The Xpert® Xpress MVP test, performed on the GeneXpert® Xpress System, 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) .
- Atopobium spp. (Atopobium vaginae, Atopobium novel species CCUG 55226) O
- 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.

Device Description

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 (BV), Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis, the agent of trichomoniasis. In the CLIA-waived environment, the Xpert Xpress MVP test is performed on the GeneXpert® Xpress System.

The latest Hub configuration of the GeneXpert Xpress System consists 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 Xpert Xpress MVP test is a PCR-based Nucleic Acid Amplification Test. Each test requires the use of a single-use disposable GeneXpert cartridge that contains all necessary reagents for the detection of DNA from BV organisms, Candida species, and Trichomonas vaginalis. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge serving as internal controls. The SPC is present to control for adequate sample processing, to monitor PCR conditions, the presence of potential inhibitor(s) and possible reagent degradation. 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. Because the cartridges are self-contained, the risk of cross- contamination between samples is minimized.

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 ancillary specimen collection kit for use with the Xpert Xpress MVP test is the Xpert Swab Specimen Collection Kit. The swab and the transport reagent included in the Xpert Swab Specimen Collection Kit are designed to collect and preserve patient specimens to allow transport to the testing site prior to analysis with the Xpert Xpress MVP test.

AI/ML Overview

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

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a numerical, threshold-based format. Instead, it presents the clinical performance results (PPA/NPA, Sensitivity/Specificity) for the Xpert Xpress MVP test. The implication is that these reported performance metrics meet internal or regulatory acceptance thresholds for substantial equivalence.

Target	Metric (Clinical Study)	Clinician-collected (CVS) Performance (95% CI)	Self-collected (SVS) Performance (95% CI)
BV	PPA	92.9% (429/462) (90.1% - 94.9%)	93.5% (434/464) (90.9% - 95.4%)
	NPA	94.5% (719/761) (92.6% - 95.9%)	93.6% (711/760) (91.6% - 95.1%)
Candida group*	Sensitivity	98.1% (360/367) (96.1% - 99.1%)	97.8% (359/367) (95.8% - 98.9%)
	Specificity	94.9% (820/864) (93.2% - 96.2%)	92.9% (804/865) (91.0% - 94.5%)
Candida glab-krus	Sensitivity (Fresh Pros.)	94.1% (32/34) (80.9% - 98.4%)	100% (33/33) (89.6% - 100%)
	Specificity (Fresh Pros.)	99.8% (1195/1197) (99.4% - 99.9%)	99.7% (1195/1199) (99.1% - 99.9%)
	Sensitivity (Contrived)	99.0% (98/99) (94.5%-99.8%)	N/A
	Specificity (Contrived)	96.4% (27/28) (82.3%-99.4%)	N/A
TV	PPA (Fresh Pros.)	98.0% (48/49) (89.3% - 99.6%)	97.9% (47/48) (89.1% - 99.6%)
	NPA (Fresh Pros.)	99.6% (1155/1160) (99.0% - 99.8%)	99.7% (1159/1162) (99.2% - 99.9%)
	PPA (Contrived)	94.4% (84/89) (87.5%-97.6%)	N/A
	NPA (Contrived)	100% (29/29) (88.3%-100%)	N/A

*Target includes C. albicans, C. tropicalis, C. parapsilosis, and C. dubliniensis

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

Sample Size:
- Clinical Study: 1,275 female patients (18 to ≥50 years of age, plus two patients 14-17 years old). A total of 2,544 vaginal swabs were tested (likely one clinician-collected and one self-collected per patient).
Data Provenance: Retrospective and prospective. The clinical study was conducted at 9 geographically diverse sites in the U.S.

3. Number of Experts Used to Establish Ground Truth and Qualifications:

The document does not specify the number or qualifications of experts used to establish the ground truth for the clinical study. It refers to "reference/comparator methods" for ground truth.

4. Adjudication Method for the Test Set:

For BV, Candida group, Candida glab-krus, and TV, the performance was determined relative to specific reference/comparator methods (see point 7).
For discrepant results, "investigation of discrepant results was performed by testing specimens with another FDA-cleared NAAT." This indicates a form of discrepancy resolution rather than a multi-expert adjudication on all cases. The exact adjudication method (e.g., 2+1, 3+1) for discrepant cases is not detailed, but it involves re-testing with an FDA-cleared NAAT.

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

No MRMC comparative effectiveness study was mentioned. The device is an in vitro diagnostic test, which typically does not involve human readers interpreting images or data to the same extent as AI-assisted diagnostic tools. Performance is typically compared against reference methods.

6. Standalone (Algorithm Only) Performance:

Yes, the entire clinical study and analytical studies described are standalone performance evaluations of the Xpert Xpress MVP device (an automated qualitative in vitro diagnostic test) without human-in-the-loop assistance in its diagnostic output. Its output is a qualitative detection result (Positive/Negative/Not Detected).

7. Type of Ground Truth Used:

Bacterial Vaginosis (BV): An FDA-cleared nucleic acid amplification test (NAAT).
Candida group (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis): Yeast culture followed by mass spectrometry for species identification.
Candida glabrata/Candida krusei: Yeast culture followed by mass spectrometry for species identification.
Trichomonas vaginalis (TV): A patient infected status (PIS) algorithm that included results from an FDA-cleared NAAT and TV culture.
Discrepant Results: Re-tested with another FDA-cleared NAAT.

8. Sample Size for the Training Set:

The document does not explicitly mention a "training set" in the context of machine learning model development. This device is a PCR-based NAAT, not an AI/ML-driven diagnostic. Therefore, the concept of a training set for an algorithm is not directly applicable in the same way as for an image-based AI device. Analytical studies (e.g., Limit of Detection, Analytical Reactivity, Analytical Specificity) and reproducibility studies served to characterize the device's performance chemically and biologically.

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

As noted above, the device is a PCR-based NAAT, not an AI/ML system, so a "training set" for an algorithm in the traditional sense is not discussed. The development and optimization of the assay's chemical and molecular components would have been guided by fundamental scientific principles and laboratory testing, rather than an algorithmic training process using labeled data. Benchmarking for analytical characteristics (like LoD) would involve preparing samples with known concentrations of organisms.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the text "FDA U.S. FOOD & DRUG ADMINISTRATION" on the right. The symbol on the left is a stylized image of a human figure, and the text on the right is in blue and white.

October 19, 2023

Cepheid Wei Zhang Manager, Regulatory Affairs 904 Caribbean Drive Sunnyvale, California 94089

Re: K231381

Trade/Device Name: Xpert Xpress MVP; GeneXpert Xpress System Regulation Number: 21 CFR 866.3975 Regulation Name: Device That Detects Nucleic Acid Sequences From Microorganisms Associated With Vaginitis And Bacterial Vaginosis Regulatory Class: Class II Product Code: PQA, OUY, OOI Dated: May 11, 2023 Received: May 12, 2023

Dear Wei Zhang:

We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"

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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely. Noel J. Gerald -S

Noel J. Gerald, Ph.D. Branch Chief Bacterial Respiratory and Medical Countermeasures Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

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Indications for Use

510(k) Number (if known) K231381

Device Name Xpert Xpress MVP

Indications for Use (Describe)

Organisms associated with bacterial vaginosis (detected organisms not reported individually) .
- Atopobium spp. (Atopobium vaginae, Atopobium novel species CCUG 55226) O
- 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

Type of Use (Select one or both, as applicable)
-------------------------------------------------

☑ Prescription Use (Part 21 CFR 801 Subpart D)
☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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Image /page/3/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design above the company name. Below the company name, the text "Xpert® Xpress MVP" is displayed, indicating a specific product or service offered by Cepheid. The text is in a simple, sans-serif font and is left-aligned.

Section 5 510(k) Summary for Xpert Xpress MVP

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Image /page/4/Picture/0 description: The image contains the Cepheid logo, which includes a stylized blue wing-like design above the company name. Below the company name, the text "Xpert® Xpress MVP" is displayed. The text is in a smaller font size than the company name, and the "Xpert" has a registered trademark symbol.

5.0 510(k) Summary	3
5.1 Device Description	3
5.2 Device Intended Use	4
5.3 Substantial Equivalence	4
5.4 Non-Clinical Study	7
5.5 Clinical Study	22
5.6 Conclusions	25

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Image /page/5/Picture/1 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design above the company name in a serif font. Below the company name, the text "Xpert® Xpress MVP" is displayed, also in a serif font. The "Xpert" is followed by the registered trademark symbol.

