(30 days)
The Xpert Xpress CoV-2/Flu/RSV plus test, performed on the GeneXpert Dx and GeneXpert Infinity Systems, 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 and 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 A, influenza B, and RSV can be similar.
The Xpert Xpress CoV-2/Flu/RSV plus test is intended for use in the differential detection of SARS-CoV-2, influenza 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 presence 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, influenza B and/or RSV infection. The results of this test should not be used as the sole basis for diagnosis, 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 Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48s and GeneXpert Infinity-80 systems, GeneXpert System with Touchscreen), which consist of an instrument, computer or touchscreen, and preloaded software for running tests and viewing the results. The GeneXpert Instrument Systems automate and integrate sample preparation, nucleic acid extraction and amplification, and detection of the target sequences in simple or complex samples using real-time reverse transcription (RT)-polymerase chain reaction (PCR) and PCR technology. Depending on the instrument, the GeneXpert Instrument Systems can have from 1 and up to 80 randomly accessible modules, each capable of performing separate sample preparation and real-time RT-PCR and PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time RT-PCR and PCR as well as detection. The systems require 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 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 instrument. 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 FDA 510(k) Clearance Letter for the Xpert Xpress CoV-2/Flu/RSV plus device describes modifications to an existing PCR test. The information provided outlines the acceptance criteria implicitly through the modifications and performance data presented. However, it's important to note that this document is a 510(k) summary, which provides a high-level overview of the submission and does not contain the full details of all studies conducted. Therefore, some requested information may not be explicitly present in the provided text.
Based on the provided text, here's an analysis:
Summary of Acceptance Criteria and Device Performance
The core of this 510(k) submission is a "Special 510(k)" which means the device (Xpert Xpress CoV-2/Flu/RSV plus) is largely the same as a previously cleared predicate device (K231481), but with minor design changes. Therefore, the acceptance criteria are implicitly tied to demonstrating that these changes do not negatively impact the previously established performance claims of the predicate device.
Specifically, the modifications include:
- Turning off Signal Loss Detection (SLD) for the Flu B channel.
- Revising the result reporting algorithm for the SARS-CoV-2 only test mode.
- Previously: SARS-CoV-2 NEGATIVE if SARS-CoV-2 analyte result is INVALID and SPC is FAIL.
- Revised: INVALID GeneXpert test result if SARS-CoV-2 analyte result is INVALID and SPC is FAIL.
Table of Acceptance Criteria (Implicit) and Reported Device Performance:
| Acceptance Criteria (Implicit) | Reported Device Performance |
|---|---|
| No impact on validity of test runs with SLD off for Flu B channel. | "the numbers of valid test runs and non-determinate (ND) test results were the same between the original ADF and the updated ADF with Flu B SLD Off." |
| No impact on non-determinate results with SLD off for Flu B channel. | "the numbers of valid test runs and non-determinate (ND) test results were the same between the original ADF and the updated ADF with Flu B SLD Off." |
| Correctly change specific "ERROR" results to "NO RESULT" due to SLD being off. | "All non-determinate GeneXpert ERROR test results with error code 5011 (SLD) were changed to NO RESULT." |
| Revised algorithm produces expected "INVALID" results for SARS-CoV-2 only test mode under specific conditions (SARS-CoV-2 INVALID and SPC FAIL). | "The revised algorithm produced the expected INVALID GeneXpert test results for the Xpress SARS-CoV-2 plus test mode." |
| Overall performance claims of the device are not impacted by the modifications. | "The assessment of the re-analysis results determined that the performance claims of the Xpert Xpress CoV-2/Flu/RSV plus test were not impacted by the modifications made to the predicate device." |
Study Details Proving Acceptance:
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Sample sizes used for the test set and the data provenance:
- Test Set (Re-analysis Data):
- Analytical Test Results: 15,645
- Clinical, Reproducibility-Precision, and Single-Site Precision Test Results: 9,525 (comprising 8,535 specimens and 990 controls).
- Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective for the re-analyzed verification and validation studies. However, since it refers to "original studies" (K231481), it implies data previously collected and used for the predicate device's clearance.
- Test Set (Re-analysis Data):
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Number of experts used to establish the ground truth for the test set and their qualifications:
- This information is not provided in the given text. For an in vitro diagnostic (IVD) device like this, ground truth is typically established by comparative methods (e.g., another FDA-cleared PCR test, or a consensus of multiple clinical/laboratory results), not by human expert readers in the way an imaging AI device might use radiologists. The "ground truth" for this device's performance would be the presence or absence of viral RNA, determined by well-established laboratory methods.
