(47 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
- o Megasphaera-1
- . Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis, species not differentiated)
- Candida glabrata/Candida krusei (species not differentiated)
- . Trichomonas vaginalis
The Xpert Xpress MVP test is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis, or trichomoniasis.
The Xpert® Xpress MVP test is an automated in vitro diagnostic test for qualitative detection of DNA targets from anaerobic bacteria associated with bacterial vaginosis. Candida species associated with vulyovaginal candidiasis, and Trichomonas vaginalis, the agent of trichomoniasis. The Xpert Xpress MVP test is performed on GeneXpert Instrument Systems. The GeneXpert Instrument Systems automate and integrate sample preparation, nucleic acid extraction and amplification, and detection of the target sequences in simple or complex samples using real-time PCR assays. The systems consist of an instrument, computer, and preloaded software for running tests and viewing the results. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is minimized.
The Xpert Xpress MVP test includes reagents for the detection of DNA from BV organisms, Candida species, and Trichomonas vaginalis from vaginal swab samples. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert System instrument. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the PCR reaction. The SPC also ensures that the PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The PCC verifies reagent rehydration, PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dye stability.
The Xpert Xpress MVP test is designed for use with the following specimens collected from symptomatic individuals: self-collected vaginal swabs (collected in a clinical setting) and clinician-collected vaginal swabs. The swab transport reagent included in the Xpert Swab Specimen Collection Kit is designed to collect and preserve patient specimens to allow transport to the laboratory prior to analysis with the Xpert Xpress MVP test.
Here's a breakdown of the acceptance criteria and study details for the Cepheid Xpert Xpress MVP device, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document primarily focuses on demonstrating equivalence between a "new design" and an "original design" of the Xpert Xpress MVP, rather than establishing de novo acceptance criteria against a clinical reference standard in this specific submission. The acceptance criteria for the analytical sensitivity equivalency study were defined internally for comparison between the two designs:
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance (New Design vs. Original) |
|---|---|---|
| Analytical Sensitivity Equivalency | LoD (Limit of Detection) & Near Cut-off Concentrations:1. Both original and new design report 19/20 or 20/20 POSITIVE/DETECTED results at LoD/Near Cut-off concentrations.2. Statistical analysis (two-sample t-test) comparing mean Ct values shows no statistically significant difference (p-value > 0.05) with a marginal difference of 1.0 Ct value. | Met:- All targets (Atopobium vaginae, Megasphaera-1, BVAB2, Candida albicans, Candida dubliniensis, Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida krusei, Trichomonas vaginalis) consistently showed 19/20 or 20/20 positive/detected results at LoD.- All BV targets showed 19/20 or 20/20 positive/detected (BV positive) results at near cut-off concentrations.- For all targets and conditions (SVM/VS matrix), the difference in mean Cts between the two designs was within 1.0 Ct, and the t-test p-values were consistently > 0.05 (most were >0.9), indicating no statistically significant difference in analytical sensitivity. |
| Clinical Specimen Equivalency (PPA/NPA) | The PPA (Positive Percent Agreement) and NPA (Negative Percent Agreement) of the new design relative to the original design for Bacterial Vaginosis (BV), Candida group, Candida glabrata/Candida krusei, and Trichomonas vaginalis (TV) targets should demonstrate equivalence. (No specific numerical thresholds provided in this summary, but the implication is "high agreement"). | Met:- BV: PPA 98.3% (56/57), NPA 99.1% (112/113)- Candida group: PPA 97.4% (38/39), NPA 98.5% (129/131)- Candida glab-krus: Overall PPA 100% (31/31), NPA 100% (159/159). (Fresh PPA 100% (11/11), Contrived PPA 100% (20/20))- TV: Overall PPA 100% (32/32), NPA 100% (158/158). (Fresh PPA 100% (12/12), Contrived PPA 100% (20/20))- Discordant results were investigated and attributed to samples near LoD or sub-LoD levels, supporting overall equivalence. |
| Non-Determinate Rate | Implicitly, the non-determinate rates for both designs should be low and acceptable. | Met:- Overall non-determinate rate for original design: 0.42% (1/236)- Overall non-determinate rate for new design: 1.4% (3/220)These rates are considered acceptable. |
| Interfering Substances | No clinically significant inhibitory effects from substances encountered in vaginal specimens, except where a limitation is appropriate. | Met:- No clinically significant inhibitory effects observed for new design, with the exception of 5.5% v/v mucin (same as original design). At 4.0% mucin, no interference was observed. A limitation for ≥5.5% mucin is included in the instructions. |
2. Sample Size Used for the Test Set and Data Provenance
-
Analytical Sensitivity Equivalency Study (LoD & Near Cut-off):
- Sample Size: 20 replicates for each target at LoD/near cut-off concentration for both the original and new designs. This included testing in Simulated Vaginal Matrix (SVM) and Pooled Negative Natural Clinical Vaginal Swab Matrix (VS) for some targets.