5.0 510(k) Summary

As required by 21 CFR Section 807.92(c).
Submitted by:	Cepheid904 Caribbean DriveSunnyvale, CA 90489Phone number: (425) 420-8349Fax number: (408) 541-4192
Contact:	Wei Zhang, PhD RAC
Date of Preparation:	October 3, 2023
Device:
Trade name:	Xpert® Xpress MVP
Common name:	Xpert Xpress MVP
Type of Test:	Qualitative real-time polymerase chain reaction(PCR) and detection test
Regulation Number,Classification Name,Product CodeDefinition:	21 CFR 866.3975, Vaginitis and Bacterial VaginosisNucleic Acid Detection System, PQA21 CFR 866.3860, Trichomonas vaginalis NucleicAcid Amplification Test System, OUY21 CFR 862.2570, Real Time Nucleic AcidAmplification System, OOI
ClassificationAdvisory Panel:	Microbiology (83)
Prescription Use:	Yes
Predicate Device:	Xpert Xpress MVP (K221160)

5.1 Device Description

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Image /page/6/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design above the company name in a simple, sans-serif font. Below the company name, the text "Xpert® Xpress MVP" is displayed, indicating a specific product or service offered by Cepheid. The text is in a smaller font size compared to the company name, with the "®" symbol indicating a registered trademark.

Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge serving as internal controls. The SPC is present to control for adequate sample processing, to monitor PCR conditions, the presence of potential inhibitor(s) and possible reagent degradation. 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. Because the cartridges are self-contained, the risk of cross- contamination between samples is minimized.

5.2 Device Intended Use

The Xpert® Xpress MVP test, performed on the GeneXpert® Xpress System, 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 ●

5.3 Substantial Equivalence

The Xpert Xpress MVP test for use with the GeneXpert Xpress System is substantially equivalent to the same Xpert Xpress MVP test for use with the GeneXpert Instrument Systems [510(k) K221160]. The following tables compare the subject device to the previously cleared predicate device.

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Table 5-1 shows similarities between the subject device and the predicate device.

Comparison
	Subject Device	Predicate Device
Attribute	Xpert® Xpress MVP, Performed on theGeneXpert Xpress System	Xpert® Xpress MVP, Performed on theGeneXpert Instrument Systems [K221160]
Regulation	Same	21CFR 866.3975Device that detects nucleic acid sequences frommicroorganisms associated with vaginitis andbacterial vaginosis
Product Code	Same	PQAVaginitis and bacterial vaginosis nucleic aciddetection system
Device Class	Same	II
Intended Use	The Xpert® Xpress MVP test, performed on theGeneXpert® Xpress System, is an automatedqualitative in vitro diagnostic test for thedetection of DNA targets from anaerobic bacteriaassociated with bacterial vaginosis (BV),Candida species associated with vulvovaginalcandidiasis, and Trichomonas vaginalis . TheXpert Xpress MVP test uses clinician-collectedand self-collected vaginal swabs (collected in aclinical setting) from patients who aresymptomatic for vaginitis/vaginosis. The XpertXpress MVP test utilizes real-time polymerasechain reaction (PCR) for the amplification ofspecific DNA targets and utilizes fluorogenictarget-specific hybridization probes to detect anddifferentiate DNA from:Organisms associated with bacterial vaginosis(detected organisms not reported individually) Atopobium spp. ( Atopobium vaginae,Atopobium novel species CCUG 55226) Bacterial Vaginosis-Associated Bacterium2 (BVAB2) Megasphaera -1 Candida spp. ( C. albicans, C. tropicalis, C.parapsilosis, C. dubliniensis , species notdifferentiated) Candida glabrata/Candida krusei (species notdifferentiated) Trichomonas vaginalis The Xpert Xpress MVP test is intended to aid inthe diagnosis of vaginal infections in women witha clinical presentation consistent with bacterial	The Xpert® Xpress MVP test, performed on theGeneXpert® Instrument Systems, is an automatedqualitative in vitro diagnostic test for thedetection of DNA targets from anaerobic bacteriaassociated with bacterial vaginosis (BV),Candida species associated with vulvovaginalcandidiasis, and Trichomonas vaginalis . TheXpert Xpress MVP test uses clinician-collectedand self-collected vaginal swabs (collected in aclinical setting) from patients who aresymptomatic for vaginitis/vaginosis. The XpertXpress MVP test utilizes real-time polymerasechain reaction (PCR) for the amplification ofspecific DNA targets and utilizes fluorogenictarget-specific hybridization probes to detect anddifferentiate DNA from:Organisms associated with bacterial vaginosis(detected organisms not reported individually) Atopobium spp. ( Atopobium vaginae,Atopobium novel species CCUG 55226) Bacterial Vaginosis-Associated Bacterium2 (BVAB2) Megasphaera -1 Candida spp. ( C. albicans, C. tropicalis, C.parapsilosis, C. dubliniensis , species notdifferentiated) Candida glabrata/Candida krusei (species notdifferentiated) Trichomonas vaginalis The Xpert Xpress MVP test is intended to aid inthe diagnosis of vaginal infections in women witha clinical presentation consistent with bacterial
Comparison
Attribute	Subject DeviceXpert® Xpress MVP, Performed on theGeneXpert Xpress System	Predicate DeviceXpert® Xpress MVP, Performed on theGeneXpert Instrument Systems [K221160]
Specimen Type	Same	Clinician- and patient-collected vaginal swabs
Organisms Detected	Same	Organisms associated with bacterial vaginosis (detected organisms not reported individually) Atopobium spp. ( Atopobium vaginae ,Atopobium novel species CCUG 55226) Bacterial Vaginosis-AssociatedBacterium 2 (BVAB2) Megasphaera -1 Candida spp. ( C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis , species not differentiated) Candida glabrata/Candida krusei (species not differentiated) Trichomonas vaginalis
Assay Technology	Same	Real-Time PCR
Single Use	Same	Yes
Automated Extraction, Detection and Result Interpretation	Same	Yes
Assay Results	Same	Qualitative
Collection Device	Same	Cepheid Xpert Swab Specimen Collection Kit
Time to Result	Same	Within 60 minutes

Table 5-1: Similarities between Subject Device and Predicate Device

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Image /page/8/Picture/0 description: The image shows the Cepheid logo with the text "Xpert® Xpress MVP" below it. The Cepheid logo consists of a stylized blue graphic above the word "Cepheid." The graphic appears to be a series of curved lines or strokes, resembling a stylized wing or a burst of energy. The text "Xpert® Xpress MVP" is written in a simple, sans-serif font.

Table 5-2 shows the differences between the subject device and the predicate device.

Table 5-2: Differences between Subject Device and Predicate Device

Comparison
Attribute	Subject Device	Predicate Device
	Xpert® Xpress MVP, Performed on theGeneXpert Xpress System	Xpert® Xpress MVP, Performed on theGeneXpert Instrument Systems [K221160]
Instrumentation	Cepheid GeneXpert Xpress System	Cepheid GeneXpert Instrument Systems

The Xpert Xpress MVP test, performed on the GeneXpert Xpress System, has the same general intended use and the same technological characteristics as the predicate device. The differences between the subject device and the predicate device do not raise different questions of safety and effectiveness. The clinical study demonstrates that performance of the subject device is acceptable for its intended use and is substantially equivalent to the predicate device described above.

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Image /page/9/Picture/0 description: The image shows the Cepheid company logo, which includes a stylized blue wing-like design above the company name in a serif font. Below the company name, the text "Xpert® Xpress MVP" is displayed, indicating a specific product or service offered by Cepheid. The registered trademark symbol is present after the word "Xpert".

The information provided in this submission including the clinical performance and comparison of the test results to comparators in this premarket notification is complete and supports a substantial equivalence decision for the Xpert Xpress MVP test.

5.4 Non-Clinical Study

Analytical study data were generated using the GeneXpert Instrument Systems (GeneXpert Dx running GeneXpert Dx software version 4.7b or higher or GeneXpert Infinity-80 running Xpertise software version 6.4b or higher). The data were re-analyzed with GeneXpert Xpress software version 6.4a and demonstrated acceptable results.

5.4.1 Analytical Sensitivity

The analytical sensitivity (Limit of Detection, LoD) of the Xpert Xpress MVP test was determined by preparing dilutions for each of the target organisms detected by the test. The LoD is defined as the lowest concentration of organism sample that can be reproducibly distinguished from negative samples with 95% confidence. The near cut-off concentrations for the BV organisms were also determined. The near cut-off concentration for the BV organisms is defined as the lowest concentrations of Atopobium vaginae and Megasphaera-1, or A. vaginae and BVAB2, or A. vaginae and Megasphaera-1 and BVAB2, or A. vaginae in the absence of Megasphaera-1 and BVAB2 that result in BV POSITIVE test results and can be reproducibly distinguished from negative samples with a 95% confidence level. Positive samples were prepared by inoculating simulated vaginal swab matrix with each representative strain or quantified stock of plasmid DNA containing the cloned genomic target of BVAB2 or Megasphaera-1. Replicates of 20 were evaluated at a minimum of five concentrations for each of the target organisms. The LoD and/or near cut-off concentrations for the target organisms were estimated by probit analysis or by the classical approach using a 95% hit rate. The LoD for each Candida spp. and Trichomonas vaginalis strain was verified in natural clinical vaginal swab matrix and simulated vaginal swab matrix. The LoD and near cut-off concentrations for each BV organism were verified in simulated vaginal swab matrix. The verified LoD and near cut-off concentrations for Xpert Xpress MVP targets are presented in Table 5-3 and Table 5-4 below.

