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The Xpert Xpress CoV-2/Flu/RSV plus test, performed on the GeneXpert Xpress System, is an automated multiplexed real-time reverse transcriptase polymerase chain reaction (RT-PCR) test intended for use in the simultaneous in vitro qualitative detection and differentiation of severe acute respiratory syndrome coronavirus (SARS-CoV-2), influenza A, influenza B, and/or respiratory syncytial virus (RSV) viral RNA in nasopharyngeal swab anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2, influenza B, and RSV can be similar.

The Xpert Xpress CoV-2/Flu/RSV plus is intended for use in the differential detection of SARS-CoV-2, influera A, influenza B, and/or RSV RNA and aids in the diagnosis of COVID-19, influenza, and/or RSV infections if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A. influenza B, and RSV viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection.

Positive results are indicative of the identified virus, but do not rule out bacterial infection or co-infection with other pathogens not detected by the test. The agent (s) detected by the Xpert Xpress CoV-2/Flu/RSV plus test may not be the definite cause of the disease.

Negative results do not preclude SARS-CoV-2, influenza A virus, and/or RSV infection. The results of this test should not be used as the sole basis for treatment or other patient management decisions.

The Xpert Xpress CoV-2/Flu/RSV plus test is an automated in vitro diagnostic test for the simultaneous qualitative detection and differentiation of SARS-CoV-2. Flu A. Flu B. and RSV viral RNA in nasopharyngeal swab (NPS) and anterior nasal swab (NS) specimens collected from individuals showing signs and symptoms of respiratory viral infection.

The Xpert Xpress CoV-2/Flu/RSV plus test is performed on GeneXpert Xpress System, which consist of a GeneXpert IV instrument that executes sample preparation, nucleic acid amplification and real-time fluorescent signal detection for the tests, and a GeneXpert Hub with preloaded GeneXpert Xpress software for running the tests and viewing the test results. The GeneXpert Hub accessory integrates the computer, touchscreen monitor and barcode scanner. Each of the GeneXpert modules in the GeneXpert IV instrument can perform independent sample preparation and testing. The GeneXpert Xpress System requires the use of single-use disposable cartridges that hold the RT-PCR reagents and host sample purification, nucleic acid amplification, and detection of the target sequences. Because the cartridges are self-contained, cross-contamination between samples is minimized.

The Xpert Xpress CoV-2/Flu/RSV plus test cartridge includes reagents for the detection of SARS-CoV-2, Flu A, Flu B and RSV viral RNA from NPS and NS specimens. The primers and probes in the Xpert Xpress CoV-2/Flu/RSV plus test are designed to amplify and detect unique sequences in the genes that encode the following proteins: SARS-CoV-2 nucleocapsid (N), SARS-CoV-2 envelope (E), SARS-CoV-2 RNA-dependent RNA polymerase (RdRP), influenza A matrix (M), influenza A basic polymerase (PB2), influenza A acidic protein (PA), influenza B matrix (M), influenza B non-structural protein (NS), and the RSV A and RSV B nucleocapsid. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert Xpress System. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the RT-PCR reaction. The SPC also ensures that the RT-PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the RT-PCR reagents are functional. The PCC verifies reagent rehydration, PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dye stability.

The Xpert Xpress CoV-2/Flu/RSV plus test is designed for use with NPS or NS specimens collected with nylon flocked swabs and placed into viral transport medium (VTM), Universal Transport Medium (UTM), or eNAT®. The ancillary specimen collection kits, swabs and transport media validated for use with the Xpert Xpress CoV-2/Flu/RSV plus test include:

• Nasopharyngeal Sample Collection Kit for Viruses
  • Copan UTM® 3C057N (Flexible Minitip Flocked Swab with UTM® Medium O without Beads)
  • Copan eNAT® Molecular Collection and Preservation Medium P/N 6U074S01 о (Flexible Minitip Flocked Swab with eNAT® Medium)
• Becton Dickinson Universal Viral Transport Kit P/N 220531 (Flexible Minitip o Flocked Swab with UVT Medium)
• Nasal Sample Collection Kit for Viruses
  • Copan UTM® 3C064N (Regular Flocked Swab with UTM® Medium without O Beads)
  • Copan eNAT® Molecular Collection and Preservation Medium P/N 6U073S01 O (Regular Flocked Swab with eNAT® Medium)
• Alternatively, swabs and transport media can be obtained separately: ●
  • Nylon flocked swab (Copan P/N 502CS01, 503CS01) o
  • Viral transport medium, 3 mL (Copan P/N 330C, 3C047N, BD Universal O Transport Medium, Remel M4RT or Remel M5)

These ancillary reagents allow NPS and NS specimens from patients to be collected, preserved and transported to laboratory prior to analysis with the Xpert Xpress CoV-2/Flu/RSV plus test.

The provided document is a 510(k) Summary for the Cepheid Xpert Xpress CoV-2/Flu/RSV plus test. It details the performance studies conducted to demonstrate substantial equivalence to a predicate device. Here's a breakdown of the acceptance criteria and study proving the device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly demonstrated through the reported performance in both analytical and clinical studies, aiming for high levels of agreement with established methods. The summarized performance data serves as the proof that the device meets these (implied) acceptance criteria.

