(207 days)
The Cepheid Xpert Xpress Flu 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 and influenza B viral RNA. The Xpert Xpress Flu Assay uses nasopharyngeal (NP) swab and nasal swab (NS) 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 2016-2017 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 for Nasopharyngeal Swabs 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/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 Xpress Flu Assay.
Ancillary Collection Kit for Nasal Swabs Indications for Use:
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 Assay.
The Xpert Xpress Flu Assay is a rapid, automated in vitro diagnostic test for the qualitative detection and differentiation of influenza A (Flu A) and influenza B (Flu B) 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 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 NS and 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 Xpress 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 universal 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 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 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 Assay is an automated, multiplex real-time RT-PCR assay for the qualitative detection and differentiation of influenza A and influenza B viral RNA from nasopharyngeal (NP) and nasal swab (NS) specimens.
Here's a breakdown of the acceptance criteria and study information:
1. Table of Acceptance Criteria and Reported Device Performance:
The document primarily focuses on demonstrating substantial equivalence to a predicate device rather than explicitly stating pre-defined acceptance criteria in terms of performance metrics. However, clinical performance data is presented, which implicitly serves as the "reported device performance" against an FDA-cleared molecular comparator assay.
| Performance Metric | Acceptance Criteria (Implicit, based on predicate equivalence) | Reported Device Performance (Xpert Xpress Flu Assay vs. Comparator) |
|---|---|---|
| Influenza A (NS) | High PPA and NPA, comparable to predicate devices. | PPA: 98.9% (96.2-99.7% CI) |
| NPA: 97.3% (96.4-98.1% CI) | ||
| Influenza B (NS) | High PPA and NPA, comparable to predicate devices. | PPA: 98.4% (91.7-99.7% CI) |
| NPA: 99.2% (98.6-99.5% CI) | ||
| Influenza A (NP Swab) | High PPA and NPA, comparable to predicate devices. | PPA: 97.5% (94.4-98.9% CI) |
| NPA: 98.0% (97.1-98.6% CI) | ||
| Influenza B (NP Swab) | High PPA and NPA, comparable to predicate devices. | PPA: 97.3% (90.6-99.2% CI) |
| NPA: 99.5% (99.0-99.7% CI) | ||
| Overall Assay Success Rate | High success rate | 99.8% |
| Overall Indeterminate Rate | Low indeterminate rate | 0.2% |
| Analytical Limit of Detection (LoD) | Reproducible detection at low concentrations (95% confidence). | See Tables 8-4 to 8-6 for specific TCID50/mL values for different strains. For example, Flu A 2009 H1N1: 0.02 TCID50/mL (NP Swab), 0.018 TCID50/mL (NS Matrix). |
| Analytical Specificity | No cross-reactivity with common respiratory pathogens (100% negative). | 100% (with 44 viral, bacterial, and yeast strains tested). |
| Analytical Reactivity (Inclusivity) | Detection of multiple influenza A and B strains at levels near LoD. | All 48 strains tested positive in all three replicates, except one Flu A H1N1 strain (2 of 3 replicates positive). |
| Interfering Substances | No interference at tested concentrations. | None of the 17 tested substances caused interference. |
| Carry-Over Contamination | No contamination of negative samples. | All 21 negative samples correctly reported as negative. |
| Competitive Interference | No, or minimal, competitive inhibitory effects. | Internal competitive inhibitory effects observed on Flu B target in presence of Flu A in some conditions (addressed in limitations). |
| Reproducibility (Total Agreement) | High overall agreement across sites, operators, and days. | Neg: 100% |
| Flu A Low Pos: 91.0% | ||
| Flu A Mod Pos: 100% | ||
| Flu B Low Pos: 93.3% | ||
| Flu B Mod Pos: 100% |
2. Sample Size Used for the Test Set and Data Provenance:
- Test Set Sample Size: A total of 3229 clinical specimens (1582 NS and 1647 NP swab) were used for the clinical comparison study.
- Data Provenance: The clinical study was conducted at fourteen institutions in the U.S. during the 2016-2017 influenza season. This indicates prospective, multi-center US data.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
The document states that the Xpert Xpress Flu Assay performance was compared to an "FDA-cleared molecular comparator assay." The "ground truth" for the clinical study was established by this comparator assay. There is no information provided about the number or qualifications of human experts (e.g., radiologists) involved in establishing the ground truth for this in vitro diagnostic device. For molecular assays, the comparator assay itself serves as the reference standard.
4. Adjudication Method for the Test Set:
Not applicable. The ground truth was established by an FDA-cleared molecular comparator assay, not by human expert review requiring an adjudication method.
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:
Not applicable. This is an in vitro diagnostic device (molecular assay) for detecting viral RNA, not an imaging device or AI-assisted diagnostic tool for human readers. Therefore, an MRMC study and effects on human reader performance are not relevant.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done:
Yes, the studies presented are for the standalone performance of the Xpert Xpress Flu Assay. It's an automated assay performed on the GeneXpert Xpress System, and its performance characteristics (analytical and clinical) are evaluated directly without human intervention or interpretation beyond loading the sample and reading the automatically generated results.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.):
- Clinical Studies: The ground truth for the clinical comparison study was an FDA-cleared molecular comparator assay.
- Analytical Studies (LoD, Specificity, Reactivity): The ground truth was established using known concentrations of purified viral strains, bacterial/yeast cultures, and defined interfering substances.
8. The Sample Size for the Training Set:
The document does not explicitly mention a "training set" in the context of an algorithm or machine learning model. This is a molecular diagnostic assay where performance is governed by assay design (primers, probes) and optimization, rather than a learning algorithm. Therefore, the concept of a "training set" for an algorithm isn't directly applicable in the same way it would be for an AI-based device. The development and optimization of the assay would involve extensive internal testing.
9. How the Ground Truth for the Training Set Was Established:
As noted above, a traditional "training set" for an algorithm is not explicitly discussed. The "ground truth" for the development and optimization of the assay itself would have been established through well-characterized laboratory reference materials, including:
- Standardized controls with known concentrations of target viruses.
- Panels of negative samples and samples containing potential interferents.
- Clinical samples previously characterized by established reference methods during the assay development phase.
§ 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.