Organism	Verified LoD
Atopobium vaginae	32 CFU/mL
BVAB2 (plasmid DNA)	50 copies/mL
Megasphaera-1 (plasmid DNA)	338 copies/mL
Candida albicans	30 CFU/mL
Candida tropicalis	750 CFU/mL
Candida parapsilosis	1,339 CFU/mL
Candida dubliniensis	1,316 CFU/mL
Candida glabrata	20 CFU/mL
Candida krusei	656 CFU/mL
Trichomonas vaginalis	5 cells/mL

		Table 5-3: Verified LoD and Near Cut-off concentrations for Xpert Xpress MVP

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BV Organism	Verified Near Cut-offConcentration
Atopobium vaginae(in the absence of Megasphaera-1 and BVAB2)	320,000 CFU/mL
Atopobium vaginae(in the presence of Megasphaera-1 and/or BVAB2)	2,750 CFU/mL
BVAB2 plasmid DNA	50 copies/mL
Megasphaera-1 plasmid DNA	390 copies/mL

Table 5-4: Verified LoD and Near Cut-off concentrations for Xpert Xpress MVP

5.4.2 Analytical Reactivity (Inclusivity)

The analytical reactivity of the Xpert Xpress MVP test was determined with 5 strains of Candida albicans, 5 strains of Candida dubliniensis, 5 strains of Candida tropicalis, 5 strains of Candida parapsilosis, 5 strains of Candida glabrata, 5 strains of Candida krusei, 11 strains of Atopobium spp. (Atopobium vaginae and/or Atopobium novel species CCUG 55226), and 10 strains of Trichomonas vaginalis that were diluted in simulated vaginal swab matrix at 3× LoD. Each Atopobium spp. strain was also evaluated at 3× near cut-off concentrations diluted in simulated vaginal swab matrix in the absence or presence of BVAB2 and/or Megasphaera-1 DNA to confirm the correct BV POSITIVE test results were reported.

The Xpert Xpress MVP test correctly identified 46 of 51 strains upon initial testing at 3× LoD. Two strains of Atopobium vaginae tested at 3× LoD and three strains of Candida albicans tested at 3× LoD were not detected and were tested at higher concentrations to determine the minimum concentration sufficient for detection. One Atopobium vaginae strain was detected at ~4× LoD and the other strain was detected at ~12× LoD. One Candida albicans strain was detected at ~4× LoD and the other two Candida albicans strains were detected at ~20× LoD.

For near cut-off concentration of Atopobium spp. in the absence of Megasphaera-1 and BVAB2, the Xpert Xpress MVP test correctly reported BV POSITIVE test result for 7 of the 11 strains upon initial testing at 3× near cut-off concentration. Four strains did not meet acceptance criteria and were further tested to determine the minimum concentration sufficient for reporting BV POSITIVE test result. One Atopobium spp. strain reported BV POSITIVE at ~4×, two strains at ~6×, and one strain at ~12× near cut-off concentration.

For the near cut-off concentration of Atopobium spp. in the presence of Megasphaera-1 and/or BVAB2, the Xpert Xpress MVP test correctly reported BV POSITIVE test result for 7 of the 11 strains upon initial testing at 3× near cut-off concentration. Four strains did not meet acceptance criteria and were further tested to determine the minimum concentration sufficient for reporting BV POSITIVE test result. Two Atopobium spp. strains reported BV POSITIVE at ~4×, one strain at ~6×, and one strain at ~7× near cut-off concentration. The analytical reactivity result summary is presented in Table 5-5.

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Image /page/11/Picture/0 description: The image shows the Cepheid company logo. The logo features a stylized blue wing-like design above the company name, "Cepheid," which is written in a bold, sans-serif font. Below the company name, the text "Xpert® Xpress MVP" is displayed in a smaller, sans-serif font, with the "®" symbol indicating a registered trademark.

Table 5-5: Analytical Reactivity of the Xpert Xpress MVP Test

			Result
OrganismStrain		Concentration	BV	Candidagroup	Candidaglab-krus	TV
	Negative Control		Negative	Not Detected	Not Detected	Not Detected
	CCUG 39382	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
	CCUG 42099	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
	CCUG 43049	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
Atopobium spp.	CCUG 44061	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
LoD(Below the near	CCUG 44116	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
cut-off	CCUG 44125	120 CFU/mL b	pos a	Not Detected	Not Detected	Not Detected
concentrations and	CCUG 44156	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
not generating BVPOSITIVE result) a	CCUG 44258	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
	CCUG 48515	400 CFU/mL c	pos a	Not Detected	Not Detected	Not Detected
	CCUG 55227	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
	CCUG 55226	96 CFU/mL	pos a	Not Detected	Not Detected	Not Detected
	CCUG 39382	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 42099	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 43049	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44061	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
Atopobium spp.	CCUG 44116	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
In the absence of	CCUG 44125	$1.2×10^6$ CFU/mL d	Positive	Not Detected	Not Detected	Not Detected
Megasphaera-1	CCUG 44156	$2.0×10^6$ CFU/mL e	Positive	Not Detected	Not Detected	Not Detected
and BVAB2	CCUG 44258	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 48515	$4.0×10^6$ CFU/mL f	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55227	$9.6×10^5$ CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55226	$2.0×10^6$ CFU/mL g	Positive	Not Detected	Not Detected	Not Detected
	CCUG 39382	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 42099	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 43049	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44061	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
Atopobium spp.	CCUG 44116	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44125	10,000 CFU/mL h	Positive	Not Detected	Not Detected	Not Detected
In the presence ofBVAB2	CCUG 44156	$17,000$ CFU/mL i	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44258	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 48515	$17,000$ CFU/mL j	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55227	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55226	$10,000$ CFU/mL k	Positive	Not Detected	Not Detected	Not Detected
Atopobium spp.	CCUG 39382	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 42099	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
			Result
Organism	Strain	Concentration	BV	Candidagroup	Candidaglab-krus	TV
In the presence ofMegasphaera-1	CCUG 43049	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44061	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44116	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44125	10,000 CFU/mL h	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44156	17,000 CFU/mL i	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44258	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 48515	20,000 CFU/mL j	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55227	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55226	10,000 CFU/mL k	Positive	Not Detected	Not Detected	Not Detected
	CCUG 39382	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 42099	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
Atopobium spp.	CCUG 43049	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44061	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44116	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
In the presence ofMegasphaera-1and BVAB2	CCUG 44125	10,000 CFU/mL h	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44156	17,000 CFU/mL i	Positive	Not Detected	Not Detected	Not Detected
	CCUG 44258	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 48515	17,000 CFU/mL j	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55227	8,250 CFU/mL	Positive	Not Detected	Not Detected	Not Detected
	CCUG 55226	10,000 CFU/mL k	Positive	Not Detected	Not Detected	Not Detected
	ATCC 38289	120 CFU/mL l	Negative	Detected	Not Detected	Not Detected
	ATCC 62376	600 CFU/mL m	Negative	Detected	Not Detected	Not Detected
Candida albicans	ATCC 96113	90 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 60193	90 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 753	600 CFU/mL n	Negative	Detected	Not Detected	Not Detected
	ATCC MYA-179	3,948 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC MYA-577	3,948 CFU/mL	Negative	Detected	Not Detected	Not Detected
Candidadubliniensis	ATCC MYA-646	3,948 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC MYA-580	3,948 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC MYA-581	3,948 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 34139	2,250 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 90874	2,250 CFU/mL	Negative	Detected	Not Detected	Not Detected
Candida tropicalis	ATCC 204318	2,250 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC MYA-2733	2,250 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC MYA-277	2,250 CFU/mL	Negative	Detected	Not Detected	Not Detected
	Candida	ATCC 7330	4,017 CFU/mL	Negative	Detected	Not Detected
	parapsilosis	ATCC 60548	4,017 CFU/mL	Negative	Detected	Not Detected
Organism	Strain	Concentration	Result
			BV	Candidagroup	Candidaglab-krus	TV
	ATCC 90875	4,017 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 96139	4,017 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 96140	4,017 CFU/mL	Negative	Detected	Not Detected	Not Detected
	ATCC 32312	60 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 32554	60 CFU/mL	Negative	Not Detected	Detected	Not Detected
Candida glabrata	ATCC 15126	60 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 2001	60 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC MYA-276	60 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 28870	1,968 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 32672	1,968 CFU/mL	Negative	Not Detected	Detected	Not Detected
Candida krusei	ATCC 90878	1,968 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 200917	1,968 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 201748	1,968 CFU/mL	Negative	Not Detected	Detected	Not Detected
	ATCC 30184	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 30187	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 30238*	15 cells/mL	Negative	Not Detected	Not Detected	Detected
Trichomonasvaginalis	ATCC 30240	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 30245	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 50139	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 50141	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 50167	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC 50183	15 cells/mL	Negative	Not Detected	Not Detected	Detected
	ATCC PRA-95	15 cells/mL	Negative	Not Detected	Not Detected	Detected

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Image /page/12/Picture/0 description: The image contains the logo for Cepheid, a molecular diagnostics company. The logo features a stylized blue graphic above the company name, "Cepheid." Below the company name is the text "Xpert® Xpress MVP," which likely refers to one of Cepheid's diagnostic products or platforms. The text is in a simple, sans-serif font and is horizontally aligned.

