites" data, but given it's an FDA submission, it's highly likely to include data from the United States. It is a prospective study during the influenza season.
3. Number of Experts and Qualifications for Ground Truth
The document does not mention the use of human experts to establish ground truth for the primary clinical performance data. The reference method for ground truth was a Molecular Assay (PCR).
4. Adjudication Method for the Test Set
Not applicable, as the ground truth was established by a molecular assay (PCR), not expert consensus.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
The document does not describe an MRMC comparative effectiveness study involving human readers with and without AI assistance. The device is a rapid chromatographic immunoassay interpreted by an instrument (BD Veritor Reader or Veritor Plus Analyzer), not an AI-assisted diagnostic for human readers.
The device itself is an automated system for interpreting rapid tests, not a tool to assist human readers in interpreting complex images or data.
6. Standalone (Algorithm Only) Performance
Yes, the study focuses on the standalone performance of the BD Veritor System (the rapid immunoassay device interpreted by the Veritor Reader or Veritor Plus Analyzer). The reported PPA and NPA values represent the performance of the device itself against a reference standard (PCR) without human interpretation.
The "Principle of the Test" section explains: "All BD Veritor System Flu A+B test devices are interpreted by a BD Veritor System Instrument, either a BD Veritor Reader or BD Veritor Plus Analyzer." The instrument's algorithms make the determination.
7. Type of Ground Truth Used
The ground truth used for the clinical performance evaluation was PCR (Polymerase Chain Reaction), which is a molecular assay for detecting influenza A and B. It is referred to as "Reference PCR" in the performance tables.
8. Sample Size for the Training Set
The document does not provide specific details on the sample size used for the training set of the device's inherent algorithms or cutoff thresholds. It mentions that "performance characteristics for influenza A and B were established during January through March of 2011," implying a dataset used for development and validation. For the comparison between Veritor Reader and Veritor Plus Analyzer, the following samples were assessed:
- 102 Flu A-/B- samples
- 52 Flu A+ samples
- 52 Flu B+ samples
These samples were used to confirm equivalency between the interpreting instruments, not necessarily as a "training set" for the assay itself.
9. How the Ground Truth for the Training Set Was Established
The document does not explicitly describe how the ground truth for any "training set" was established. However, given the context, it's highly probable that if a training set was used for algorithm development, the ground truth would also have been established by a highly sensitive and specific reference method like PCR or viral culture, similar to how the ground truth for the test set was established.
§ 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.