- Data Provenance: Not explicitly stated, but these are analytical studies meaning they used prepared samples (cultures, specific concentrations) rather than clinical patient samples.
-
Equivalency Study using Clinical Specimens:
- Sample Size:
- Initial Enrollment: 174 participants (174 clinician-collected vaginal swabs).
- Included in Final Analysis: 170 prospectively collected ("fresh") clinician-collected vaginal swab specimens.
- Additional Contrived Specimens: 20 contrived C. glabrata and C. krusei specimens, and 20 contrived T. vaginalis specimens.
- Data Provenance:
- Country of Origin: United States (three sites).
- Retrospective or Prospective: Prospectively collected. Clinician-collected vaginal swabs were taken from symptomatic female patients ≥ 14 years of age. All testing was performed at Cepheid (Sunnyvale, CA).
- Sample Size:
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
This submission is about demonstrating equivalence between two versions of the same diagnostic device, not evaluating the device against a clinical reference standard with expert interpretation for ground truth. Therefore, experts were not used to establish the "ground truth" for the test set in the traditional sense of clinical diagnosis.
Instead, the "ground truth" in the clinical equivalency study was the result produced by the predicate device (original design of Xpert Xpress MVP).
4. Adjudication Method for the Test Set
No adjudication method using human experts was described for the clinical equivalency study. The comparison was directly between the test results of the new device and the predicate device. Discordant results were investigated by retesting with both designs if enough sample volume remained, but these retest results were for information only and not used for adjudication in the primary data analysis.
5. (MRMC) Multi-Reader Multi-Case Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was NOT done. This document describes the analytical and clinical performance equivalence of a device modification to its predicate, not a study evaluating human reader performance with or without AI assistance.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
- Yes, this is essentially a standalone (algorithm only) performance study. The Xpert Xpress MVP system is an automated in vitro diagnostic test that provides a qualitative result. While human operators are involved in sample preparation and loading, the "performance" described here (detection of DNA targets) is that of the automated system and its reagents/software, acting as an algorithm-only device in the context of its defined output. There isn't a human-in-the-loop component being evaluated in these studies.
7. Type of Ground Truth Used
- Analytical Sensitivity Study: The ground truth was based on known concentrations of target organisms (CFU/mL or copies/mL) spiked into matrices.
- Clinical Specimen Equivalency Study: The "ground truth" for comparison was the results obtained from the predicate device (original Xpert Xpress MVP K212213). The study aimed to show agreement with the predicate device, not with an external clinical gold standard.
8. Sample Size for the Training Set
No information about a training set is provided. This document describes validation studies for a device, not the development or training of an AI algorithm. If there were internal machine learning components in the original device, their training data would have been part of the original K212213 submission.
9. How the Ground Truth for the Training Set Was Established
As no training set is mentioned, this information is not applicable to the provided document.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA) along with the Department of Health & Human Services. The FDA logo features a blue square with the letters "FDA" in white, followed by the words "U.S. FOOD & DRUG" in blue, and "ADMINISTRATION" in a smaller font size below. To the left of the FDA logo is the symbol of the Department of Health & Human Services, which consists of a stylized human figure.
June 7, 2022
Cepheid Wei Zhang Senior Regulatory Affairs Specialist 904 Caribbean Drive Sunnyvale, California 94089
Re: K221160
Trade/Device Name: Xpert Xpress MVP, GeneXpert Dx System, GeneXpert Infinity 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, OOI Dated: April 20, 2022 Received: April 21, 2022
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 (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 located 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.
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
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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 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 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, Ph.D. Chief Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known)
Device Name
Indications for Use (Describe)
| 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/1 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 their diagnostic products or platforms. The registered trademark symbol is present after the word "Xpert".