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Image /page/13/Picture/0 description: The image shows the Cepheid logo, which includes a stylized blue wing-like graphic above the word "Cepheid." Below the logo, the text "Xpert® Xpress MVP" is displayed. The "Xpert" has a registered trademark symbol next to it.

a The LoD for Atopobium vaginae is for information only. All Atopobium spp. strains tested at ~3× LoD level reported BV NEGATIVE result calls as expected, as the concentration of Atopobium spp. strains tested was below the near cut-off concentration either in the presence of Megal-BVAB2 target. Replicates reporting Atop gp Ct values of ≤ 40.0 was treated as positive (pos) when Atopobium spp. strains were tested at ~ 3× LoD.

b Atopobium vaginae CCUG 44125 was tested at ~ 4× LoD (120 CFU/mL) to obtain 3 of 3 Atop gp Ct values of ≤ 40.0 results.

° Atopobium vaginae CCUG 48515 was tested at ~ 12× LoD (400 CFU/mL) to obtain 3 of 3 Atop gp Ct values of ≤ 40.0 results.

d Atopobium vaginae CCUG 44125 was tested at ~ 4× near cut-off concentration (1.2×10° CFU/mL) in the absence of BVAB2 and Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.

° Atopobium vaginae CCUG 44156 was tested at ~ 6× near cut-off concentration (2.0×10° CFU/mL) in the absence of BVAB2 and Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.

5 Atopobium vaginae CCUG 48515 was tested at ~ 12× near cut-off concentration (4.0×10° CFU/mL) in the absence of BVAB2 and Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.

8 Atopobium novel species CCUG 55226 was tested at ~ 6× near cut-off concentration (2.0×10° CFU/mL) in the absence of BV AB2 and Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.

h Atopobium vaginae CCUG 44125 was tested at ~ 4× near cut-off concentration (10,000 CFU/mL) in the presence of BVAB2 and/or Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.

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Image /page/14/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design. Below the logo, the text "Cepheid." is displayed in a simple font. Underneath "Cepheid.", the text "Xpert® Xpress MVP" is written, with the "®" symbol indicating a registered trademark.

1 Atopobium vaginae CCUG 44156 was tested at ~ 6× near cut-off concentration (17,000 CFU/mL) in the presence of BVAB2 and/or Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.

1 Atopobium vaginae CCUG 48515 was tested at ~ 6× (17,000 CFU/mL) to ~ 7× (20,000 CFU/mL) near cut-off concentration in the presence of BVAB2 and/or Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.
k Atopobium novel species CCUG 55226 was tested at ~ 4× near cut-off concentration (10,000 CFU/mL) in the presence of BVAB2 and/or Megasphaera-1 to obtain 3 of 3 BV POSITIVE result calls.
1 Candida albicans ATCC 38289 was tested at ~ 4× LoD (120 CFUmL) to obtain 3 of 3 Candida group DETECTED result calls.

m Candida albicans ATCC 62376 was tested at ~ 20× LoD (600 CFU/mL) to obtain 3 of 3 Candida group DETECTED result calls.

" Candida albicans ATCC 753 was tested at ~ 20× LoD (600 CFU/mL) to obtain 3 of 3 Candida group DETECTED result calls. * metronidazole-resistant strain

5.4.3 Analytical Specificity (Exclusivity)

The analytical specificity of the Xpert Xpress MVP test was evaluated by testing a panel of 115 potentially cross-reactive microorganisms that are likely to be found in the vaginal flora/female genital tract. All strains were tested in triplicates in simulated vaginal swab matrix at a concentration of at least 106 CFU/mL, 105 cells/mL, 105 TCID50/mL, or 104 International Unit (IU)/mL. No cross-reactivity was observed for all microorganisms tested with the Xpert Xpress MVP test at the concentrations listed in Table 5-6.

Organism	Concentration	Organism	Concentration
Bacteria		Bacteria
Acinetobacter baumannii	1×106 CFU/mL	Neisseria gonorrhoeae	1×106 CFU/mL
Acinetobacter calcoaceticus	1×106 CFU/mL	Olsenella uli	1×106 CFU/mL
Actinomyces israelii	1×106 CFU/mL	Pantoea agglomerans	1×106 CFU/mL
Actinomyces pyogenes	1×106 CFU/mL	Peptoniphilus asaccharolyticus	1×106 CFU/mL
Aerococcus viridans	1×106 CFU/mL	Peptoniphilus anaerobius	1×106 CFU/mL
Alcaligenes faecalis	1×106 CFU/mL	Peptostreptococcus anaerobius	1×106 CFU/mL
Anaerococcus tetradius	1×106 CFU/mL	Plesiomonas shigelloides	1×106 CFU/mL
Atopobium minutum	1×106 CFU/mL	Porphyromonas asaccharolytica	1×106 CFU/mL
Atopobium parvulum	1×106 CFU/mL	Prevotella bivia	1×106 CFU/mL
Atopobium rimae	1×106 CFU/mL	Prevotella melaninogenica	1×106 CFU/mL
Bacillus subtilis	1×106 CFU/mL	Prevotella oralis	1×106 CFU/mL
Bacteroides caccae	1×106 CFU/mL	Propionibacterium acnes	1×106 CFU/mL
Bacteroides fragilis	1×106 CFU/mL	Proteus mirabilis	1×106 CFU/mL
Bacteroides stercoris	1×106 CFU/mL	Providencia stuartii	1×106 CFU/mL
Bacteroides ureolyticus	1×106 CFU/mL	Pseudomonas aeruginosa	1×106 CFU/mL
Bifidobacterium adolescentis	1×106 CFU/mL	Salmonella typhimurium	1×106 CFU/mL
Bifidobacterium breve	1×106 CFU/mL	Serratia marcescens	1×106 CFU/mL
Bifidobacterium longum	1×106 CFU/mL	Shigella flexneri	1×106 CFU/mL
Brevibacterium linens	1×106 CFU/mL	Sneathia amnii	1×106 CFU/mL
Organism	Concentration	Organism	Concentration
Burkholderia cepacian	1×106 CFU/mL	Sneathia sanguinegens	1×106 CFU/mL
BVAB1	1×106 copies/mL	Staphylococcus aureus	1×106 CFU/mL
Campylobacter jejuni	1×106 CFU/mL	Staphylococcus epidermidis	1×106 CFU/mL
Chlamydia trachomatis	1×106 CFU/mL	Streptococcus agalactiae	1×106 CFU/mL
Citrobacter freundii	1×106 CFU/mL	Streptococcus mitis	1×106 CFU/mL
Clostridium perfringens	1×106 CFU/mL	Streptococcus mutans	1×106 CFU/mL
Corynebacterium genitalium	1×106 CFU/mL	Streptococcus salivarius	1×106 CFU/mL
Dialister micraerophilus	1×106 CFU/mL	Treponema pallidum	1×106 copies/mL
Eikenella corrodens	1×106 CFU/mL	Veillonella atypica	1×106 CFU/mL
Enterobacter aerogenes	1×106 CFU/mL	Veillonella parvula	1×106 CFU/mL
Enterococcus faecalis	1×106 CFU/mL	Vibrio parahaemolyticus	1×106 CFU/mL
Enterococcus faecium	1×106 CFU/mL	Yersinia enterocolitica	1×106 CFU/mL
Erysipelothrix rhusiopathiae	1×106 CFU/mL	Protozoans
Escherichia coli	1×106 CFU/mL	Pentatrichomonas hominis	5×104 cells/mL
Finegoldia magna	1×106 CFU/mL	Trichomonas tenax	10 cells/mL
Fusobacterium nucleatum	1×106 CFU/mL	Yeasts
Gardnerella vaginalis	1×106 CFU/mL	Candida catenulate	1×106 CFU/mL
Gemella haemolysans	1×106 CFU/mL	Candida famata	1×106 CFU/mL
Kingella denitrificans	1×106 CFU/mL	Candida haemulonii	1×106 CFU/mL
Klebsiella pneumoniae	1×106 CFU/mL	Candida inconspicua	1×106 CFU/mL
Kocuria rhizophila	1×106 CFU/mL	Candida intermedia	1×106 CFU/mL
Lactobacillus acidophilus	1×106 CFU/mL	Candida kefyr	1×106 CFU/mL
Lactobacillus crispatus	1×106 CFU/mL	Candida lusitaniae	1×106 CFU/mL
Lactobacillus gasseri	1×106 CFU/mL	Candida norvegica	1×106 CFU/mL
Lactobacillus helveticus	1×106 CFU/mL	Candida orthopsilosis	1×102 CFU/mL
Lactobacillus iners	1×106 CFU/mL	Candida rugosa	1×106 CFU/mL
Lactobacillus jensenii	1×106 CFU/mL	Candida utilis	1×106 CFU/mL
Lactobacillus johnsonii	1×106 CFU/mL	Kodamaea ohmeri b	1×106 CFU/mL
Lactobacillus vaginalis	1×106 CFU/mL	Pichia fermentans	1×106 CFU/mL
Legionella pneumophila	1×106 CFU/mL	Pichia norvegensis c	1×106 CFU/mL
Mageeibacillus indolicus a	1×106 CFU/mL	Pichia occidentalis d	1×106 CFU/mL
Megasphaera-2	1×106 copies/mL	Saccharomyces cerevisiae	1×106 CFU/mL
Megasphaera elsdenii	1×106 CFU/mL	Viruses
Mobiluncus curtisii	1×106 CFU/mL	Hepatitis B virus	1×105 IU/mL
Mobiluncus mulieris	1×106 CFU/mL	Hepatitis C virus	1×105 IU/mL
Moraxella catarrhalis	1×106 CFU/mL	Herpes simplex virus I	1×105 TCID50/mL
Morganella morganii	1×106 CFU/mL	HIV-1	3×104 IU/mL e
Mycobacterium smegmatis	1×106 CFU/mL	Human herpesvirus 2	1×105 TCID50/mL
Organism	Concentration	Organism	Concentration
Mycoplasma genitalium	1×106 CFU/mL	Human papilloma virus	4.3×105 cells/mL
Mycoplasma hominis	1×106 CFU/mL	Varicella-zoster virus	1×105 copies/mL

