(41 days)
The Alere™ Influenza A & B Test is an in vitro immunochromatographic assay for the qualitative detection of influenza A and B nucleoprotein antigens in nasal swab specimens collected from symptomatic patients. It is intended to aid in the rapid differential diagnosis of influenza A and B viral infections. Negative test results are presumptive and should be confirmed by cell culture or an FDA-cleared influenza A and B molecular assay. 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 Alere™ Influenza A & B Test is an immunochromatographic membrane assay that uses highly sensitive monoclonal antibodies to detect influenza type A and B nucleoprotein antigens in nasal swab specimens. These antibodies and a control protein are immobilized onto a membrane support as three distinct lines and are combined with other reagents/pads to construct a Test Strip.
Nasal swab samples are added to a Coated Reaction Tube to which an extraction reagent has been added. An Alere™ Influenza A & B Test Strip is then placed in the Coated Reaction Tube holding the extracted liquid sample. Test results are interpreted at 10 minutes based on the presence of pink-to-purple colored Sample Lines. The yellow Control Line turns blue in a valid test.
Here's an analysis of the provided text, outlining the acceptance criteria and study details for the Alere™ Influenza A & B Test:
The Alere™ Influenza A & B Test is an in vitro immunochromatographic assay for the qualitative detection of influenza A and B nucleoprotein antigens in nasal swab specimens. It's intended to aid in the rapid differential diagnosis of influenza A and B viral infections.
Acceptance Criteria and Device Performance
The provided document details the performance of the Alere™ Influenza A & B Test against viral culture as the ground truth. While explicit "acceptance criteria" are not stated as target thresholds in this document, the reported performance metrics are presented against the comparison method. We can infer the implied acceptance would be that the device demonstrates adequate diagnostic accuracy (sensitivity and specificity) to be useful for its intended purpose.
Here's the performance as reported in the clinical study:
| Metric | Influenza Type A (Alere Test vs. Culture) | Influenza Type B (Alere Test vs. Culture) |
|---|---|---|
| Sensitivity | 93.8% (95% CI: 83.2, 97.9%) | 77.0% (95% CI: 67.4, 85.0%) |
| Specificity | 95.8% (95% CI: 93.5, 97.3%) | 98.0% (95% CI: 96.1, 99.0%) |
| Invalid Rate | 1.9% (95% CI: 1.0%, 3.5%) - overall | 1.9% (95% CI: 1.0%, 3.5%) - overall |
Study Details
2. Sample Size and Data Provenance
- Test Set Sample Size: A total of 470 prospective nasal swab specimens were evaluated.
- Data Provenance:
- Country of Origin: The study was conducted at seven U.S. trial sites.
- Retrospective/Prospective: The study was a "multi-center, prospective, clinical study conducted at seven U.S. trial sites during the 2008-2009 respiratory season."
3. Number of Experts and Qualifications for Ground Truth
The document does not explicitly state the number or specific qualifications of experts used to establish the ground truth (viral culture). Viral culture itself is a laboratory gold standard, and its interpretation would typically be performed by trained laboratory personnel or microbiologists.
4. Adjudication Method for the Test Set
The document does not describe a formal adjudication method (e.g., 2+1, 3+1) for discordant results between the Alere™ Influenza A & B Test and viral culture for the primary clinical study. However, for the 19 samples where the Alere™ test was negative but culture was positive for influenza B, an investigational RT-PCR assay was used. "Ten (10) of these samples were negative for influenza B by PCR," suggesting a form of secondary confirmation for these specific discrepancies.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
There is no indication that a multi-reader multi-case (MRMC) comparative effectiveness study was done to assess how much human readers improve with AI vs. without AI assistance. This device is a rapid diagnostic test (immunochromatographic assay), not an AI-assisted diagnostic tool for image interpretation or complex data analysis that would typically involve human readers interpreting results.
6. Standalone Performance
Yes, the clinical study directly assesses the standalone performance (algorithm only, without human-in-the-loop performance) of the Alere™ Influenza A & B Test. The reported sensitivity, specificity, and invalid rate are for the device itself against the viral culture.
7. Type of Ground Truth Used
The primary ground truth used for the clinical study was viral culture.
For discordant Influenza B results (Alere negative, culture positive), an investigational RT-PCR assay was used as a secondary confirmation method.
8. Sample Size for the Training Set
The document does not specify a separate "training set" sample size in the context of device development for this immunochromatographic assay. Such devices are typically developed through analytical studies and optimization of reagents, rather than machine learning models that require distinct training sets. The "Analytical Sensitivity" section involved testing various concentrations of influenza viruses, which could be considered part of the development and optimization process, but not a typical "training set" in the AI sense.
9. How Ground Truth for the Training Set Was Established
As there is no explicit "training set" in the context of a machine learning algorithm, the concept of establishing ground truth for a training set does not directly apply here. The analytical studies (Analytical Sensitivity, Analytical Reactivity, Analytical Specificity) used well-characterized viral strains and microorganisms, where their presence and concentration served as the known "ground truth" for evaluating the immunoassay's performance characteristics. This would involve laboratory-established concentrations and identification of these biological agents.
§ 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.