Section 5
510(k) Summary for Xpert Xpress MVP
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Table of Contents
| 5.0 510(k) Summary |
|---|
| 5.1 Device Description |
| 5.2 Device Intended Use |
| 5.3 Substantial Equivalence |
| 5.4 Non-Clinical Study |
| 5.5 Clinical Studies |
| 5.6 Conclusions |
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Image /page/5/Picture/0 description: The image shows the Cepheid logo, which includes a stylized blue wing-like design above the word "Cepheid." Below the logo, the text "Xpert® Xpress MVP" is displayed. The word "Xpert" has a registered trademark symbol next to it. The text is black and centered.
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: | April 20, 2022 |
| Device: | |
| Trade name: | Xpert® Xpress MVP |
| Common name: | Xpert Xpress MVP |
| Type of Test: | Qualitative real-time polymerase chain reaction (PCR) anddetection test |
| Regulation number,Classification name, | 21 CFR 866.3975, Vaginitis and Bacterial Vaginosis NucleicAcid Detection System, PQA |
| Product codeDefinition | 21 CFR 862.2570, Real Time Nucleic Acid AmplificationSystem, OOI |
| ClassificationAdvisory Panel | Microbiology (83) |
| Prescription Use | Yes |
| Predicate Device: | Xpert Xpress MVP (K212213) |
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Image /page/6/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue graphic resembling three curved lines above the company name. Below the logo, 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, and the "®" symbol denotes a registered trademark.
5.1 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. Candida species associated with vulyovaginal candidiasis, and Trichomonas vaginalis, the agent of trichomoniasis. The Xpert Xpress MVP test is performed on GeneXpert Instrument Systems. The GeneXpert Instrument Systems automate and integrate sample preparation, nucleic acid extraction and amplification, and detection of the target sequences in simple or complex samples using real-time PCR assays. The systems consist of an instrument, computer, and preloaded software for running tests and viewing the results. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is minimized.
The Xpert Xpress MVP test includes reagents for the detection of DNA from BV organisms, Candida species, and Trichomonas vaginalis from vaginal swab samples. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert System instrument. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the PCR reaction. The SPC also ensures that the PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The PCC verifies reagent rehydration, PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dye stability.
The Xpert Xpress MVP test is designed for use with the following specimens collected from symptomatic individuals: self-collected vaginal swabs (collected in a clinical setting) and clinician-collected vaginal swabs. The swab transport reagent included in the Xpert Swab Specimen Collection Kit is designed to collect and preserve patient specimens to allow transport to the laboratory prior to analysis with the Xpert Xpress MVP test.
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Image /page/7/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, indicating a specific product or service offered by Cepheid. The text is in a smaller, sans-serif font, with the "®" symbol indicating a registered trademark.
5.2 Device Intended Use
The Xpert® Xpress MVP test, performed on the GeneXpert® Instrument Systems, is an automated qualitative in vitro diagnostic test for the detection of DNA targets from anaerobic bacteria associated with bacterial vaginosis (BV). Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis. The Xpert Xpress MVP test uses clinician-collected and self-collected vaginal swabs (collected in a clinical setting) from patients who are symptomatic for vaginitis/vaginosis. The Xpert Xpress MVP test utilizes real-time polymerase chain reaction (PCR) for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA from:
- . Organisms associated with bacterial vaginosis (detected organisms not reported individually)
- o Atopobium spp. (Atopobium vaginae, Atopobium novel species CCUG 55226)
- Bacterial Vaginosis-Associated Bacterium 2 (BVAB2) O
- o Megasphaera-1
- . Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis, species not differentiated)
- Candida glabrata/Candida krusei (species not differentiated)
- . Trichomonas vaginalis
The Xpert Xpress MVP test is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis, or trichomoniasis.
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Image /page/8/Picture/1 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.
5.3 Substantial Equivalence
The new design of the Xpert Xpress MVP test is substantially equivalent to the original design of the Xpert Xpress MVP (K212213, the predicate device).