Table 5-6: Organisms Tested for Analytical Specificity

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Image /page/15/Picture/0 description: The image shows the logo for Cepheid, a molecular diagnostics company. The logo features a stylized blue graphic above the company name, "Cepheid." Below the company name is the text "Xpert® Xpress MVP", which likely refers to one of Cepheid's diagnostic products or platforms. The text is black and the background is white.

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Image /page/16/Picture/0 description: The image shows the Cepheid logo with the text "Cepheid." in a stylized font. Below the logo, the text "Xpert® Xpress MVP" is displayed. The Cepheid logo features a blue, wing-like design above the company name.

a Mageeibacillus indolicus is formerly named BVAB3.

b Kodamaea ohmeri is also reported as Pichia ohmeri and Candida guilliermondii.

& Pichia norvegensis is also reported as Candida norvegensis.

d Pichia occidentalis is also reported as Issatchenkia occidentalis and Candida sorbose.

e Evaluated at highest concentration available

5.4.4 Microbial Interference

An interfering microorganism study was performed to assess the inhibitory effects of microorganisms that may be encountered in vaginal specimens on the performance of Xpert Xpress MVP. Thirteen microorganisms were tested for potential interference at ≥10° CFU/mL for bacteria and at ≥104 International Unit/mL or cells/mL for viruses (Table 5-7). Each of the microorganisms was tested in simulated vaginal swab matrix in the presence of a mixture of Atopobium vaginae at 3× near cut-off concentrations, Megasphaera-1 and BVAB2 targets each at ~1.5× near cut-off concentrations, and Candida albicans, Candida glabrata and Trichomonas vaginalis targets each at 3× LoD, in the absence of any Xpert Xpress MVP test targets. The results showed that the presence of the tested microorganisms did not interfere with the performance of the Xpert Xpress MVP test.

Microorganism
Dialister micraerophilus
Gardnerella vaginalis
Lactobacillus crispatus
Lactobacillus jensenii
Lactobacillus iners
Mageeibacillus indolicus
Mobiluncus curtisii
Porphyromonas asaccharolytica
Prevotella bivia
Sneathia amnii
Streptococcus agalactiae
HIV-1*
Human papilloma virus**

Table 5-7: Potentially Interfering Microorganisms Tested

Evaluated at highest concentration available (3×104 IU/mL)

** Evaluated at 1×104 cells/mL

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Image /page/17/Picture/0 description: The image shows the logo for Cepheid, a molecular diagnostics company. Below the logo, the text "Xpert® Xpress MVP" is displayed. The logo features a stylized blue wing-like shape above the company name, which is written in a serif font.

5.4.5 Competitive Interference

Competitive interference between targets (BV, Candida group, Candida glab-krus and TV) of the Xpert Xpress MVP test caused by co-infections was evaluated by testing each target at low positive concentration in the presence of another target at high concentration in simulated vaginal swab matrix. Competitive inhibitory effects between the BV analytes (Atop gp and Megal-BVAB2) were also evaluated in simulated vaginal swab matrix. The conditions simulating co-infections were presented in Table 5-8. Under the conditions of this study, competitive inhibitory effects were not observed between MVP targets or between BV analytes with the Xpert Xpress MVP test.

	Testing Panel	Testing Target/Organisms(Low Positive)	Competitive Target/Organisms(High Positive)
Competitive InterferenceEvaluation betweenMVP Targets	1	Atopobium vaginae( $ <3 \times $ near cut-off concentration) andBVAB2( $ <3 \times $ near cut-off concentration)	Candida albicans(1×106 CFU/mL)
	2		Candida glabrata(1×106 CFU/mL)
	3		Trichomonas vaginalis(1×105 cells/mL)
	4	Atopobium vaginae( $ <3 \times $ near cut-off concentration) andMegasphaera-1( $ <3 \times $ near cut-off concentration)	Candida albicans(1×106 CFU/mL)
	5		Candida glabrata(1×106 CFU/mL)
	6		Trichomonas vaginalis(1×105 cells/mL)
	7	Atopobium vaginae( $ <3 \times $ near cut-off concentration),BVAB2( $ <1.5 \times $ near cut-off concentration) andMegasphaera-1( $ <1.5 \times $ near cut-off concentration)	Candida albicans(1×106 CFU/mL)
	8		Candida glabrata(1×106 CFU/mL)
	9		Trichomonas vaginalis(1×105 cells/mL)
	10	Atopobium vaginae( $ <3 \times $ near cut-off concentration)in the absence of BVAB2 andMegasphaera-1	Candida albicans(1×106 CFU/mL)
	11		Candida glabrata(1×106 CFU/mL)
	12		Trichomonas vaginalis(1×105 cells/mL)
	13	Candida albicans( $ <3 \times $ LoD)	Atopobium vaginae(1×107 CFU/mL),BVAB2(1×107 copies/mL) andMegasphaera-1
	Testing Panel	Testing Target/Organisms(Low Positive)	Competitive Target/Organisms(High Positive)
	14		Atopobium vaginae(1×107 CFU/mL)in the absence of BVAB2 andMegasphaera-1
	15		Candida glabrata(1×106 CFU/mL)
	16		Trichomonas vaginalis(1×105 cells/mL)
	17		Atopobium vaginae(1×107 CFU/mL),BVAB2(1×107 copies/mL) andMegasphaera-1(1×107 copies/mL)
Competitive InterferenceEvaluation between BVOrganisms	18	Candida glabrata(<3× LoD)	Atopobium vaginae(1×107 CFU/mL)in the absence of BVAB2 andMegasphaera-1
	19		Candida albicans(1×106 CFU/mL)
	20		Trichomonas vaginalis(1×105 cells/mL)
	21		Atopobium vaginae(1×107 CFU/mL),BVAB2(1×107 copies/mL) andMegasphaera-1(1×107 copies/mL)
	22	Trichomonas vaginalis(< 3× LoD)	Atopobium vaginae(1×107 CFU/mL)in the absence of BVAB2 andMegasphaera-1
	23		Candida albicans(1×106 CFU/mL)
	24		Candida glabrata(1×106 CFU/mL)
	25	Atopobium vaginae(<3× near cut-off concentration)	BVAB2(1×107 copies/mL) andMegasphaera-1(1×107 copies/mL)
	26	BVAB2(<3× near cut-off concentration)	Atopobium vaginae(1×106 CFU/mL)
	27	Megasphaera-1	Atopobium vaginae
Testing Panel	Testing Target/Organisms(Low Positive)	Competitive Target/Organisms(High Positive)
	( $ < 3 \times$ near cut-off concentration)	( $1 \times 10^6$ CFU/mL)
28	BVAB2( $< 1.5 \times$ near cut-off concentration) andMegasphaera-1( $< 1.5 \times$ near cut-off concentration)	Atopobium vaginae( $1 \times 10^6$ CFU/mL)

Table 5-8: Competitive Interference Testing Conditions

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Image /page/18/Picture/0 description: The image shows the logo for Cepheid, a molecular diagnostics company. The logo features a stylized blue graphic above the company name, followed by the text "Xpert® Xpress MVP" in a smaller font size. The graphic consists of several curved lines that resemble a stylized wing or a series of arcs.

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Image /page/19/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design on the left and the company name "Cepheid" in a sans-serif font on the right. Below the logo, the text "Xpert® Xpress MVP" is displayed, with the registered trademark symbol after "Xpert". The text is in a smaller font size compared to the company name.

