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The Xpert® Xpress MVP test, performed on the GeneXpert® Instrument Systems, is an automated qualitative in vitro diagnostic test for the detection of DNA targets from anaerobic bacteria associated with bacterial vaginosis (BV). Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis. The Xpert Xpress MVP test uses clinician-collected and self-collected vaginal swabs (collected in a clinical setting) from patients who are symptomatic for vaginitis/vaginosis. The Xpert Xpress MVP test utilizes real-time polymerase chain reaction (PCR) for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA from:

• . Organisms associated with bacterial vaginosis (detected organisms not reported individually)
  • o Atopobium spp. (Atopobium vaginae, Atopobium novel species CCUG 55226)
  • Bacterial Vaginosis-Associated Bacterium 2 (BVAB2) O
  • o Megasphaera-1
• . Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis, species not differentiated)
• Candida glabrata/Candida krusei (species not differentiated)
• . Trichomonas vaginalis

The Xpert Xpress MVP test is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis, or trichomoniasis.

The Xpert® Xpress MVP test is an automated in vitro diagnostic test for qualitative detection of DNA targets from anaerobic bacteria associated with bacterial vaginosis. Candida species associated with vulyovaginal candidiasis, and Trichomonas vaginalis, the agent of trichomoniasis. The Xpert Xpress MVP test is performed on GeneXpert Instrument Systems. 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 PCR assays. The systems consist of an instrument, computer, and preloaded software for running tests and viewing the results. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is minimized.

The Xpert Xpress MVP test includes reagents for the detection of DNA from BV organisms, Candida species, and Trichomonas vaginalis from vaginal swab samples. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert System 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 PCR reaction. The SPC also ensures that the PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the 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 MVP test is designed for use with the following specimens collected from symptomatic individuals: self-collected vaginal swabs (collected in a clinical setting) and clinician-collected vaginal swabs. The swab transport reagent included in the Xpert Swab Specimen Collection Kit is designed to collect and preserve patient specimens to allow transport to the laboratory prior to analysis with the Xpert Xpress MVP test.

Here's a breakdown of the acceptance criteria and study details for the Cepheid Xpert Xpress MVP device, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on demonstrating equivalence between a "new design" and an "original design" of the Xpert Xpress MVP, rather than establishing de novo acceptance criteria against a clinical reference standard in this specific submission. The acceptance criteria for the analytical sensitivity equivalency study were defined internally for comparison between the two designs:

1. Both original and new design report 19/20 or 20/20 POSITIVE/DETECTED results at LoD/Near Cut-off concentrations.
2. Statistical analysis (two-sample t-test) comparing mean Ct values shows no statistically significant difference (p-value > 0.05) with a marginal difference of 1.0 Ct value. | Met:

• All targets (Atopobium vaginae, Megasphaera-1, BVAB2, Candida albicans, Candida dubliniensis, Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida krusei, Trichomonas vaginalis) consistently showed 19/20 or 20/20 positive/detected results at LoD.
• All BV targets showed 19/20 or 20/20 positive/detected (BV positive) results at near cut-off concentrations.
• For all targets and conditions (SVM/VS matrix), the difference in mean Cts between the two designs was within 1.0 Ct, and the t-test p-values were consistently > 0.05 (most were >0.9), indicating no statistically significant difference in analytical sensitivity. |
  | Clinical Specimen Equivalency (PPA/NPA) | The PPA (Positive Percent Agreement) and NPA (Negative Percent Agreement) of the new design relative to the original design for Bacterial Vaginosis (BV), Candida group, Candida glabrata/Candida krusei, and Trichomonas vaginalis (TV) targets should demonstrate equivalence. (No specific numerical thresholds provided in this summary, but the implication is "high agreement"). | Met:
• BV: PPA 98.3% (56/57), NPA 99.1% (112/113)
• Candida group: PPA 97.4% (38/39), NPA 98.5% (129/131)
• Candida glab-krus: Overall PPA 100% (31/31), NPA 100% (159/159). (Fresh PPA 100% (11/11), Contrived PPA 100% (20/20))
• TV: Overall PPA 100% (32/32), NPA 100% (158/158). (Fresh PPA 100% (12/12), Contrived PPA 100% (20/20))
• Discordant results were investigated and attributed to samples near LoD or sub-LoD levels, supporting overall equivalence. |
  | Non-Determinate Rate | Implicitly, the non-determinate rates for both designs should be low and acceptable. | Met:
• Overall non-determinate rate for original design: 0.42% (1/236)
• Overall non-determinate rate for new design: 1.4% (3/220)
  These rates are considered acceptable. |
  | Interfering Substances | No clinically significant inhibitory effects from substances encountered in vaginal specimens, except where a limitation is appropriate. | Met:
• No clinically significant inhibitory effects observed for new design, with the exception of 5.5% v/v mucin (same as original design). At 4.0% mucin, no interference was observed. A limitation for ≥5.5% mucin is included in the instructions. |

2. Sample Size Used for the Test Set and Data Provenance

• Analytical Sensitivity Equivalency Study (LoD & Near Cut-off):

  • Sample Size: 20 replicates for each target at LoD/near cut-off concentration for both the original and new designs. This included testing in Simulated Vaginal Matrix (SVM) and Pooled Negative Natural Clinical Vaginal Swab Matrix (VS) for some targets.
  • Data Provenance: Not explicitly stated, but these are analytical studies meaning they used prepared samples (cultures, specific concentrations) rather than clinical patient samples.