The following tables compare the new design of the Xpert Xpress MVP test to the original design of the Xpert Xpress MVP test (K212213). Table 5-1 shows similarities between the new design and the original design (K212213).
| Comparison | ||
|---|---|---|
| Attribute | New Device | Predicate Device |
| Xpert Xpress MVP (New Design) | Xpert Xpress MVP (K212213) | |
| Regulation | Same | 21CFR 866.3975Device that detects nucleic acid sequencesfrom microorganisms associated withvaginitis and bacterial vaginosis |
| Product Code | Same | PQAVaginitis and bacterial vaginosis nucleic aciddetection system |
| Device Class | Same | II |
| Intended Use | Same | The Xpert® Xpress MVP test, performed onthe GeneXpert® Instrument Systems, is anautomated qualitative in vitro diagnostic testfor the detection of DNA targets fromanaerobic bacteria associated with bacterialvaginosis (BV), Candida species associatedwith vulvovaginal candidiasis, andTrichomonas vaginalis . The Xpert XpressMVP test uses clinician-collected and self-collected vaginal swabs (collected in aclinical setting) from patients who aresymptomatic for vaginitis/ vaginosis. TheXpert Xpress MVP test utilizes real-timepolymerase chain reaction (PCR) for theamplification of specific DNA targets andutilizes fluorogenic target-specifichybridization probes to detect anddifferentiate DNA from:Organisms associated with bacterialvaginosis (detected organisms notreported individually) Atopobium spp. ( Atopobiumvaginae , Atopobium novel speciesCCUG 55226)Bacterial Vaginosis-AssociatedBacterium 2 (BVAB2)Megasphaera-1 Candida spp. ( C. albicans , C.tropicalis , C. parapsilosis , C. |
| Comparison | ||
| Attribute | New Device | Predicate Device |
| Xpert Xpress MVP (New Design) | Xpert Xpress MVP (K212213) | |
| • 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. | ||
| Laboratory Users | Same | CLIA Moderate Complexity |
| Specimen Type | Same | Clinician-collected and self-collected vaginal swabs (collected in a clinical setting) |
| Assay Technology | Same | Real-Time PCR |
| Organisms Detected | Same | • Organisms associated with bacterial vaginosis (detected organisms not reported individually)• Atopobium spp. (Atopobium vaginae, Atopobium novel species CCUG 55226)• Bacterial Vaginosis-Associated Bacterium 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 |
| Test Cartridge Technology | Same | Disposable single-use, multi-chambered fluidic cartridge |
| Sample Preparation | Same | Self-contained and automated after mixed specimen is added to cartridge. All other reagents are contained in the cartridge. |
| Assay Type | Same | Qualitative |
| Instrument Systems | Same | Cepheid GeneXpert Instrument Systems |
| Collection Device | Same | Cepheid Xpert Swab Specimen Collection kit |
| Time to Result | Same | Within 60 minutes |
| Comparison | ||
| Attribute | New Device | Predicate Device |
| Xpert Xpress MVP (New Design) | Xpert Xpress MVP (K212213) | |
| Reagents inCartridge | Cartridge Version 2(Minor modifications to the reagents in theself-contained, single-use disposablecartridges) | Cartridge Version 1 |
| Assay DefinitionFile (ADF) | ADF Version 2(Minor command modifications toaccommodate reagent changes) | ADF Version 1 |
Table 5-1: Similarities between New Device and Predicate Device
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Image /page/9/Picture/0 description: The image contains the Cepheid company logo. The logo consists of a blue graphic element resembling stylized wings or feathers, followed by the company name "Cepheid" in a clean, sans-serif font. Below the company name is the text "Xpert® Xpress MVP", with the "®" symbol indicating a registered trademark.
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Image /page/10/Picture/1 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.
Table 5-2 shows the differences between the new device and the predicate.
Table 5-2: Differences between New Device and Predicate Device
The new design of the Xpert Xpress MVP test has the same intended use and the same technological characteristics as the original design (K212213, the predicate device). The differences between the new design of the Xpert Xpress MVP test and the original design include minor cartridge and ADF modifications, which do not raise different questions of safety and effectiveness. The risk analysis and equivalency study demonstrate that performance of the new design of Xpert Xpress MVP is acceptable for its intended use and is substantially equivalent to the original design of Xpert Xpress MVP (K212213) described above.
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Image /page/11/Picture/1 description: The image contains the Cepheid company logo. The logo consists of a blue graphic element resembling stylized wings or a swoosh above the company name "Cepheid." Below the company name, the text "Xpert® Xpress MVP" is displayed, indicating a specific product or service offered by Cepheid.
5.4 Non-Clinical Study Analytical Sensitivity
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for Analytical Sensitivity of the Xpert Xpress MVP test.