5.4.6 Interfering Substances

Twenty substances that may be present in the vaginal swab specimens with the potential to interfere with the performance of the Xpert Xpress MVP test were evaluated. The potentially interfering substances included prescription and over-the-counter drugs, creams and/or gels, blood, hormones, semen and mucus. The substances, active ingredients, and concentrations tested are listed in Table 5-9. Potential interferents were tested in simulated vaginal swab matrix in the presence and absence of Xpert Xpress MVP targets at 3× LoD/3× near cut-off concentrations. With the exception of the 5.5% concentration of mucin (from porcine stomach), no clinically significant inhibitory effects from substances that may be encountered in vaginal specimens were observed on the performance of the Xpert Xpress MVP test. When mucin was tested at a concentration of 4.0%, no clinically significant inhibitory effect was observed on the performance of the Xpert Xpress MVP test.

Substance/Class	Active Ingredient	Concentration Tested
Blood	Blood	5.0% v/v
Seminal Fluid	Semen	5.0% v/v
Mucus	Mucin (porcine stomach)	5.5% v/v (Interference Observed)4.0% v/v (Interference not Observed)
Leukocytes	Leukocytes	105 cells/mL
Intravaginal Hormones	Estradiol; Progesterone	7mg/mL Progesterone + 0.07mg/mL Beta Estradiol
Over the counter (OTC)Vaginal Products;Contraceptives; Vaginaltreatments	Benzocaine 5%; Resorcinol 2%	0.25% w/v
	Clotrimazole 2%	0.25% w/v
	Miconazole Nitrate 4%	0.25% w/v
	Tioconazole 6.5%	0.25% w/v
	5% w/w acyclovir	0.25% w/v
	Glycerin, Propylene glycol	0.25% w/v
	Glycerin; carbomer	0.25% w/v
	Glycerin; sodium hydroxide; carbomer	0.25% w/v
	Glycerin, Hydroxyethyl celluloseBerberis Vulgaris 6X HPUS (Barberry), Borax 3X HPUS (Sodium Borate), Collinsonia Canadensis 3X HPUS (Stone Root), Hamamelis	0.25% w/v

Table 5-9: Potential Interfering Substances Tested

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Image /page/20/Picture/0 description: The image shows the logo for Cepheid Xpert Xpress MVP. The word "Cepheid" is in a bold, sans-serif font, with a blue swoosh above it. Below that is "Xpert® Xpress MVP" in a smaller, serif font. The "®" symbol is next to the word "Xpert".

Substance/Class	Active Ingredient	Concentration Tested
	Virginiana 6X HPUS (Witch Hazel),Bacillus coagulans (Lactospore®)
	Povidone-iodine 10% (topical)	0.25% v/v
	Povidone-iodine 0.3% (douche)	0.25% v/v
	Nonoxynol-9 12.5%	0.25% w/v
	Metronidazole 0.75%	0.25% w/v
Hemorrhoidal Cream	Glycerin 14%; Pramoxine HCl 1%	0.25% w/v

5.4.7 Carry-Over Contamination

A study was conducted to demonstrate that single-use, self-contained GeneXpert cartridges prevent specimen and amplicon carry-over contamination from very high titer positive samples into successively run negative samples when processed in the same GeneXpert module. The study consisted of a negative sample processed in the same GeneXpert module immediately after processing a very high BV positive sample (an A. vaginge strain at 2.8×107 CFU/mL and BVAB2 plasmid DNA at 5.0×10° copies/mL), a very high Candida group positive sample (a C. albicans strain at 3.0×10€ CFU/mL), or a very high TV positive sample (a T. vaginalis strain at 5.0×106 cells/mL) in simulated vaginal swab matrix. The testing scheme was repeated 20 times in a single GeneXpert module for a total of 41 runs (20 high positive samples and 21 negative samples per module) across 3 GeneXpert modules. There was no evidence of any carry-over contamination. All 63 negative samples were correctly reported as negative/not detected. All 60 positive samples were correctly reported as positive/detected.

5.4.8 Time to Result

The time to result is defined as the time from the initiation of cartridge processing on the GeneXpert Xpress System to the time a result is displayed on the test screen. The time to result for the Xpert Xpress MVP test was determined by evaluating the test time of 50 random tests that were conducted as part of an analytical study. The Xpert Xpress MVP test has a turnaround time of within 60 minutes.

5.4.9 Reproducibility and Precision

Reproducibility and precision of the Xpert Xpress MVP test was established by untrained users through a multicenter (3 sites) representative of a CLIA-waived environment, blinded study utilizing a multi-factor nested design consisting of contrived panel members spanning the relevant limit of detection (LoD) spectrum (or, in the case of BV, the near cut-off concentration) for the 4 intended target types.

A panel of ten panel members with varying concentrations of the intended target types were tested by three operators in duplicate on five different days at three sites using one lot of Xpert Xpress MVP test cartridges. The total number of tests for each panel member was 90 (3 sites × 5 days × 3 operators × 1 run × 2 replicates). The three concentrations for each intended target type included two positive levels (moderate positives at ~3× LoD/near cut-off concentration, low positives at ~1× LoD/near cut-off concentration) and one negative. For the BV target, a high negative level (<1× near the cut-off concentration) was also included.

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Image /page/21/Picture/0 description: The image shows the logo for Cepheid, a molecular diagnostics company. The logo features a stylized blue wing-like graphic above the company name, "Cepheid." Below the company name is the text "Xpert® Xpress MVP", which likely refers to one of their diagnostic products or platforms. The text is in a simple, sans-serif font.

Percent agreement for each panel member was analyzed across each of the 9 operators and across each of the 3 sites. Overall percent agreement for each panel member was calculated, as well as the Wilson Score 95% confidence interval for each proportion of concordance (Table 5-10).

It should be noted that during phase I of the study, site 01 had low percent agreement for three specific panel members. Low positive C. albicans, low positive C. glabrata, and moderate positive C. albicans had a percent agreement of 40% (12/30), 80% (24/30), and 86.7% (26/30), respectively. An investigation revealed that the operators at site 01 failed to follow certain sample transfer steps of the Quick Reference Instructions, by not vigorously shaking the sample tube and/or adding an excessive amount of sample to the cartridge, which could generate false negative results as demonstrated by flex studies, leading to low percent agreement. Consequently, all reproducibility data from site 01 in phase I were excluded and phase II was conducted on all panel members at an additional fourth site (site 04) with three new untrained operators.

	Phase I					Phase II				Overall
PanelMember	Site 02			Subtotal	Site 03			Subtotal	Site 04			Subtotal	Agreementwith 95% CI
Negative	100%(30/30)	100%(30/30)	100%(30/30)	100%(90/90)	100%(30/30)	100%(30/30)	100%(30/30)	100%(90/90)	96.7%(29/30)	100%(30/30)	100%(30/30)	98.9%(89/90)	99.6%(269/270)97.9% - 99.9%
BV,High Neg	90.0%(9/10)	70.0%(7/10)	80.0%(8/10)	80.0%(24/30)	60.0%(6/10)	70.0%(7/10)	40.0%(4/10)	56.7%(17/30)	80.0%(8/10)	87.5%(7/8)	60.0%(6/10)	75.0%(21/28)	70.5%(62/88)60.2% - 79.0%
BV.Low Pos	100%(10/10)	90.0%(9/10)	100%(10/10)	96.7%(29/30)	80.0%(8/10)	100%(10/10)	100%(10/10)	93.3%(28/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	96.7%(87/90)90.7% - 98.9%
BV.Mod Pos	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(9/9)	100%(10/10)	100%(29/29)	100%(89/89)95.9% - 100.0%
C. albicans,Low Pos	100%(10/10)	100%(10/10)	90.0%(9/10)	96.7%(29/30)	100%(9/9)	100%(9/9)	100%(9/9)	100%(27/27)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	98.9%(86/87)93.8% - 99.8%
C. albicans.Mod Pos	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(90/90)95.9% - 100.0%
C.glabrata,Low Pos	100%(10/10)	100.0%(10/10)	90.0%(9/10)	96.7%(29/30)	100%(10/10)	100%(9/9)	100%(10/10)	100%(29/29)	100%(10/10)	100%(9/9)	100%(10/10)	100%(29/29)	98.9%(87/88)93.8% - 99.8%
C.glabrata.Mod Pos	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(90/90)95.9% - 100.0%
TV,Low Pos	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(90/90)95.9% - 100.0%
TV,Mod Pos	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(10/10)	100%(10/10)	100%(10/10)	100%(30/30)	100%(90/90)95.9% - 100.0%

Table 5-10: Summary of Reproducibility and Precision Results

Abbreviations: Mod, moderate; Neg, negative; Op, operator; Pos, positive

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Image /page/22/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design above the company name. Below the company name, the text "Xpert® Xpress MVP" is displayed. The text is in a smaller font size than the company name, and the "Xpert" is followed by a registered trademark symbol.