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Adjudication method for the test set:
- This information is not provided and is generally not applicable to the type of re-analysis done for an IVD device where ground truth is established by laboratory methods rather than human interpretation requiring adjudication.
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If a multi-reader multi-case (MRMC) comparative effectiveness study was done:
- No, an MRMC study was not done. This type of study is primarily relevant for imaging AI devices that assist human readers in interpretation. This device is an automated, standalone diagnostic test.
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If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- Yes, implicitly. The re-analysis of performance data, particularly the comparison between the original and updated Assay Definition Files (ADF) and the verification of the revised algorithm, represents the standalone performance of the device's software (algorithm) logic. The device itself is an automated system.
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The type of ground truth used:
- Implicitly, the ground truth was established by laboratory reference methods (e.g., RT-PCR) for the original clinical specimens. For the re-analysis, the "ground truth" for evaluating the impact of the changes was the consistency of results and proper operation of the updated algorithm against the expected behavior, confirmed by the original analytical and clinical study data. For the SARS-CoV-2 algorithm change, "test cartridges were simulated to generate SARS-CoV-2 INVALID and SPC FAIL conditions," meaning the ground truth for this specific verification was a controlled simulation designed to trigger the specific algorithm conditions.
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The sample size for the training set:
- Not explicitly stated in relation to this Special 510(k) submission. As this is a modification to an existing device, it's likely that the original training/development data for the predicate device were used, but the size of that dataset is not provided here. The 15,645 analytical test results and 9,525 clinical/precision test results mentioned are re-analyzed verification and validation data, not training data.
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How the ground truth for the training set was established:
- Not explicitly stated in the provided text. For an RT-PCR diagnostic, the ground truth for training/development would typically involve characterized clinical samples or contrived samples with known viral concentrations and presence/absence of targets, verified by highly sensitive and specific reference methods (e.g., sequencing, confirmatory PCRs, or sometimes clinical outcomes correlated with virology).
§ 866.3981 Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test.
(a)
Identification. A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes and targets the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(3) The labeling required under § 809.10(b) of this chapter must include:
(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;
(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, precision, reproducibility, and clinical studies;
(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;
(iv) A warning statement that viral culture should not be attempted in cases of positive results for SARS-CoV-2 and/or any similar microbial agents unless a facility with an appropriate level of laboratory biosafety (
e.g., BSL 3 and BSL 3+, etc.) is available to receive and culture specimens; and(v) A prominent statement that device performance has not been established for specimens collected from individuals not identified in the intended use population (
e.g., when applicable, that device performance has not been established in individuals without signs or symptoms of respiratory infection).(vi) Limiting statements that indicate that:
(A) A negative test result does not preclude the possibility of infection;
(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) There is a risk of incorrect results due to the presence of nucleic acid sequence variants in the targeted pathogens;
(D) That positive and negative predictive values are highly dependent on prevalence;
(E) Accurate results are dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and
(F) When applicable (
e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer-reviewed literature), that the clinical performance may be affected by testing a specific clinical subpopulation or for a specific claimed specimen type.(4) Design verification and validation must include:
(i) Detailed documentation, including performance results, from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. The clinical study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator that FDA has determined is appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.
(ii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains (
e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately.(iii) A detailed description of the identity, phylogenetic relationship, and other recognized characterization of the respiratory pathogen(s) that the device is designed to detect. In addition, detailed documentation describing how to interpret the device results and other measures that might be needed for a laboratory diagnosis of respiratory infection.
(iv) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device (
e.g., saturation level of hybridization and maximum amplification and detection cycle number, etc.), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable.(v) A detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.
(vi) For devices intended for the detection and identification of microbial agents for which an FDA recommended reference panel is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference panel of characterized samples. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens, the design verification and validation must include a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. An evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(5) When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device's labeling under § 809.10(b) of this chapter.
(6) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens in addition to detection of SARS-CoV-2 and similar microbial agents, the required labeling under § 809.10(b) of this chapter must include the following:
(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation.
(ii) Where applicable, a warning statement that reads 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.
(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required followup actions or retesting in the case of an unusual or unexpected device result.
(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated (
i.e., H1-2009 and H3), this result requires notification of appropriate local, State, or Federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.(7) If one of the actions listed at section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those influenza viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized influenza viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's website, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the website containing this information and must allow unrestricted viewing access.