Analytical Sensitivity Equivalency Study
To determine if the analytical sensitivity of the new design was equivalent to that of the original design, an equivalency study was conducted comparing the limit of detection (LoD) and the near cut-off concentration of the original design (K212213) and the new design of the Xpert Xpress MVP 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 concentration for the BV targets 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.
For BV organisms, testing at LoD and near cut-off concentrations was performed in simulated vaginal swab matrix (SVM) only. For Candida group, Candida glab-krus and TV targets, testing was conducted with samples diluted in both SVM and pooled negative natural clinical vaginal swab matrix (VS) independently.
The analytical sensitivity of the two designs were deemed equivalent when both the original design (K212213) and the new design reported 19/20 or 20/20 POSITIVE/DETECTED results when tested at LoD/Near Cut-off concentration for each testing condition/target organism, and statistical analysis comparing the difference of mean Ct values of the original design (K212213) and the new design using a two-sample t-test with a marginal difference of 1.0 Ct value and the assumption of equal variances demonstrated that the results were not statistically different (p-value of > 0.05).
Results from the equivalency study at LoD concentrations are shown in Table 5-3. The number of positive results obtained out of the total number of replicates tested for each target at the LoD concentrations, the difference in the mean Cts between the two designs, and the ttest statistical analysis of the mean Ct values are presented.
| Table 5-3: Mean Ct Values and Differences Between the Two Designs of Xpert Xpress | ||
|---|---|---|
| MVP Test at LoD Concentrations |
| Organism | ConcentrationTested (1× LoD) | Matrix | Design | Replicates reportedpositive results/Total Replicates | Difference inMean Cts ofTwo Designs | t-testp -value |
|---|---|---|---|---|---|---|
| Atopobiumvaginae | 32 CFU/mL | SVM | Original design (K212213) | 20/20 | 0.1 | >0.999 |
| New design | 20/20 | |||||
| Megasphaera-1 | 338 copies/mL | SVM | Original design (K212213) | 19/20 | 0.1 | 0.999 |
| New design | 19/20 | |||||
| BVAB2 | 50 copies/mL | SVM | Original design (K212213) | 19/20 | 0.6 | 0.916 |
| New design | 19/20 |
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Image /page/12/Picture/0 description: The image shows the Cepheid logo. The logo consists of a blue graphic element resembling stylized wings or a swoosh above the word "Cepheid." Below "Cepheid" is the text "Xpert® Xpress MVP".
| Organism | ConcentrationTested (1× LoD) | Matrix | Design | Replicates reportedpositive results/Total Replicates | Difference inMean Cts ofTwo Designs | t-testp-value |
|---|---|---|---|---|---|---|
| Candidaalbicans | 30 CFU/mL | SVM | Original design (K212213) | 19/20 | 0.5 | 0.911 |
| New design | 20/20 | |||||
| VS | Original design (K212213) | 19/20 | 0.4 | 0.965 | ||
| New design | 20/20 | |||||
| Candidadubliniensis | 1,316 CFU/mL | SVM | Original design (K212213) | 20/20 | 0.9 | 0.620 |
| New design | 20/20 | |||||
| VS | Original design (K212213) | 20/20 | 0.2 | >0.999 | ||
| New design | 20/20 | |||||
| Candidatropicalis | 750 CFU/mL | SVM | Original design (K212213) | 19/20 | 0.7 | 0.826 |
| New design | 20/20 | |||||
| VS | Original design (K212213) | 20/20 | 0.1 | >0.999 | ||
| New design | 20/20 | |||||
| Candidaparapsilosis | 1,339 CFU/mL | SVM | Original design (K212213) | 20/20 | 0.3 | >0.999 |
| New design | 20/20 | |||||
| VS | Original design (K212213) | 20/20 | 0.0 | >0.999 | ||
| New design | 20/20 | |||||
| Candidaglabrata | 20 CFU/mL | SVM | Original design (K212213) | 20/20 | 0.3 | 0.936 |
| New design | 20/20 | |||||
| VS | Original design (K212213) | 20/20 | 0.3 | 0.999 | ||
| New design | 20/20 | |||||
| Candida krusei | 656 CFU/mL | SVM | Original design (K212213) | 20/20 | 0.3 | >0.999 |
| New design | 20/20 | |||||
| VS | Original design (K212213) | 20/20 | 0.2 | >0.999 | ||
| New design | 20/20 | |||||
| Trichomonasvaginalis | 5 cells/mL | SVM | Original design (K212213) | 20/20 | 0.3 | 0.989 |
| New design | 19/20 | |||||
| VS | Original design (K212213) | 19/20 | 0.1 | 0.993 | ||
| New design | 20/20 |
Results from the equivalency study at near cut-off concentrations are shown in Table 5-4. The number of positive results obtained out of the total number of replicates tested for each BV organism at the near cut-off concentrations, the difference in the mean Cts between the two designs, and the t-test statistical analysis of the mean Ct values are presented.