The reproducibility of the Xpert Xpress MVP test was also evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) between-sites, between-days, between-operators, and within-run for each panel member are presented in Table 5-11.

	Analyte	Na	MeanCt	Site		Day		Operator		Within-Run		Total
PanelMember				SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)

Negative	SPC	270	32.4	0.25	0.8	0	0	0.26	0.8	1.02	3.2	1.08	3.3
BV, HighNegative		88	32.2	0.04	0.1	0.12	0.4	0.16	0.5	0.26	0.8	0.33	1.0
BV, LowPositive	Atop gp	90	31.4	0	0	0.09	0.3	0.31	1.0	0.43	1.4	0.54	1.7
BV, ModeratePositive		89	30.1	0.01	0	0	0	0.22	0.7	0.33	1.1	0.39	1.3
BV, HighNegative		76b	40.4	0	0	0.08	0.2	0.44	1.1	1.23	3.1	1.31	3.3
BV, LowPositive	Megal-BVAB2	90	36.3	0.10	0.3	0	0	0.41	1.1	0.71	2.0	0.83	2.3
BV, ModeratePositive		89	34.5	0.33	1	0.28	0.8	0	0	0.84	2.4	0.95	2.7
C. albicans,Low Positive	Cgroup	86	36.1	0.18	0.5	0	0	0.20	0.6	0.93	2.6	0.96	2.7
C. albicans,ModeratePositive		90	34.2	0.55	1.6	0	0	0.74	2.2	0.74	2.2	1.18	3.5
C. glabrata,Low Positive	Cglab-krus	88	30.5	0.55	1.8	0	0	1.18	3.9	1.33	4.4	1.86	6.1
C. glabrata,ModeratePositive		90	28.5	0.22	0.8	0	0	0.51	1.8	0.78	2.7	0.96	3.4
TV, Lowpositive	TV	90	37.4	0	0	0	0	0.55	1.5	0.92	2.5	1.08	2.9
TV, Moderatepositive		90	35.0	0.05	0.1	0.14	0.4	0	0	0.42	1.2	0.45	1.3

Table 5-11. Results of Reproducibility for the Xpert Xpress MVP Test

Abbreviations: Atop gp, Atopobium group; Cglab-krus, C. glabrata/C. krusei; Cgroup, Candida spp.; CV, coefficient of variation; Megal; Megasphaera-1; Mod, moderate; Neg, negative; Pos, positive; SD, standard deviation; SPC; sample processing control a Number of samples with non-zero Ct values out of 90.

b Twelve (12) out of 88 samples with Mega1-BVAB2 Ct = 0 were excluded from the ANOVA analysis.

Note: The variance estimate from some factors may be numerically negative, which can occur if the variability due to those factors is very small. When this occurs, the variability as measured with SD and CV is set to 0.

5.4.10 Precision of the BV Target

Due to the diversity of organisms associated with the detection of BV, a separate single-site study was conducted to establish precision of the BV target. To establish the assay precision for the BV target in the Xpert Xpress MVP test, a single-center, blinded precision study was conducted utilizing samples with unique combinations of contrived BV organisms.

A panel of nine panel members were tested by two operators in duplicate on ten different days

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Image /page/23/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design above the company name in black. Below the company name, the text "Xpert® Xpress MVP" is displayed, indicating a specific product or service offered by Cepheid. The text is also in black and appears to be a part of the company's branding or product identification.

using one lot of Xpert Xpress MVP test cartridges. The total number of tests for each panel member was 80 (1 site × 1 lot × 10 days × 2 operators × 2 runs × 2 replicates). The panel included 1 negative panel member, a high negative level (<1× the near cut-off concentration), and two positive levels (low positives at ~1× the near cut-off concentration, and moderate positives at ~3× the near cut-off concentration) utilizing unique combinations of the BV organisms (Atopobium vaginae, Megasphaera-1, and BVAB2). Testing was performed on the GeneXpert Infinity System using GeneXpert Xpertise software version 6.4b and were reanalyzed using the GeneXpert Xpress software version 6.4a. The re-analyzed data generated acceptable results.

Table 5-12 presented agreement for each panel member, as well as the Wilson Score 95% confidence interval for each proportion of concordance.

Sample Type	OverallAgreement	95% CI
Negative	100% (80/80)	95.4% - 100%
A. vaginae, Low positive	97.5% (78/80)	91.3% - 99.3%
A. vaginae and BVAB2, High negative	66.3% (53/80)	55.4% - 75.7%
A. vaginae and BVAB2, Low positive	97.5% (78/80)	91.3% - 99.3%
A. vaginae and Megasphaera-1, High negative	23.8% (19/80)	15.8% - 34.1%
A. vaginae and Megasphaera-1, Low positive	95.0% (76/80)	87.8% - 98.0%
A. vaginae, BVAB2, and Megasphaera-1, High negative	53.8% (43/80)	42.9% - 64.3%
A. vaginae, BVAB2, and Megasphaera-1, Low positive	96.3% (77/80)	89.5% - 98.7%
A. vaginae, BVAB2, and Megasphaera-1, Moderate positive	100% (80/80)	95.4% - 100%

Table 5-12: Summary of Precision Results for the BV Target

Abbreviations: A. vaginae; Atopobium vaginae

Precision for BV targets was evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) between-days, between-operators, between-runs and within-run for each panel member are presented in Table 5-13.

Panel member	Analyte	Na	MeanCt	Day		Operator		Between-Run		Within-run		Total
				SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Negative	SPC	80	32.84	0.00	0.0	0.49	1.5	0.22	0.7	0.90	2.7	1.05	3.2
A. vaginae , Low Pos	Atop gp	80	24.98	0.00	0.0	0.00	0.0	0.03	0.1	0.32	1.3	0.32	1.3
A. vaginae andBVAB2, High Neg	SPC	80	32.64	0.17	0.5	0.17	0.5	0.12	0.4	0.37	1.1	0.46	1.4
	Atop gp	80	32.35	0.00	0.0	0.16	0.5	0.00	0.0	0.20	0.6	0.26	0.8
	Mega1-BVAB2b	75	41.30	0.37	0.9	0.00	0.0	0.26	0.6	1.15	2.8	1.24	3.0

Table 5-13: Results of Precision for the BV Target

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Image /page/24/Picture/0 description: The image contains the Cepheid logo. The logo consists of a blue graphic element resembling stylized wings or a series of curved lines, followed by the word "Cepheid." in a sans-serif font. Below the logo, the text "Xpert® Xpress MVP" is displayed, with the "®" symbol indicating a registered trademark.

Panel member	Analyte	N a	MeanCt	Day		Operator		Between-Run		Within-run		Total
				SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
A. vaginae andBVAB2, Low Pos	Atop gp	80	32.20	0.00	0.0	0.04	0.1	0.08	0.3	0.22	0.7	0.24	0.7
	Megal-BVAB2 b	80	40.03	0.00	0.0	0.00	0.0	0.30	0.7	0.90	2.2	0.94	2.4
A. vaginae andMega-1, High Neg	SPC	80	32.63	0.11	0.3	0.17	0.5	0.00	0.0	0.39	1.2	0.44	1.3
	Atop gp	80	32.62	0.00	0.0	0.04	0.1	0.00	0.0	0.33	1.0	0.34	1.0
	Megal-BVAB2 b	28	38.98	0.00	0.0	1.01	2.6	0.21	0.6	0.84	2.2	1.33	3.4
A. vaginae andMega-1, Low Pos	Atop gp	79	32.07	0.00	0.0	0.15	0.5	0.18	0.6	0.41	1.3	0.47	1.5
	Megal-BVAB2 b	80	35.48	0.00	0.0	0.29	0.8	0.00	0.0	0.71	2.0	0.77	2.2
A. vaginae, BVAB2,and Mega-1,High Neg	SPC	80	32.74	0.15	0.5	0.12	0.4	0.17	0.5	0.33	1.0	0.41	1.3
	Atop gp	80	32.53	0.00	0.0	0.15	0.5	0.00	0.0	0.22	0.7	0.27	0.8
	Megal-BVAB2 b	63	41.57	0.30	0.7	0.00	0.0	0.39	0.9	1.02	2.5	1.13	2.7
A. vaginae, BVAB2.and Mega-1,Low Pos	Atop gp	79	31.81	0.00	0.0	0.22	0.7	0.28	0.9	1.16	3.6	1.21	3.8
	Megal-BVAB2 b	80	36.25	0.15	0.4	0.00	0.0	0.10	0.3	0.69	1.9	0.71	2.0
A. vaginae, BVAB2,and Mega-1,Mod Pos	Atop gp	80	30.67	0.13	0.4	0.09	0.3	0.00	0.0	0.33	1.1	0.37	1.2
	Megal-BVAB2 b	80	35.64	0.00	0.0	0.26	0.7	0.00	0.0	0.48	1.3	0.54	1.5

Abbreviations: Atop gp, Atopobium group; CV, coefficient of variation; Mega1; Mod; moderate; Neg, negative; Pos, positive; SD, standard deviation; SPC, sample processing control

" Number of samples with non-zero Ct values out of 80.

b Samples with Mega1-BVAB2 that did not generate a Ct value were excluded from analysis.

