(174 days)
The Cepheid Xpert® Xpress Flu/RSV Assay, performed on the GeneXpert® Instrument Systems, is an automated, multiplex real-time, reverse transcriptase chain reaction (RT-PCR) assay intended for the in vitro qualitative detection and differentiation of influenza B. and respiratory syncytial virus (RSV) viral RNA. The Xpert Xpress Flu/ RSV Assay uses nasopharyngeal (NP) swab specimens with signs and symptoms of respiratory infection. The Xpert Xpress Flu/RSV Assav is intended as an aid in the diagnosis of influenza and respiratory syncytial virus infections in conjunction with clinical and epidemiological risk factors.
Negative results do not preclude influenza virus or RSV 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.
Ancillary Collection Kit Indications for Use:
The Xpert® Nasopharyngeal Sample Collection Kit is designed to collect, preserve, and transport nasopharyngeal swab specimens and to preserve and transport nasal aspirate/wash specimens containing viruses from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Flu Assay or the Xpert Flu/RSV XC Assay.
The Xpert® Nasopharyngeal Sample Collection Kit is designed to collect, preserve, and transport nasopharyngeal swab specimens containing viruses from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Flu+RSV Xpress Assay or the Xpert Xpress Flu/RSV Assay.
The Xpert Xpress Flu/RSV Assay is a rapid, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A (Flu A), influenza B (Flu B), and respiratory syncytial virus (RSV) viral RNA directly from nasopharyngeal (NP) swab specimens. The assay is performed on the Cepheid GeneXpert® Instrument Systems.
The Xpert Xpress Flu/RSV Assay includes reagents for the simultaneous detection and differentiation of the target viruses. The primers and probes in the Xpert Xpress Flu/RSV Assay detect the presence of nucleic acid sequences for Flu A, Flu B, and RSV 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/RSV 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 and RSV 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 Cepheid Xpert® Xpress Flu/RSV Assay 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, influenza B, and respiratory syncytial virus (RSV) viral RNA from nasopharyngeal (NP) swab specimens. It is designed to aid in the diagnosis of influenza and respiratory syncytial virus infections.
Here's an analysis of the acceptance criteria and the studies performed:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a table format with performance targets, but rather presents the results of clinical and analytical studies to demonstrate substantial equivalence to a predicate device. Based on the clinical comparison study, the implicit acceptance criteria would be high Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to an FDA-cleared molecular comparator assay.
| Metric (vs. Comparator Assay) | Target (Implicit) | Reported Device Performance (Combined Dataset, N=2065 NP swabs) |
|---|---|---|
| Influenza A | PPA: High (e.g., >95%) | 98.1% (95% CI: 93.4-99.5) |
| NPA: High (e.g., >95%) | 98.4% (95% CI: 97.7-98.8) | |
| Influenza B | PPA: High (e.g., >95%) | 100.0% (95% CI: 95.3-100.0) |
| NPA: High (e.g., >95%) | 98.7% (95% CI: 98.1-99.1) | |
| RSV | PPA: High (e.g., >95%) | 98.5% (95% CI: 91.8-99.7) |
| NPA: High (e.g., >95%) | 98.8% (95% CI: 98.2-99.2) | |
| Analytical Specificity (Exclusivity) | 100% | 100% |
| Reproducibility (Total Agreement) | High (e.g., >90%) | Negative: 100%; Flu A-Low Pos: 93.7%; Flu A-Mod Pos: 100%; Flu B-Low Pos: 95.1%; Flu B-Mod Pos: 98.6%; RSV-Low Pos: 94.4%; RSV-Mod Pos: 100% |
| Limit of Detection (LoD) | Lowest concentration for 95% confidence | Ranges from 0.01 to 2.30 TCID50/mL depending on the viral strain. |
2. Sample Size for the Test Set and Data Provenance:
- Sample Size for Clinical Comparison Test Set: A total of 2065 NP swab specimens were used.
- 1142 were fresh, prospectively collected.
- 923 were consecutively collected, frozen specimens (to supplement for low prevalence and difficulty in obtaining fresh positive samples).
- Additionally, 102 pre-selected frozen NP swab specimens were tested and analyzed separately.
- Data Provenance: The specimens were collected from individuals exhibiting signs and symptoms of respiratory infection. The study was a multi-center clinical study conducted at eleven institutions in the U.S. during the 2015-2016 influenza season.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications:
The document indicates that the Xpert Xpress Flu/RSV Assay performance was compared to an FDA-cleared molecular comparator assay. This comparator assay served as the primary method for establishing ground truth.
For discordant results between the Xpert Xpress Flu/RSV Assay and the comparator assay, bi-directional sequencing was performed. The document does not specify the number or qualifications of experts involved in interpreting the results of the comparator assay or the bi-directional sequencing for ground truth establishment. It implies that these are standard laboratory procedures that yield definitive results for the presence or absence of viral RNA.
4. Adjudication Method for the Test Set:
Discordant results between the Xpert Xpress Flu/RSV Assay and the FDA-cleared molecular comparator assay were analyzed by bi-directional sequencing using primers different from those used in the Xpert Xpress Flu/RSV Assay. This sequencing served as a tie-breaker or confirmatory test for discrepancies. The report states that this sequencing data was "provided for informational purposes only" in relation to the primary comparison with the predicate, suggesting the comparator assay was the direct reference. However, the interpretation of the "true" positive/negative status for performance calculation likely involved considering the sequencing results.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study:
No MRMC comparative effectiveness study was performed as this is a diagnostic assay for viral RNA detection, not an imaging device requiring human reader interpretation. The device itself performs the detection and differentiation.
6. Standalone Performance:
Yes, the studies reported are for the standalone performance of the Xpert Xpress Flu/RSV Assay. The clinical comparison study directly evaluates the device's accuracy (PPA and NPA) against a comparator assay without human-in-the-loop assistance for interpretation of the assay's results.
7. Type of Ground Truth Used:
The primary ground truth used was an FDA-cleared molecular comparator assay. For discrepant results, bi-directional sequencing provided additional confirmatory evidence. This falls under the category of expert consensus (implied by FDA-cleared and sequencing interpretation) and laboratory/molecular pathology findings.
8. Sample Size for the Training Set:
The document does not explicitly state the size of a training set for the Xpert Xpress Flu/RSV Assay. As this is a molecular diagnostic assay using RT-PCR, its design and optimization (e.g., primer/probe selection, assay conditions) are based on known viral sequences and extensive analytical validation rather than a "training set" in the machine learning sense. The clinical studies (1142 fresh, 923 frozen, and 102 pre-selected frozen specimens) serve as a validation set to demonstrate clinical performance.
9. How the Ground Truth for the Training Set Was Established:
Since a distinct "training set" in the machine learning context is not described, the concept of establishing ground truth for it is not applicable here. The assay development likely involved internal analytical studies to optimize reagents and parameters, where the ground truth would be precisely characterized laboratory samples with known viral presence and concentration.
§ 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.