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Image /page/13/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 registered trademark symbol is present after the word "Xpert".
Table 5-4: Mean Ct Values and Differences Between the Two Designs of Xpert Xpress MVP at Near Cut-off Concentrations of BV Organisms
| Organism | Concentrationtested (1× nearCut-offConcentration) | Matrix | Design | Replicatesreported BVpositive results/Total Replicates | Differencein MeanAtop gp Cts | t-testp-value | Differencein MeanMega1-BVAB2 Cts | t-testp-value |
|---|---|---|---|---|---|---|---|---|
| A. vaginae | $3.2×10^5$ CFU/mL | SVM | Original design(K212213) | 19/20 | 0.1 | >0.999 | N/A | N/A |
| A. vaginae ;Megasphaera -1 | 2,750 CFU/mL;390 copies/mL | SVM | Original design(K212213) | 20/20 | 0.1 | >0.999 | 0.4 | 0.993 |
| A. vaginae ;BVAB2 | 2,750 CFU/mL;50 copies/mL | SVM | Original design(K212213) | 20/20 | 0.1 | >0.999 | 0.4 | 0.999 |
| A. vaginae ;Megasphaera -1;BVAB2 | 2,750 CFU/mL;390 copies/mL;50 copies/mL | SVM | Original design(K212213) | 20/20 | 0.2 | >0.999 | 0.3 | 0.996 |
| A. vaginae | $3.2×10^5$ CFU/mL | SVM | New design | 20/20 | ||||
| A. vaginae ;Megasphaera -1 | 2,750 CFU/mL;390 copies/mL | SVM | New design | 19/20 | ||||
| A. vaginae ;BVAB2 | 2,750 CFU/mL;50 copies/mL | SVM | New design | 20/20 | ||||
| A. vaginae ;Megasphaera -1;BVAB2 | 2,750 CFU/mL;390 copies/mL;50 copies/mL | SVM | New design | 20/20 |
The Xpert Xpress MVP original design (K212213) and new design both verified the LoD and near cut-off concentrations with at least 19 of 20 replicates reported POSITIVE/DETECTED results in the head to-head testing. In addition, the differences in mean target Cts were within the marginal difference of 1.0 Ct value, and no statistically significant differences in the mean Ct values were observed for all test targets between the two designs, demonstrating that the analytical sensitivity of the two designs of Xpert Xpress MVP is equivalent.
Equivalencv Study using Clinical Specimens
A study using prospectively collected clinician-collected vaginal swab specimens was performed to demonstrate equivalence in performance of the Xpert Xpress MVP test between the original design (K212213) and the new design. The positive percent agreement (PPA) and negative percent agreement (NPA) of the new design of Xpert Xpress MVP for Bacterial Vaginosis (BV), Candida group, Candida glabrata/Candida krusei and Trichomonas vaginalis (TV) targets were determined relative to the original design (K212213) using clinical specimens to further support the equivalency claim for the two designs of the Xpert Xpress MVP test. Three sites in the United States participated in the prospective specimen collection, and one clinician-collected vaginal swab was collected from each symptomatic patient, defined as female patients ≥ 14 years of age who presented with signs and/or symptoms of vaginitis/vaginosis (including abnormal vaginal discharge; dysuria; vulvar/vaginal itching, burning, irritation, pain or vulvar edema; or vaginal odor). The specimens were transported to Cepheid (Sunnyvale, CA) and all testing was performed by a trained operator at Cepheid.
