(209 days)
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.
| Test Parameter | Acceptance Criteria (Implied) | Reported Performance (Xpert Xpress MVP) | Sample Type | Comparator/Reference Method | Ground Truth Type |
|---|---|---|---|---|---|
| Bacterial Vaginosis (BV) | High PPA and NPA | PPA: 93.8% (531/566) | Clinician-collected (CVS) | FDA-cleared NAAT | NAAT results |
| NPA: 93.8% (808/861) | Clinician-collected (CVS) | FDA-cleared NAAT | NAAT results | ||
| PPA: 94.0% (533/567) | Self-collected (SVS) | FDA-cleared NAAT | NAAT results | ||
| NPA: 92.9% (794/855) | Self-collected (SVS) | FDA-cleared NAAT | NAAT results | ||
| Candida group | High Sensitivity and Specificity | Sensitivity: 98.0% (396/404) | Clinician-collected (CVS) | Yeast culture + mass spectrometry | Culture + MS |
| Specificity: 94.6% (984/1040) | Clinician-collected (CVS) | Yeast culture + mass spectrometry | Culture + MS | ||
| Sensitivity: 97.5% (393/403) | Self-collected (SVS) | Yeast culture + mass spectrometry | Culture + MS | ||
| Specificity: 92.1% (954/1036) | Self-collected (SVS) | Yeast culture + mass spectrometry | Culture + MS | ||
| Candida glabrata/krusei (C. glab-krus) | High Sensitivity and Specificity | Sensitivity: 93.6% (44/47) | Clinician-collected (CVS) | FDA-cleared NAAT (for discrepants) | Culture + MS (primary), NAAT (discrepant) |
| Specificity: 99.6% (1392/1397) | Clinician-collected (CVS) | FDA-cleared NAAT (for discrepants) | Culture + MS (primary), NAAT (discrepant) | ||
| Sensitivity: 97.8% (45/46) | Self-collected (SVS) | FDA-cleared NAAT (for discrepants) | Culture + MS (primary), NAAT (discrepant) | ||
| Specificity: 99.4% (1384/1393) | Self-collected (SVS) | FDA-cleared NAAT (for discrepants) | Culture + MS (primary), NAAT (discrepant) | ||
| Sensitivity (Contrived): 99.0% (98/99) | Clinician-collected (CVS) | Not specified (presumably internal reference) | Contrived specimens | ||
| Specificity (Contrived): 96.4% (27/28) | Clinician-collected (CVS) | Not specified (presumably internal reference) | Contrived specimens | ||
| Trichomonas vaginalis (TV) | High PPA and NPA | PPA: 97.3% (73/75) | Clinician-collected (CVS) | Patient Infected Status (PIS) algorithm (FDA-cleared NAAT + TV culture) | PIS algorithm |
| NPA: 99.6% (1332/1337) | Clinician-collected (CVS) | Patient Infected Status (PIS) algorithm (FDA-cleared NAAT + TV culture) | PIS algorithm | ||
| PPA: 97.3% (72/74) | Self-collected (SVS) | Patient Infected Status (PIS) algorithm (FDA-cleared NAAT + TV culture) | PIS algorithm | ||
| NPA: 99.8% (1330/1333) | Self-collected (SVS) | Patient Infected Status (PIS) algorithm (FDA-cleared NAAT + TV culture) | PIS algorithm |
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.
§ 866.3975 Device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis.
(a)
Identification. A device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis is a qualitative in vitro diagnostic device intended for the detection of microbial nucleic acid sequences in vaginal specimens collected from patients with signs and symptoms of vaginitis or bacterial vaginosis. This device is intended to aid in the diagnosis of vaginitis or bacterial vaginosis when used in conjunction with clinical signs and symptoms and other laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include:
(i) Documentation with a detailed device description of device components; ancillary reagents required but not provided; and explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection.
(ii) Documentation with information that demonstrates the performance characteristics of the device, including:
(A) Limit of Detection;
(B) Precision (reproductivity);
(C) Analytical specificity;
(D) Analytical reactivity (inclusivity);
(E) Specimen stability; and
(F) Effects of interfering substances.
(iii) Detailed documentation from a prospective clinical study. As appropriate to the intended use, the prospective clinical study must be performed on an appropriate study population, including women of various ages and ethnicities. The prospective clinical study must compare the device performance to results obtained from well-accepted comparator methods.
(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) A detailed explanation of the interpretation of results and acceptance criteria;
(ii) For devices with an intended use that includes detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, clinical performance stratified by patient demographics such as race, ethnicity, age, and pregnancy status.
(iii) For devices with an intended use that includes detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, a summary of device results in an asymptomatic population with demographic characteristics appropriate to the intended use population.
(iv) For devices with an intended use that includes detection of either Candida species or bacteria associated with bacterial vaginosis, a limitation that
Candida species and bacterial compositions associated with bacterial vaginosis can be present as part of normal vaginal flora and results should be considered in conjunction with available clinical information.