(164 days)
The Cepheid Xpert® Xpress Flu Assay, performed on the GeneXpert® Instrument Systems, is an automated, multiplex real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay intended for the in vitro qualitative detection and differentiation of influenza A and influenza B viral RNA. The Xpert Xpress Flu Assay uses nasopharyngeal (NP) swab specimens collected from patients with signs and symptoms of respiratory infection. The Xpert Xpress Flu Assay is intended as an aid in the diagnosis of influenza infections in conjunction with clinical and epidemiological risk factors.
Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions.
Performance characteristics for influenza A were established during the 2015-2016 influenza season. When other novel influenza A viruses are emerging, performance characteristics may vary.
If infection with a novel influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
The Xpert Xpress Flu Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A) and influenza B (Flu B) viral RNA directly from nasopharyngeal (NP) swab specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.
The Xpert Xpress Flu Assay includes reagents for the simultaneous detection and differentiation of the target viruses. The primers and probes in the Xpert Xpress Flu Assay detect the presence of nucleic acid sequences for Flu A and Flu B directly from NP swab specimens collected from patients with signs and symptoms of respiratory infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Instrument System platform. The SPC is present in every assay to control for adequate processing of the target viruses and to monitor for the presence of inhibitor(s) in the PCR assay to avoid false-negative results. The PCC verifies reagent rehydration, real-time PCR tube filling in the cartridge, probe integrity, and dye stability.
The specimens are collected in viral transport medium and transported to the GeneXpert area. The specimen is prepared according to package insert instructions and transferred to the sample chamber (large opening) of the Xpert Xpress Flu Assay cartridge. The GeneXpert cartridge is loaded onto the GeneXpert Instrument System platform, which performs hands-off automated sample processing and real-time RT-PCR for detection of Flu viral RNA. Summary and detailed test results are obtained in approximately 30 minutes or less. The results are automatically generated at the end of the process in a report that can be viewed and printed.
The provided document describes the Cepheid Xpert Xpress Flu Assay, an automated, multiplex real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay for the qualitative detection and differentiation of influenza A and influenza B viral RNA. The study referenced aims to demonstrate the substantial equivalence of this device to a legally marketed predicate device, the Xpert Flu/RSV XC Assay (K142045).
Here's a breakdown of the requested information 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 specific thresholds for PPA (Positive Percent Agreement) and NPA (Negative Percent Agreement) that the device must meet. However, the reported performance is compared to an FDA-cleared molecular comparator assay to demonstrate substantial equivalence. The reported performance can be interpreted as implicitly meeting the expectation for substantial equivalence.
| Metric (Target) | Acceptance Criteria (Implicit) | Reported Device Performance (Combined Dataset) |
|---|---|---|
| PPA (Influenza A) | Performance comparable to FDA-cleared molecular comparator assay | 98.1% (CI: 93.4-99.5) |
| NPA (Influenza A) | Performance comparable to FDA-cleared molecular comparator assay | 98.4% (CI: 97.7-98.8) |
| PPA (Influenza B) | Performance comparable to FDA-cleared molecular comparator assay | 100.0% (CI: 95.3-100.0) |
| NPA (Influenza B) | Performance comparable to FDA-cleared molecular comparator assay | 98.7% (CI: 98.1-99.1) |
| Analytical Specificity | 100% (No cross-reactivity with common respiratory pathogens) | 100% |
| Analytical Reactivity (Inclusivity) | All tested influenza strains to be detected | Positive in all three replicates for all but one strain (which was 2/3 at 0.1 TCID50/mL) |
| Carry-Over Contamination | No contamination of negative samples | 100% correct reporting for all negative samples (Flu A NEGATIVE; Flu B NEGATIVE) |
| Fresh vs. Frozen Sample Equivalency | No difference in performance between fresh and freeze-thaw samples | No difference; all positive and negative replicates correctly identified |
| Competitive Interference | Identification of potential inhibitory effects | Competitive inhibitory effects observed under specific conditions |
2. Sample Size Used for the Test Set and Data Provenance
-
Sample Size (Clinical Comparison Study - NP Swab Specimens):
- Total: 2065 NP swab specimens
- Fresh, prospectively collected: 1142 specimens
- Consistently collected, frozen: 923 specimens
- Pre-selected frozen NP swab specimens (analyzed separately): 102 specimens
-
Data Provenance: The study was conducted at eleven institutions in the U.S. during the 2015-2016 influenza season. The data includes both prospectively collected fresh specimens and retrospectively (consecutively) collected 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 specify the number or qualifications of experts used to establish the ground truth for the clinical test set. The ground truth for the clinical comparison study was established by an "FDA-cleared molecular comparator assay."
4. Adjudication Method for the Test Set
- For discordant results between the Xpert Xpress Flu Assay and the comparator assay, bi-directional sequencing was performed. The text states this was "for informational purposes only," implying it was used to investigate discrepancies rather than for primary adjudication that would re-classify initial ground truth results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted as described in the document. This study focuses on the performance of the assay itself compared to a reference method, not on human reader performance with or without AI assistance.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
- Yes, the clinical comparison study directly evaluates the standalone performance of the Xpert Xpress Flu Assay (the algorithm/device) against an FDA-cleared molecular comparator assay. The results provided in Table 8-9 (PPA, NPA) are for the device alone.
7. Type of Ground Truth Used
- Clinical Comparison Study: The ground truth for the clinical comparison study was established using an FDA-cleared molecular comparator assay. For discordant results, bi-directional sequencing was used for informational purposes.
- Analytical Studies (LoD, Specificity, Reactivity, Interference): Ground truth was established by known concentrations of purified viruses or bacterial/yeast strains in simulated matrices.
8. Sample Size for the Training Set
- The document describes a submission for a medical device (assay) and its performance evaluation. It does not refer to an "AI algorithm" in the common sense of machine learning that would have a separate "training set" of data. The assay's design and optimization would have involved internal development and validation, but this is not presented as a distinct "training set" in the context of typical AI device submissions. The analytical and clinical studies describe the test set used to validate the final device.
9. How the Ground Truth for the Training Set Was Established
- As mentioned above, the concept of a "training set" in the context of an AI algorithm is not explicitly applicable here. The device is a molecular diagnostic assay. Its "training" (development and optimization) would involve standard laboratory methods, reagent formulation, and protocol refinement to achieve optimal detection and differentiation of target nucleic acid sequences. The ground truth for this development phase would be established through controlled experiments using known positive and negative controls, spiked samples, and characterized clinical samples, as outlined in the non-clinical studies (e.g., LoD, inclusivity, specificity studies).
§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.
(a)
Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.