(19 days)
The RAMP® Influenza A/B Assay is a qualitative immunochromatographic assay used to identify the presence of Influenza A and Influenza B nucleoprotein antigens in nasal wash, nasal aspirate, nasopharyngeal aspirate, and nasopharyngeal swab specimens from symptomatic patients. It is an in vitro diagnostic assay that aids in the rapid differential diagnosis of influenza viral infections in symptomatic patients. A negative test is presumptive and it is recommended these results be confirmed by cell culture. Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other management decisions.
The test performance characteristics for Influenza B were established primarily with retrospective, frozen specimens. Users may wish to further evaluate the sensitivity performance of this test for Influenza B using fresh samples.
The RAMP Influenza A/B Assay is a qualitative immunochromatographic test that utilizes the RAMP 200 instrument for the differential determination of Influenza B in nasal wash/aspirate, nasopharyngeal aspirate, and nasopharyngeal swab samples. A wash/aspirate or swab sample is mixed with Sample buffer and applied into the sample well of the Test Cartidge. The sample migrates along the strip. Fluorescent-dyed latex (test) particles, coated with anti-Influenza A and anti-Influenza B antibodies bind to Influenza A or B antigens, respectively, if present in the sample. As the sample migrates along the strip, Influenza-bound particles are captured at either the Influenza A or the Influenza B detection zone, and additional particles are captured at the internal standard zone.
The instrument then measures the amount of fluorescence emitted by the complexes at the two detection zones (Influenza A and Influenza B) and at the internal standard zone. The instrument calculates a ratio (RAMP Ratio) using the fluorescence reading of each detection zone (A or B) and the internal standard zone. The instrument compares these ratios to pre-defined threshold limits to determine a positive or negative result for Influenza B in the tested sample.
The provided text describes the analytical reactivity study for the RAMP® Influenza A/B Assay, specifically for the K093116 submission, which provides additional analytical reactivity information for the previously cleared K071591 device.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance:
The document focuses on analytical reactivity rather than clinical performance (e.g., sensitivity, specificity in patient samples). The implicit acceptance criterion for analytical reactivity is that the device should consistently detect the target antigen at a certain concentration, and not detect at a lower, non-target concentration.
| Characteristic | Acceptance Criteria (Implicit from Study Design) | Reported Device Performance (Influenza A/Swine NY/02/2009) |
|---|---|---|
| Analytical Reactivity | Consistently detect Influenza A at a specified viral load. | Detected Influenza A at 1.0 x 10^2 TCID50/mL with 5/5 positive results. |
| Non-reactivity | Not detect Influenza A at concentrations below the specified viral load. | Did not detect Influenza A at 1.0 x 10^1 TCID50/mL. |
| Cross-reactivity | Not detect Influenza B when only Influenza A is present. | All Influenza B results were negative (5/5 Neg) when testing Influenza A. |
2. Sample Size Used for the Test Set and Data Provenance:
- Test Set Sample Size: For the analytical reactivity study, 5 replicates were tested at each concentration of the Influenza A (Swine NY/02/2009) isolate. This means a total of 25 tests were performed for Influenza A detection (5 concentrations x 5 replicates).
- Data Provenance: The study was conducted using an isolate strain of Influenza A (Swine NY/02/2009) prepared in Copan UTM. This indicates a laboratory-based, analytical study rather than a clinical study with patient samples. The document does not specify a country of origin for the isolate beyond it being "Swine NY/02/2009". It is a prospective study in the sense that the testing was performed specifically for this submission.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts:
- Number of Experts: Not applicable. The ground truth for this analytical study was established by the known concentration of the Influenza A isolate (TCID50/mL), which is a quantitative measure determined through laboratory techniques (e.g., cell culture, endpoint dilution assays). It does not involve human expert consensus for qualitative assessment of clinical samples.
- Qualifications of Experts: Not applicable for this type of analytical study.
4. Adjudication Method for the Test Set:
- Adjudication Method: Not applicable. The results are quantitative (TCID50/mL) and instrument-read (RAMP instrument calculates a ratio and determines positive/negative based on predefined thresholds). There is no human adjudication process described.
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:
- MRMC Study: No. This document describes an analytical reactivity study of a diagnostic device (RAMP® Influenza A/B Assay) which is an "immunochromatographic test that utilizes the RAMP 200 instrument". It is not an AI-based device, and therefore, an MRMC comparative effectiveness study involving human readers with/without AI assistance is not relevant or described.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Standalone Performance: Yes, in a way. The RAMP® Influenza A/B Assay with the RAMP 200 instrument determines the result based on measurement of fluorescence and calculation of a ratio against predefined thresholds. This process is automated ("algorithm only") and does not involve real-time human interpretation or human-in-the-loop performance during the test itself. The study confirms the performance of this automated system in detecting the target analyte.
7. The Type of Ground Truth Used:
- Ground Truth: The ground truth for the analytical reactivity study was the known concentration of the viral isolate (Influenza A/Swine NY/02/2009), quantified in Tissue Culture Infectious Dose 50% (TCID50/mL). This is a precise laboratory-derived standard.
8. The Sample Size for the Training Set:
- Training Set Sample Size: Not specified or applicable in the provided text. This document describes a verification study of an already developed device. It is not clear if an explicit "training set" in the context of machine learning was used, as this is primarily a chemical/immunological assay with an automated reader rather than an AI/machine learning algorithm that requires extensive training data. The "pre-defined threshold limits" for the RAMP instrument would have been established during the device's initial development, but the data used for that is not part of this document.
9. How the Ground Truth for the Training Set Was Established:
- Ground Truth for Training Set: Not specified. As mentioned above, the concept of a "training set" as commonly understood in AI/machine learning isn't explicitly addressed here. The "pre-defined threshold limits" for the RAMP instrument (which guide the positive/negative determination) would have been established during the development of the K071591 device (the predicate). This would likely involve testing characterized positive and negative samples at various concentrations to set appropriate cut-offs, but the details of that process are not included in this submission.
§ 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.