Note: The variance estimate from some be numerically negative, which can occur if the variability due to those factors is very small. When this occurs, the variability as measured with SD and CV is set to 0.

5.5 Clinical Study

A blinded clinical study was conducted to evaluate the performance of the Xpert Xpress MVP test at 9 geographically diverse sites in the U.S. Subjects included female patients > 14 years of age who presented with signs and/or symptoms of vaginosis/vaginitis. For eligible subjects, one (1) self-collected (collected in a clinical setting, SVS) and five (5) clinician-collected vaginal swab (CVS) specimens were obtained for testing with the Xpert Xpress MVP test and reference/comparator testing. Patient management continued at the site per the standard practice, independent of investigational test results.

Performance of the Xpert Xpress MVP test in vaginal swab specimens was determined relative to reference/comparator methods. Specifically, positive percent agreement (PPA)/negative percent agreement (NPA) for BV was assessed relative to an FDA-cleared nucleic acid amplification test (NAAT). Sensitivity and specificity for Candida group and Candida glab-krus targets were assessed relative to yeast culture followed by mass spectrometry for species

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Image /page/25/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wing-like design above the company name in black. Below the company name, the text "Xpert® Xpress MVP" is displayed, indicating a specific product or service offered by Cepheid. The text is also in black and appears to be a part of the company's branding or product identification.

identification. PPA and NPA for TV were assessed relative to a patient infected status (PIS) algorithm that included results from an FDA-cleared NAAT and TV culture. When applicable, investigation of discrepant results was performed by testing specimens with another FDAcleared NAAT.

The study population comprised of 1,275 female patients 18 to ≥ 50 years of age. Additionally, two patients between 14-17 years of age were enrolled in the study. A total of 2,544 vaginal swabs were tested and were eligible for inclusion in the Xpert Xpress MVP study.

Performance of the Xpert Xpress MVP test is presented in Table 5-14. The Xpert Xpress MVP test demonstrated positive percent agreement (PPA) and negative percent agreement (NPA) of 92.9% and 94.5% for BV detection in CVS specimens, respectively, and 93.6% in SVS specimens, respectively. For Candida group detection, the Xpert Xpress MVP test demonstrated sensitivity and specificity of 98.1% and 94.9% in CVS specimens, respectively, and 97.8% and 92.9% in SVS specimens, respectively. The Xpert Xpress MVP test demonstrated sensitivity and specificity of 94.1% and 99.8% for Candida glab-krus detection in CVS specimens, respectively, and 100% and 99.7% in SVS specimens, respectively. For TV detection, the Xpert Xpress MVP test demonstrated PPA and NPA of 98.0% and 99.6% in CVS specimens, respectively, and 97.9% and 99.7% in SVS specimens, respectively.

		Clinician-collected (CVS)	Self-collected (SVS)
	Sensitivity/PPA(95% CI)	Specificity/NPA(95% CI)	Sensitivity/PPA(95% CI)	Specificity/NPA(95% CI)
BV	92.9%429/462 a(90.1% - 94.9%)	94.5%719/761 b(92.6% - 95.9%)	93.5%434/464 c(90.9% - 95.4%)	93.6%711/760 d(91.6% - 95.1%)
Candida group*	98.1%360/367 e(96.1% - 99.1%)	94.9%820/864 f(93.2% - 96.2%)	97.8%359/367 g(95.8% - 98.9%)	92.9%804/865 h(91.0% - 94.5%)
Candida glab-krusFresh Prospective	94.1%32/34 i(80.9% - 98.4%)	99.8%1195/1197 j(99.4% - 99.9%)	100%33/33(89.6% - 100%)	99.7%1195/1199 k(99.1% - 99.9%)
Candida glab-krusContrived**	99.0%98/99(94.5%-99.8%)	96.4%27/28(82.3%-99.4%)	N/A	N/A
TVFresh Prospective	98.0%48/49 l(89.3% - 99.6%)	99.6%1155/1160 m(99.0% - 99.8%)	97.9%47/48 n(89.1% - 99.6%)	99.7%1159/1162 o(99.2% - 99.9%)
TVContrived**	94.4%84/89(87.5%-97.6%)	100%29/29(88.3%-100%)	N/A	N/A

Table 5-14: Overall Performance of the Xpert Xpress MVP Test

Target includes C. albicans, C. tropicalis, C. parapsilosis, and C. dubliniensis

** Contrived specimens were prepared using individual negative clinical CVS and SVS specimens.

a Testing results with a second FDA-cleared NAAT: 15 were also negative and 18 were positive.

b Testing results with a second FDA-cleared NAAT: 21 were also positive and 21 were negative.

6 Testing results with a second FDA-cleared NAAT: 9 were also negative and 21 were positive.

d Testing results with a second FDA-cleared NAAT: 20 were also positive and 29 were negative.

e Testing results with an FDA-cleared NAAT: 5 were also negative and 2 were positive.

f Testing results with an FDA-cleared NAAT: 25 were also positive and 19 were negative.

8 Testing results with an FDA-cleared NAAT: 4 were also negative and 4 were positive.

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Image /page/26/Picture/0 description: The image shows the Cepheid logo. The logo consists of a blue graphic element resembling stylized wings or feathers above the word "Cepheid." The text is in a simple, sans-serif font. The logo appears to be for a company or organization named Cepheid.

Xpert® Xpress MVP

h Testing results with an FDA-cleared NAAT: 30 were also positive and 31 were negative.

i Testing results with an FDA-cleared NAAT: 1 was also negative and 1 was positive.

J Testing results with an FDA-cleared NAAT: 2 were negative.
k Testing results with an FDA-cleared NAAT: 4 were negative.
1 Testing results with a second FDA-cleared NAAT: 1 was positive.
m Testing results with a second FDA-cleared NAAT: 4 were also positive and 1 had no result.
n Testing results with a second FDA-cleared NAAT: 1 was positive.

º Testing results with a second FDA-cleared NAAT: 3 were also positive

5.5.1 Asymptomatic Population

Although the Xpert Xpress MVP test is not intended for use in an asymptomatic patient population, positivity rates were calculated from CVS and SVS specimens collected from asymptomatic patients to assess how often patients who, despite being asymptomatic, harbored microbial flora associated with vaginosis and candidiasis that could be detected by the Xpert Xpress MVP test. Positivity rates are presented by target and by race/ethnicity in Table 5-15.

Table 5-15: Positivity Rates in Asymptomatic Patients According to the Xpert Xpress MVP Test

	Target	Overall	Black /AfricanAmerican^	White		Other*
CVS	BV	32.9%(52/158)	51.0%(26/51)	Hispanic/Latino	Not Hispanic/Latino	36.4%(4/11)
CVS	Candidagroup	17.1%(27/158)	25.5%(13/51)	16.4%(9/55)	7.3%(3/41)	18.2%(2/11)
CVS	Candida glab-krus	4.4%(7/158)	2.0%(1/51)	5.5%(3/55)	4.9%(2/41)	9.1%(1/11)
SVS	BV	31.5%(51/162)	49.1%(26/53)	24.1%(13/54)	16.3%(7/43)	41.7%(5/12)
SVS	Candidagroup	19.1%(31/162)	28.3%(15/53)	18.5%(10/54)	7.0%(3/43)	25.0%(3/12)
SVS	Candida glab-krus	4.9%(8/162)	1.9%(1/53)	7.4%(4/54)	4.7%(2/43)	8.3%(1/12)

^Includes one Black/African American who was of Hispanic or Latino descent for CVS specimens; includes two Black/African Americans who were of Hispanic or Latino descent for SVS specimens. *Including: American Indian or Alaska Native, Asian, Mixed/Unknown

5.5.2 Non-Determinate Rate

Of the 2,544 Xpert Xpress MVP runs performed in the clinical study, 126 resulted in nondeterminate ("INSTRUMENT ERROR" or "NO RESULT - REPEAT TEST") results on first attempt. Upon retest of these 126 specimens, 21 remained non-determinate. The initial nondeterminate rate was 5.0% (126/2544) and the overall non-determinate rate was 0.8% (21/2544). The initial non-determinate rate for CVS specimens was 4.6% (59/1269) and the overall nondeterminate rate was 0.6% (8/1269). The initial non-determinate rate for SVS specimens was 5.3% (67/1275) and the overall non-determinate rate was 1.0% (13/1275).

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Image /page/27/Picture/0 description: The image shows the Cepheid company logo and product name. The logo features a stylized blue graphic above the company name, "Cepheid," which is written in a cursive font. Below the company name is the product name, "Xpert® Xpress MVP," with the "Xpert" having a registered trademark symbol.

5.6 Conclusions

The results of the non-clinical analytical and clinical performance studies summarized above demonstrated that the Xpert Xpress MVP test for use with GeneXpert Xpress System is substantially equivalent to the predicate device.

Regulation Number and Section

§ 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.