A total of 174 participants were enrolled and provided 174 clinician-collected vaginal swabs (VS) for this study. Two VS specimens were not tested, as there was not enough volume in the specimen tubes upon receipt of the specimens to support testing with both the original design (K212213) and the new design of the Xpert Xpress MVP test. After initial testing,
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Image /page/14/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. Below the company name is the text "Xpert® Xpress MVP", which likely refers to one of Cepheid's diagnostic products or platforms.
three runs provided non-determinate results (2 INVALID and 1 ERROR). One specimen could not be retested as there was insufficient specimen volume remained. One run still resulted in a non-determinate result (INVALID) upon retesting. After retesting, one run vielded a valid result and was included in the final data analysis. The first two specimens could not be included in the final data analysis, as there were no valid results from both the original design (K212213) and the new design of the test for comparison. Therefore, a total of 170 prospectively collected ("fresh") VS specimens was included in the final data analysis for all targets. In addition, there were 20 contrived C. glabrata and C. krusei specimens for the Candida glab-krus target, and 20 contrived T. vaginalis specimens for the TV target.
As an attempt to further investigate specimens with discordant results (i.e. difference in test results between Xpert Xpress MVP original design (K212213) and new design), specimens were retested with both the original design (K212213) and the new design if enough specimen volume remained. The retest results were for information only and were not included in the final data analysis.
The overall performance of the Xpert Xpress MVP new design relative to the original design (K212213) is presented in Table 5-5. The results of the repeat testing are provided as footnotes to the table.
| PPA(95% CI) | NPA(95% CI) | |
|---|---|---|
| BV | 98.3%56/57 a(90.6% - 100%) | 99.1%112/113 b(95.2% - 100%) |
| Candida group | 97.4%38/39 c(86.5% - 99.9%) | 98.5%129/131 d(94.6% - 99.8%) |
| Candida glab-krus Overall | 100%31/31(90.8% - 100%) | 100%159/159(98.1% - 100%) |
| Fresh | 100%11/11(76.2% - 100%) | 100%159/159(98.1% - 100%) |
| Contrived | 100%20/20(86.1% - 100%) | N/A |
| TV Overall | 100%32/32(91.1% - 100%) | 100%158/158(98.1% - 100%) |
| Fresh | 100%12/12(77.9% - 100%)) | 100%158/158(98.1% - 100%) |
Table 5-5: Overall Performance of Xpert Xpress MVP New Design relative to the Original Design (K212213)
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Image /page/15/Picture/0 description: The image shows the Cepheid company logo along with the product name Xpert Xpress MVP. The Cepheid logo features a stylized blue wing-like design above the company name, which is written in a clean, sans-serif font. Below the company name, the product name "Xpert Xpress MVP" is displayed, with the "R" in "Xpert" enclosed in a circle, indicating a registered trademark.
| Contrived | 100%20/20(86.1% - 100%) | N/A |
|---|---|---|
| ----------- | --------------------------------- | ----- |
N/A: Not Applicable
a There was one specimen that reported BV NEGATIVE test result with Xpert Xpress MVP new design but was BV POSITIVE with Xpert Xpress MVP original design (K212213). Upon retesting of this specimen, both the original design (K212213) and the new design reported BV POSITIVE test results.
b There was one specimen that reported BV POSITIVE test result with Xpert Xpress MVP new design but was BV NEGATIVE with Xpert Xpress MVP original design (K212213). Upon retesting of this specimen, the original design (K212213) reported BV POSITIVE test result and the new design reported BV NEGATIVE test result.
C There was one specimen that reported Candida group NOT DETECTED test result with Xpert Xpress MVP new design but was Candida group DETECTED with Xpert Xpress MVP original design (K212213). Upon retesting of this specimen, both the original design and the new design reported Candida group NOT DETECTED test results.
d There were two specimens that reported Candida group DETECTED test results with Xpert Xpress MVP new design but were Candida group NOT DETECTED with Xpert Xpress MVP original design (K212213). Upon retesting, both the original design (K212213) and the new design reported Candida group NOT DETECTED test results for these two specimens.
The investigation of both the false positive and false negative results showed that these specimens had Ct values close to the assay cut-off. This suggested that the discrepancies were most likely due to specimens which were near LoD or sub-LoD levels.
Of the 456 runs in this study (including external controls), four runs (4/456, 0.88%) provided non-determinate GeneXpert results (3 INVALID, 1 ERROR). Of these four non-determinates (ND), one run was from the 236 runs of the original design (K212213) and the overall nondeterminate rate was 0.42% (1/236); three runs were from the 220 runs of the new design and the overall non-determinate rate was 1.4% (3/220).
Analytical Reactivity (Inclusivity)
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for Analytical Reactivity (Inclusivity) of the Xpert Xpress MVP test. No additional testing was conducted.