• Equivalency Study using Clinical Specimens:

  • Sample Size:
    • Initial Enrollment: 174 participants (174 clinician-collected vaginal swabs).
    • Included in Final Analysis: 170 prospectively collected ("fresh") clinician-collected vaginal swab specimens.
    • Additional Contrived Specimens: 20 contrived C. glabrata and C. krusei specimens, and 20 contrived T. vaginalis specimens.
  • Data Provenance:
    • Country of Origin: United States (three sites).
    • Retrospective or Prospective: Prospectively collected. Clinician-collected vaginal swabs were taken from symptomatic female patients ≥ 14 years of age. All testing was performed at Cepheid (Sunnyvale, CA).

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications

This submission is about demonstrating equivalence between two versions of the same diagnostic device, not evaluating the device against a clinical reference standard with expert interpretation for ground truth. Therefore, experts were not used to establish the "ground truth" for the test set in the traditional sense of clinical diagnosis.

Instead, the "ground truth" in the clinical equivalency study was the result produced by the predicate device (original design of Xpert Xpress MVP).

4. Adjudication Method for the Test Set

No adjudication method using human experts was described for the clinical equivalency study. The comparison was directly between the test results of the new device and the predicate device. Discordant results were investigated by retesting with both designs if enough sample volume remained, but these retest results were for information only and not used for adjudication in the primary data analysis.

5. (MRMC) Multi-Reader Multi-Case Comparative Effectiveness Study

• No, an MRMC comparative effectiveness study was NOT done. This document describes the analytical and clinical performance equivalence of a device modification to its predicate, not a study evaluating human reader performance with or without AI assistance.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Yes, this is essentially a standalone (algorithm only) performance study. The Xpert Xpress MVP system is an automated in vitro diagnostic test that provides a qualitative result. While human operators are involved in sample preparation and loading, the "performance" described here (detection of DNA targets) is that of the automated system and its reagents/software, acting as an algorithm-only device in the context of its defined output. There isn't a human-in-the-loop component being evaluated in these studies.

7. Type of Ground Truth Used

• Analytical Sensitivity Study: The ground truth was based on known concentrations of target organisms (CFU/mL or copies/mL) spiked into matrices.
• Clinical Specimen Equivalency Study: The "ground truth" for comparison was the results obtained from the predicate device (original Xpert Xpress MVP K212213). The study aimed to show agreement with the predicate device, not with an external clinical gold standard.

8. Sample Size for the Training Set

No information about a training set is provided. This document describes validation studies for a device, not the development or training of an AI algorithm. If there were internal machine learning components in the original device, their training data would have been part of the original K212213 submission.

9. How the Ground Truth for the Training Set Was Established

As no training set is mentioned, this information is not applicable to the provided document.

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The Xpert Xpress MVP test, performed on the GeneXpert Instrument Systems, is an automated qualitative in vitro diagnostic test for the detection of DNA targets from anaerobic bacteria associated with bacterial vaginosis (BV), Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis. The Xpert Xpress MVP test uses clinician-collected and self-collected vaginal swabs (collected in a clinical setting) from patients who are symptomatic for vaginitis/vaginosis. The Xpert Xpress MVP test utilizes real-time polymerase chain reaction (PCR) for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA from:

• . Organisms associated with bacterial vaginosis (detected organisms not reported individually)
  • o Atopobium spp. (Atopobium vaginae, Atopobium novel species CCUG 55226)
  • Bacterial Vaginosis-Associated Bacterium 2 (BVAB2) o
  • Megasphaera-1 o
• Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis, species not differentiated)
• Candida glabrata/Candida krusei (species not differentiated)
• . Trichomonas vaginalis

The Xpert Xpress MVP test is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis, or trichomoniasis.

The Xpert® Xpress MVP test is an automated in vitro diagnostic test for qualitative detection of DNA targets from anaerobic bacteria associated with bacterial vaginosis, Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis, the agent of trichomoniasis. The Xpert Xpress MVP test is performed on GeneXpert Instrument Systems.

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 PCR assays. The systems consist of an instrument, computer, and preloaded software for running tests and viewing the results. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is minimized.

