(85 days)
The BD Directigen™ EZ Flu A+B test is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral antigens from nasopharyngeal washes/aspirates, nasopharyngeal swabs and throat swabs of symptomatic patients. The BD Directigen EZ Flu A+B test 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. All negative test results should be confirmed by cell culture because negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other management decisions.
The BD Directigen EZ Flu A+B test is a chromatographic assay to qualitatively detect influenza A and B viral antigens in samples processed from respiratory specimens. When specimens are processed and added to the test device, influenza A or B viral antigens bind to anti-influenza antibodies conjugated to visualizing particles in the corresponding A and B test strips. The antigen-conjugate complex migrates across the test strip to the reaction area and is captured by the line of antibody on the membrane. A positive result for influenza A is visualized as a reddish-purple line at the Test "T" position and the Control "C" position in the BD Directigen EZ device Flu A read window. A positive result for influenza B is visualized as a reddish-purple line at the Test "T" position and the Control "C" position in the BD Directigen EZ device Flu B read window.
Here's a breakdown of the acceptance criteria and study details based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for sensitivity and specificity. Instead, the study aims to demonstrate substantial equivalence to viral cell culture. The reported performance is as follows:
| Target Performance (Implicit Acceptance Criteria: Substantial Equivalence to Viral Cell Culture) | Reported Device Performance (BD Directigen™ EZ Flu A+B Test) |
|---|---|
| Influenza A | |
| Sensitivity (Prospective Nasopharyngeal Swabs) | 90.7% (146/161) |
| Specificity (Prospective Nasopharyngeal Swabs) | 93.2% (275/295) |
| Positive Agreement (Retrospective Nasopharyngeal Swabs) | 85.7% (6/7) |
| Negative Agreement (Retrospective Nasopharyngeal Swabs) | 96.2% (50/52) |
| Influenza B | |
| Sensitivity (Prospective Nasopharyngeal Swabs) | 100.0% (1/1) |
| Specificity (Prospective Nasopharyngeal Swabs) | 100.0% (455/455) |
| Positive Agreement (Retrospective Nasopharyngeal Swabs) | 74.4% (32/43) |
| Negative Agreement (Retrospective Nasopharyngeal Swabs) | 100.0% (16/16) |
2. Sample Size Used for the Test Set and Data Provenance
- Prospective Test Set: 456 nasopharyngeal swab specimens. The study was a "geographically diverse multi-center study."
- Retrospective Test Set: 59 nasopharyngeal swab specimens. These were "frozen specimens."
- Provenance: The document doesn't specify the exact countries of origin but states it was a "geographically diverse multi-center study," implying multiple locations within potentially different regions. The retrospective samples are specifically noted as "frozen specimens."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not mention the use of experts to establish ground truth. The comparison is made against viral cell culture, which serves as the reference standard. Therefore, there's no information about the number or qualifications of human experts involved in ground truth establishment for this specific study.
4. Adjudication Method for the Test Set
Not applicable. The ground truth was established by viral cell culture, not via human expert consensus requiring adjudication.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) test that produces a qualitative result (positive/negative for influenza A or B). Its performance is evaluated directly against a reference method (viral cell culture), not in terms of how it assists human readers.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, this is a standalone performance study of the device. The BD Directigen™ EZ Flu A+B test is a rapid chromatographic immunoassay, meaning it is a self-contained test that provides results without human interpretation beyond reading the built-in visual lines (reddish-purple lines at "T" and "C" positions). There is no "human-in-the-loop" component in the sense of a diagnostic aid to an interpreting clinician or a software algorithm; it's a direct diagnostic device.
7. The Type of Ground Truth Used
The ground truth used was viral cell culture. For Influenza B, retrospective, frozen specimens were also used, with viral cell culture again serving as the reference standard.
8. The Sample Size for the Training Set
The document does not provide information about a separate "training set" in the context of machine learning or algorithm development. This is an immunoassay device, and its performance characteristics are established through clinical validation studies as described, not through training data in the AI sense.
9. How the Ground Truth for the Training Set Was Established
Not applicable. As noted above, there's no mention of a traditional training set as would be used for an AI/ML algorithm. The performance of the immunoassay is intrinsically defined by its chemical and biological components.
§ 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.