(180 days)
The Cepheid Xpert® Xpress Flu/RSV Assay, performed on the GeneXpert® Xpress System, 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. The Xpert Xpress Flu/RSV Assay uses nasopharyngeal (NP) swab and nasal swab (NS) specimens collected from patients with signs and symptoms of respiratory infection. The Xpert Xpress Flu/RSV Assay 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 2016-2017 influenza season when influenza A/H3N2 and A/HINI pandemic were the predominant influenza A viruses in circulation. 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 Nasopharyngeal Swab Specimen Collection Kit for Viruses:
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, Xpert Xpress Flu/RSV Assay or the Xpert Xpert Flu Assay.
Ancillary Nasal Swab Specimen Collection Kit for Viruses:
The Xpert® Nasal Sample Collection Kit is designed to collect, preserve, and transport nasal swab specimens containing viruses from patients with signs and symptoms of respiratory infection prior to analysis with the Xpert Xpress Flu/RSV Assay and the Xpert Xpress Flu 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 and nasal swab (NS) specimens. The assay is performed on the Cepheid GeneXpert® Xpress System.
The Xpert Xpress Flu/RSV Assay includes reagents for the detection and differentiation of influenza A, influenza B, and RSV viral RNA directly from NP swab and NS specimens from patients with signs and symptoms of respiratory tract infection. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Xpress System platform. The SPC is present to control for an adequate extraction and processing of the target sequences and to monitor for the presence of inhibitor in the PCR reaction. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.
The specimens are collected in viral transport medium and transported to the GeneXpert Xpress 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 Xpress 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.
Here's a breakdown of the acceptance criteria and the study details for the Cepheid Xpert® Xpress Flu/RSV Assay, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document describes the device's performance in terms of Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to an FDA-cleared molecular comparator assay. Implicit acceptance criteria are that these percentages should be high, indicating substantial equivalence.
| Acceptance Criteria (Implicit) | Reported Device Performance (Xpert Xpress Flu/RSV Assay) |
|---|---|
| High PPA and NPA for Influenza A in NS specimens | PPA: 98.9% (96.2-99.7), NPA: 97.5% (96.6-98.2) |
| High PPA and NPA for Influenza A in NP swab specimens | PPA: 97.6% (94.4-99.0), NPA: 98.2% (97.4-98.8) |
| High PPA and NPA for Influenza A (Overall) | PPA: 98.2% (96.4-99.1), NPA: 97.9% (97.3-98.3) |
| High PPA and NPA for Influenza B in NS specimens | PPA: 98.4% (91.7-99.7), NPA: 99.3% (98.7-99.6) |
| High PPA and NPA for Influenza B in NP swab specimens | PPA: 97.3% (90.6-99.2), NPA: 99.6% (99.1-99.8) |
| High PPA and NPA for Influenza B (Overall) | PPA: 97.8% (93.8-99.3), NPA: 99.4% (99.1-99.6) |
| High PPA and NPA for RSV in NS specimens | PPA: 98.2% (95.8-99.2), NPA: 99.1% (98.4-99.5) |
| High PPA and NPA for RSV in NP swab specimens | PPA: 98.2% (95.9-99.2), NPA: 98.5% (97.7-99.0) |
| High PPA and NPA for RSV (Overall) | PPA: 98.2% (96.7-99.0), NPA: 98.8% (98.3-99.1) |
| High analytical sensitivity (low Limit of Detection) | See Tables 8-4 to 8-8 for specific TCID50/mL values. |
| 100% analytical specificity (no cross-reactivity) | 100% |
| No significant interference from common respiratory substances | None of the tested substances caused interference. |
| No carry-over contamination | All 40 positive and 42 negative samples were correct. |
| Acceptable reproducibility across sites, days, and operators | High agreement (e.g., 100% for negative and moderate positive) for qualitative results and low CV for Ct values. |
2. Sample Size for the Test Set and Data Provenance
- Sample Size (Clinical Comparison Study):
- Influenza A/B: 3265 specimens (1598 Nasal Swab (NS) and 1667 Nasopharyngeal (NP) swab)
- RSV: 3103 specimens (1543 NS and 1560 NP swab)
- Data Provenance: The specimens were collected from individuals exhibiting signs and symptoms of respiratory infection in the U.S. during the 2016-2017 influenza season. The study was a prospective, multi-center clinical study conducted at fourteen institutions.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
The document states that the Xpert Xpress Flu/RSV Assay performance was compared to an FDA-cleared molecular comparator assay. This implies that the ground truth for the clinical comparison study was established by the results of the FDA-cleared molecular comparator assay, rather than by human experts directly adjudicating individual cases.
4. Adjudication Method for the Test Set
The primary method for establishing agreement was comparison against an FDA-cleared molecular comparator assay. For discrepant results between the Xpert Xpress Flu/RSV Assay and the comparator method, "Discrepant Testing" was performed as indicated in Table 8-10 footnotes. The nature of this discrepant testing (e.g., a third, highly sensitive method or expert panel review) is not fully detailed, but it appears to be a form of 2-way agreement with a third test for discrepancies.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study
There is no mention of a Multi Reader Multi Case (MRMC) comparative effectiveness study, nor any data on how much human readers improve with AI vs. without AI assistance. This device is an automated molecular diagnostic assay, not an AI-assisted interpretation tool for human readers.
6. Standalone Performance (Algorithm Only without Human-in-the-Loop Performance)
Yes, a standalone performance study was done. The entire clinical comparison study (Section "Clinical Studies" and Table 8-10) evaluates the Xpert Xpress Flu/RSV Assay's performance directly against a comparator method, without any human interaction (interpretation assistance) being part of the reported performance metrics (PPA and NPA). The device is an automated RT-PCR assay.
7. The Type of Ground Truth Used
The ground truth for the clinical comparison study was established by an FDA-cleared molecular comparator assay.
8. The Sample Size for the Training Set
The document describes a "clinical comparison study" which serves as the test set for performance evaluation. It does not explicitly state details about a separate "training set" with respect to the development of the assay itself. For molecular diagnostic assays, the "training" equivalent often involves extensive analytical validation and optimization (e.g., Limit of Detection, inclusivity, specificity) using characterized samples and strains, rather than a distinct clinical "training set" in the same vein as machine learning models.
9. How the Ground Truth for the Training Set Was Established
As noted above, a distinct "training set" in the typical machine learning sense is not described. The analytical studies (LoD, specificity, inclusivity) involved testing known concentrations of viral strains and known panels of microorganisms. The ground truth for these analytical studies was based on the known characteristics and titrations of the biological materials used (e.g., TCID50/mL values for viral strains, CFU/mL for bacterial/yeast strains).
§ 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.