The Xpert Xpress MVP test includes reagents for the detection of DNA from BV organisms, Candida species, and Trichomonas vaginalis from vaginal swab samples. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert System 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 PCR reaction. The SPC also ensures that the PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the 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 MVP test is designed for use with the following specimens collected from symptomatic individuals: self-collected vaginal swabs (collected in a clinical setting) and clinician-collected vaginal swabs. The swab transport reagent included in the Xpert Swab Specimen Collection Kit is designed to collect and preserve patient specimens to allow transport to the laboratory prior to analysis with the Xpert Xpress MVP test.

Here's an analysis of the acceptance criteria and study proving the device meets those criteria, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct numerical targets for sensitivity, specificity, and agreement rates in the provided document. However, the performance outcomes of the Xpert Xpress MVP test are presented and can be interpreted as the device meeting the performance standards considered acceptable for its intended use, especially given the FDA's 510(k) clearance based on "substantial equivalence." The document compares the device's performance to an FDA-cleared predicate device.

For the purpose of this table, "Acceptance Criteria" will be inferred from the reported performance, as it highlights what the device achieved and what was deemed sufficient for clearance.

2. Sample Size Used for the Test Set and Data Provenance

• Sample Size (Clinical Study/Test Set):
  • Patients: 1,478 female patients (14 to ≥ 50 years of age).
  • Vaginal Swabs Tested: 2,947 (one self-collected vaginal swab (SVS) and five clinician-collected vaginal swab (CVS) specimens per patient).
• Data Provenance:
  • Country of Origin of the Data: United States (multi-site clinical study with 12 sites from geographically diverse locations in the U.S.).
  • Retrospective or Prospective: Prospective observational, method comparison clinical study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

The document does not specify the number or qualifications of experts (e.g., radiologists, pathologists) used to establish the ground truth for the clinical test set. The ground truth for the clinical study was established by comparator methods (FDA-cleared NAATs, yeast culture followed by mass spectrometry, and a PIS algorithm). These methods are analytical laboratory tests, not dependent on expert visual review.

4. Adjudication Method for the Test Set

• The document states: "When applicable, investigation of discrepant results was performed by testing specimens with another FDA-cleared NAAT."
• This indicates a form of adjudication for discrepant results, where a third, independent, FDA-cleared NAAT was used to resolve disagreements between the Xpert Xpress MVP test and the initial comparator method. The specific rule (e.g., 2 out of 3 agreement) for this discrepancy resolution is not detailed, but the use of an independent NAAT as a tie-breaker or confirming tool is implied.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

• No, an MRMC comparative effectiveness study was not done.
• This study evaluates an in vitro diagnostic (IVD) device that detects nucleic acid sequences from microorganisms using real-time PCR. It is not an imaging-based AI device that would typically involve human readers interpreting images. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply to this type of device.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

• Yes, the primary performance evaluation of the Xpert Xpress MVP test in the clinical study was standalone.
• The device is an automated, qualitative in vitro diagnostic test that performs sample preparation, nucleic acid extraction and amplification, and detection, and provides results "within 60 minutes." The clinical performance tables (Table 5-13) represent the direct output of the device compared to reference methods, without human interpretation of the device's signal directly impacting the final result reported by the device itself.
• Human involvement is in specimen collection, loading the cartridge, and reviewing the system's final reported result for the pathogen. The device's diagnostic output for a given sample is fully automated.

7. The Type of Ground Truth Used

The ground truth varied by the target organism:

• Bacterial Vaginosis (BV): An FDA-cleared nucleic acid amplification test (NAAT).
• Candida group and Candida glabrata/krusei: Yeast culture followed by mass spectrometry for species identification. For Candida glabrata/krusei, there was also a "contrived" study, meaning the ground truth was based on known concentrations of the organisms.
• Trichomonas vaginalis (TV): A Patient Infected Status (PIS) algorithm that included results from an FDA-cleared NAAT and TV culture.
• Discrepancy Resolution: For all targets, a second FDA-cleared NAAT was used for investigation of discrepant results, effectively serving as an adjudication method to establish the clinical ground truth for those specific samples.

8. The Sample Size for the Training Set

The document describes the clinical study as a "performance evaluation" and "method comparison clinical study" used to demonstrate substantial equivalence. It does not explicitly reference or describe a separate "training set" for the device's algorithm in the context of machine learning, because this is a molecular diagnostic test based on PCR, not an adaptable AI algorithm that is trained on data in the traditional sense. The development of such a device involves assay design and optimization rather than machine learning training sets.

9. How the Ground Truth for the Training Set Was Established

Since there is no explicit mention of a "training set" in the context of an AI/ML algorithm for this PCR-based diagnostic device, the concept of establishing ground truth for a training set as typically described for AI/ML devices doesn't apply. The development and validation of the device would have involved extensive laboratory (non-clinical) studies, including analytical sensitivity (LoD), analytical reactivity (inclusivity), analytical specificity (exclusivity), microbial interference, competitive interference, interfering substances, and carry-over contamination studies (as described in Section 5.4), where the "ground truth" for these studies would be precisely controlled laboratory-prepared samples with known concentrations of target organisms and potential interferents.

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