(19 days)
Remel Xpect® Flu A&B is a rapid in vitro immunochromatographic test for the direct, qualitative detection of influenza A and influenza B viral antigens (nucleoprotein) from nasal wash, nasal swab, and throat swab specimens from symptomatic patients. The test is intended as an aid in the rapid diagnosis of influenza A and influenza B viral infections. Negative tests should be confirmed by cell culture.
The Xpect® Flu A&B is a chromatographic immunoassay for the qualitative detection of influenza A and influenza B viral antigens. The test device incorporates separate membrane strips for influenza A and for influenza B. To perform the test, the patient specimen is diluted and added to the sample wells of the device. The mixture moves along the membranes by capillary action. If present, influenza A or B viral antigens in the patient sample bind anti-influenza A or B conjugated antibodies. A visible line forms as a complex of antibodyantigen-antibody coated colored particles is captured in the test region (T). Antibody coated colored particles not bound at the test line are later captured in the control region (C) containing goat anti-mouse antibody. A visible line will always appear in the control region indicating that the test is working properly. The presence of a control line combined with the absence of a visible test line is interpreted as a negative test result.
Here's an analysis of the provided text regarding the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria & Reported Device Performance
The provided text describes a 510(k) submission for a device modification (K092423) that expands the reactivity table of an existing device (Remel Xpect® Flu A&B, K031565). The core acceptance criteria revolve around analytical sensitivity, specifically the detection limits for various influenza strains.
| Acceptance Criteria (Stated) | Reported Device Performance (Remel Xpect® Flu A&B - Additional Reactivity Claim) |
|---|---|
| Analytical Sensitivity: Detection of various influenza A and B strains at specified concentrations. The critical new addition for this 510(k) is the detection of A/California/04/2009 (H1N1) at a specified concentration. | Analytical Sensitivity: The device was tested against 16 influenza strains (10 influenza A and 6 influenza B) in a titration study to determine the positive endpoint. |
The key new data point relevant to this specific 510(k) (K092423) is the inclusion of the A/California/04/2009 (H1N1) strain with a detected limit of 4.41 x 10^2 TCID50/ml.
Other key strains and their detection limits are provided in the "Summary of Performance Data" table within the text, for example:
- A/New Caledonia/20/1999 (H1N1): 1.63 x 10^2 TCID50/ml
- A/Fort Monmouth/1/47 (H1N1): 7.9 x 10^1 CEID50/ml
- A/Hong Kong/8/68 (H3N2): 2.8 x 10^1 CEID50/ml
- B/Allen/45 (B): 4 x 10^0 CEID50/ml |
| Intended Use: Rapid in vitro immunochromatographic test for direct, qualitative detection of influenza A and B viral antigens from nasal wash, nasal swab, and throat swab specimens from symptomatic patients, as an aid in rapid diagnosis. Negative tests should be confirmed by cell culture. | Intended Use: The intended use of the modified device has not changed from the predicate device and aligns with the acceptance criteria. |
| Fundamental Scientific Technology: No changes to the fundamental scientific technology. | Fundamental Scientific Technology: The submission explicitly states, "This modification has not had any effect or caused any changes to the FUNDAMENTAL SCIENTIFIC TECHNOLOGY of this device." This was accepted by the reviewer. |
| Risk Assessment: Address risks of false positive and false negative results, with mitigation through labeling, training, QC, and confirmation of negative results. | Risk Assessment: The study indicates that "The risks of false positive and false negative test results as related to the risks to patients, were addressed with labeling, appropriate training for users, customer quality control and confirmation of all negative results by cell culture." |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size (Test Set): For the analytical sensitivity study (which serves as the primary test set for this modification), the study used 16 influenza strains (10 influenza A and 6 influenza B). Each strain was quantitated and subjected to serial titration to determine the detection limit. This is a laboratory-based analytical study, not a clinical study with patient samples.
- Data Provenance: The data is from a retrospective analytical study conducted in a laboratory setting. There is no information provided about the country of origin of the data beyond the applicant "Thermo Fisher Scientific Remel Products" being based in Lenexa, KS, USA, implying the study was conducted internally or contracted within the US. The strains themselves are named with geographic locations (e.g., A/California/04/2009, A/Puerto Rico/8/34), but this refers to the strain's isolation origin, not the origin of the study data.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
- Number of Experts: Not applicable. For this analytical sensitivity study, the "ground truth" for each virus strain's concentration (TCID50/ml or CEID50/ml) would have been established through standardized laboratory methods (e.g., cell culture titration) rather than expert consensus on individual test results.
- Qualifications of Experts: Not applicable. The "ground truth" for viral concentration is determined by quantitative assay rather than human interpretation.
4. Adjudication Method for the Test Set
- Adjudication Method: Not applicable. This was an analytical study determining the detection limit of viral strains. The endpoint was reached when a positive result was consistently observed, implying a clear, objective assessment rather than a need for adjudicated interpretations of ambiguous results.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size
- MRMC Study: No, an MRMC comparative effectiveness study was not conducted. This submission specifically addresses an analytical modification (expanded reactivity) and not a change in the device's human-in-the-loop performance or clinical utility compared to human readers.
- Effect Size: Not applicable as no MRMC study was performed.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
- Standalone Performance: Yes, the analytical sensitivity study is a standalone performance assessment. The device (Remel Xpect® Flu A&B) is an immunochromatographic test, meaning it produces a visual result (a line) directly. The analytical sensitivity study determined the lowest concentration of virus the device could detect on its own, without human interpretation adding to or detracting from its direct reactivity.
7. The Type of Ground Truth Used
- Type of Ground Truth: For the analytical sensitivity study, the ground truth was quantitated viral concentration (expressed as TCID50/ml or CEID50/ml). This is a laboratory-based quantitative measurement of infectious virus particles, which is highly objective.
8. The Sample Size for the Training Set
- Sample Size (Training Set): The document does not provide a specific sample size for a "training set." This is because the device is a rapid in vitro diagnostic (IVD) immunoassay, not a machine learning or AI-driven device that typically undergoes a training phase. Its performance relies on the biochemical interactions of antigens and antibodies. The "training" in this context would be the initial development and optimization of the assay's reagents and format, for which specific sample sizes are not typically reported in such regulatory summaries.
9. How the Ground Truth for the Training Set Was Established
- Ground Truth (Training Set): As mentioned above, there isn't a traditional "training set" in the context of an AI/ML device. For an immunochromatographic assay like the Xpect® Flu A&B, the optimization and development would involve:
- Selection and characterization of antibodies: Ensuring high specificity and affinity for influenza A and B nucleoproteins.
- Optimization of reagent concentrations: Determining the ideal amounts of conjugated antibodies, capture antibodies, and other components for optimal signal-to-noise ratio and sensitivity.
- Optimization of membrane characteristics and flow properties.
- Ground truth during this development phase would be established by testing against a range of known positive (cultured virus, clinical samples confirmed by cell culture or RT-PCR) and negative samples (other respiratory viruses, healthy controls) to refine the assay parameters. Quantitative viral loads (TCID50/ml or CEID50/ml) would likely have been used as the internal ground truth during these developmental stages to guide improvements in detection limits.
§ 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.