(43 days)
The ZstatFlu® Test for Influenza Type A and B Viruses is an endogenous viral-encoded enzyme assay (EVEA) and is intended for use in the qualitative determination of influenza types A and B from throat swab specimens. The ZstatFlu® Test for Influenza Type A and B Viruses is not intended for the detection of influenza C. This test is indicated for the direct testing of patients presenting with influenza-like illnesses.
The Improved ZstatFlu® Test for Influenza Types A and B Virus is an endogenous viralencoded enzyme assay (EVEA) and is intended for use in the qualitative determination of influenza types A and B from throat swab specimens. The Improved ZstatFlu® Test for Influenza Types A and B Virus is not intended for the detection of influenza C. Influenza types A and B virus possess surface glycoproteins with neuraminidase activity, that hydrolyze substrates which contain alpha-ketosidically linked N-acetyIneuraminic acid (Neu5Ac). A modified Neu5Ac molecule has been synthesized and coupled to a chromogen to produce the neuraminidase substrate. In the presence of influenza types A and B virus the chromogenic substrate is then cleaved by the action of viral neuraminidase, releasing a free chromogen. This free chromogen precipitates to produce a blue color. The blue precipitate is then concentrated and collected from the reaction mixture onto a filter device.
Here's a breakdown of the acceptance criteria and study details for the ZstatFlu® Test for Influenza Types A and B Virus, based on the provided document:
Acceptance Criteria and Device Performance
The document does not explicitly state pre-defined "acceptance criteria" with numerical thresholds for sensitivity and specificity that the device was required to meet. Instead, it reports the observed performance characteristics from the clinical study. The FDA's letter of clearance (K982429) confirms that the device was found substantially equivalent to legally marketed predicate devices, implying that its performance was deemed acceptable for its intended use.
Here are the reported performance characteristics:
| Performance Metric | Reported Device Performance (%) |
|---|---|
| Detection of Influenza Types A and B | |
| Sensitivity (Positive Agreement) | 62.2% (51/82) |
| Specificity (Negative Agreement) | 98.7% (74/75) |
| Detection of Influenza Type A | |
| Sensitivity (Positive Agreement) | 65.3% (32/49) |
| Specificity (Negative Agreement) | 99.1% (107/108) |
| Detection of Influenza Type B | |
| Sensitivity (Positive Agreement) | 57.6% (19/33) |
| Specificity (Negative Agreement) | 99.2% (123/124) |
| Reproducibility | 100% correlation |
Study Details
-
Sample Size used for the test set and the data provenance:
- Sample Size: 157 throat swab specimens.
- Data Provenance:
- Country of Origin: United States.
- Retrospective or Prospective: The specimens were collected from field sites during the 1995-96 influenza season (November 11, 1995 to March 29, 1996) and then tested. This indicates a prospective collection for the purpose of the study.
- Collection Sites: Seven separate locations throughout the United States, including physician offices, laboratories, clinics, and hospital settings. Specifically, six physicians and their nurses and technicians from two physician offices in a Southwest region participated in collection and testing.
-
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not explicitly state the number of individual experts or their specific qualifications (e.g., radiologist with X years of experience).
- However, it mentions "the reference method of viral isolation and culture confirmation with monoclonal antibodies" conducted at a "Southwestern viral testing laboratory." This implies that trained laboratory personnel and virologists were involved in establishing the ground truth, but specific numbers and detailed qualifications are not provided.
-
Adjudication method for the test set:
- The document does not mention an adjudication method (like 2+1 or 3+1) for the interpretation of the reference method results. It simply states the reference method was "viral isolation and culture confirmation with monoclonal antibodies."
-
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, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This is an in vitro diagnostic device (IVD) for direct detection of viruses, and the study design focuses on comparing the device's performance against a laboratory reference standard, not human reader performance.
-
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, the performance data presented is for the device in a standalone manner (algorithm only, without human-in-the-loop performance in terms of interpretation, other than operating the test according to instructions). The test is an "endogenous viral-encoded enzyme assay (EVEA)" that produces a visible color change, which is then presumably read and interpreted by the user of the device. The reproducibility studies, however, did assess variations across different users and settings.
-
The type of ground truth used:
- The ground truth used was laboratory reference standard: viral isolation and culture confirmation with monoclonal antibodies.
-
The sample size for the training set:
- The document does not specify a separate training set or its sample size. The ZstatFlu® test is described as an "endogenous viral-encoded enzyme assay (EVEA)" based on a chemical reaction, not a machine learning algorithm that typically requires a training set. Manufacturers of such diagnostic kits typically validate the assay's performance characteristics through analytical and clinical studies, rather than "training" an AI model.
-
How the ground truth for the training set was established:
- Not applicable, as there is no mention of a traditional "training set" for a machine learning model.
§ 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.