Table of Acceptance Criteria and Reported Device Performance:

Since explicit acceptance criteria values (e.g., "PPA must be >= 95%") are not explicitly stated in the provided text as separate criteria, I will infer them from the reported strong performance and the nature of a 510(k) submission, where substantial equivalence to a predicate device is the goal. The reported performance is the validation that it meets the expected performance for such a device.

Study Details:

1. Sample sizes used for the test set and the data provenance:

   • Analytical Studies (LoD, Inclusivity, Specificity, Interference, Carryover, Reproducibility): These studies used "replicates" (e.g., 20, 3, 8) of contrived/simulated samples rather than patient samples for their test sets.
     • LoD: 20 replicates per virus/lot combination.
     • Inclusivity (wet-testing): 3 replicates for each of 102 respiratory viral strains.
     • Exclusivity (wet-testing): 3 replicates of each microorganism pool.
     • Microbial Interference: 8 replicates of positive samples for each target virus and microbial interference strain combination.
     • Competitive Interference: 3 replicates for each target strain and competitive strain combination (adjusted as needed).
     • Potentially Interfering Substances: 8 negative and 8 positive samples (pooled) for each substance.
     • Carryover Contamination: 40 positive and 42 negative samples (20 pairs per module, 2 modules).
     • Reproducibility: 90 observations per panel member (3 Sites x 3 Operators x 1 Lot x 5 Days x 1 Run x 2 Replicates).
   • Clinical Performance Study:
     • Total Specimens: 4561 (NPS=2300, NS=2261)
     • Test Set for SARS-CoV-2 Performance: 3147 valid specimens (1565 NPS, 1582 NS).
     • Test Set for Flu A, Flu B, RSV Performance: 4310 valid specimens (2175 NPS, 2135 NS).
     • Data Provenance:
       • Fresh (Category I): 3333 specimens (1 frozen specimen in this category). Prospectively collected in 2022 from 23 geographically diverse sites in the United States.
       • Archived Frozen (Category II): 1228 specimens. Prospectively collected during the 2016-2017 influenza season (pre-pandemic), used to supplement Flu/RSV sample size. These were collected in the US.
     • Retrospective/Prospective: Primarily prospective (Category I) with a significant portion of archived prospective (Category II) specimens.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • The document implies that the ground truth for the clinical test set was established by U.S. FDA-cleared molecular diagnostic tests (a molecular respiratory panel for SARS-CoV-2 and a molecular Flu A/B/RSV test).
   • For discrepant results, additional U.S. FDA EUA SARS-CoV-2 molecular tests or U.S. FDA-cleared molecular respiratory panels were used.
   • The document does not specify the number or qualifications of human experts directly involved in establishing the ground truth for the clinical test set. The ground truth relies on the results of the comparator molecular assays.

3. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

   • For the clinical performance study, results were compared "side-by-side" with a U.S. FDA-cleared molecular respiratory panel.
   • Discrepant results were investigated using a different U.S. FDA EUA SARS-CoV-2 molecular test or U.S. FDA-cleared molecular respiratory panel. This suggests an adjudication process for discrepancies, where an additional, independent test confirms or refutes the initial finding of the comparator or investigational device. The exact "X+Y" method (e.g., 2+1) is not explicitly stated, but the process of re-testing discrepant samples with a "tie-breaker" method is described.

4. 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:

   • No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This document describes the validation of an in vitro diagnostic (IVD) PCR test kit, not an AI-assisted diagnostic imaging or interpretation system that would involve human "readers" or "interpreters." The device is largely automated.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • This is a standalone diagnostic test in the sense that the GeneXpert Xpress System performs the sample preparation, nucleic acid amplification, and real-time fluorescent signal detection to produce a result (qualitative positive/negative). Human input is for specimen collection, loading the cartridge, and reviewing the auto-generated results. The performance metrics presented (PPA, NPA, LoD, etc.) are of the "device only" system. So, yes, a standalone performance was done for the device.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

   • For analytical studies: Contrived samples with known concentrations of viral strains or microorganisms, often verified against internal standards or external reference materials.
   • For clinical studies: Results from U.S. FDA-cleared and U.S. FDA EUA molecular diagnostic tests served as the ground truth (comparator method). Discrepancies were resolved using additional molecular tests.

7. The sample size for the training set:

   • The document does not provide information on a training set size. This is common for traditional IVD device submissions, where analytical and clinical validation data (test set) are collected after the assay design (analogous to "training") is complete. The "training" in this context would likely refer to the internal assay development and optimization, for which specific sample sizes might not be publicly disclosed or directly relevant to the regulatory submission for substantial equivalence.

8. How the ground truth for the training set was established:

   • As no explicit "training set" is mentioned in the context of device performance validation, the method for establishing its ground truth is not described. For assay development, ground truth would be established through a combination of highly characterized samples, pure cultures, and perhaps clinical samples with confirmed results from gold-standard methods (e.g., viral culture, sequencing, or highly sensitive and specific lab-developed tests).

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