Analytical Specificity (Exclusivity)
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for Analytical Specificity (Exclusivity) of the Xpert Xpress MVP test. No additional testing was conducted.
Microbial Interference
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for Microbial Interference of the Xpert Xpress MVP test. No additional testing was conducted.
Competitive Interference
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for Competitive Interference of the Xpert Xpress MVP test. No additional testing was conducted.
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Image /page/16/Picture/0 description: The image contains the Cepheid company logo, which features a stylized blue wave-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.
Interfering Substances
The potentially inhibitory effects of substances encountered in vaginal specimens on the performance of the original design of the Xpert Xpress MVP test were evaluated in the absence or presence of MVP targets. Among all potentially interfering substances tested. clinically significant inhibitory effects were previously observed in the positive samples containing mucin at a concentration of 5.5% when tested with the original design of the Xpert Xpress MVP test. A retest at 4% concentration of mucin showed no interfering effect when tested with the original design of the Xpert Xpress MVP test. Refer to the Xpert Xpress MVP 510(k) #K212213 (Section 18.8 Potentially Interfering Substances Study Summary) for details.
The test conditions that had previously produced clinically and/or statistically significant inhibitory effects on the performance of the Xpert Xpress MVP original design (K212213) were also evaluated with the new design of the Xpert Xpress MVP test. The substances and concentrations tested are listed in Table 5-6. Potential interferents were tested in simulated vaginal swab matrix in the presence and absence of Xpert Xpress MVP test targets at 3× LoD or at 3× near cut-off concentrations (for BV analytes). 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 new design 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 new design of the Xpert Xpress MVP test. A limitation is included in the instructions for use indicating that interference was observed in samples containing mucin (≥5.5% v/v).
| Substance/Class | Active Ingredient | Concentration Tested |
|---|---|---|
| Blood | Blood | 5.0% v/v |
| Mucus | Mucin | 5.5% v/v (InterferenceObserved) |
| 4.0% v/v (No interferenceObserved) | ||
| Buffy Coat | Leukocytes | $1.0×10^5$ cells/mL |
| Intravaginal Hormones | Estradiol; Progesterone | 7mg/mL Progesterone +0.07mg/mL Beta Estradiol |
| Seminal Fluid | Semen | 5.0% v/v |
| Over the Counter (OTC)Vaginal Products;Contraceptives; Vaginaltreatments | Nonoxynol-9 12.5% | 0.25% w/v |
| Clotrimazole 2% | 0.25% w/v | |
| Tioconazole 6.5% | 0.25% w/v | |
| Benzocaine 5%;Resorcinol 2% | 0.25% w/v | |
| 5% w/w Acyclovir | 0.25% w/v | |
| Glycerin; Carbomer | 0.25% w/v | |
| Glycerin; Sodium Hydroxide; Carbomer | 0.25% w/v | |
| Berberis Vulgaris 6X HPUS (Barberry), Borax 3XHPUS (Sodium Borate), Collinsonia Canadensis 3XHPUS (Stone Root), Hamamelis Virginiana 6X HPUS | 0.25% w/v | |
| (Witch Hazel), Bacillus coagulans (Lactospore®) | 0.25% w/v |
Table 5-6: Potential Interfering Substances Tested
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Image /page/17/Picture/0 description: The image contains the logo for Cepheid, a molecular diagnostics company. The logo features a stylized blue wing-like graphic above the company name, "Cepheid.", written in a clean, sans-serif font. Below the company name is the text "Xpert® Xpress MVP", which likely refers to one of Cepheid's diagnostic products or platforms.
| Substance/Class | Active Ingredient | Concentration Tested |
|---|---|---|
| Povidone-iodine 0.3% | 0.25% v/v | |
| Povidone-iodine 10% | 0.25% v/v | |
| Hemorrhoidal Cream | Glycerin 14%;Pramoxine HCl 1% | 0.25% w/v |
Carry-Over Contamination
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for Carry-Over Contamination of the Xpert Xpress MVP test. No additional testing was conducted.
Time to Result
The time to result is defined as the time from the initiation of cartridge processing on the GeneXpert 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 the Xpert Xpress MVP equivalency study with clinical specimens. The Xpert Xpress MVP test has a time to result of within 60 minutes, and the data from this study is representative for the GeneXpert Instrument Systems.
Reproducibility and Precision
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for reproducibility/precision of the Xpert Xpress MVP test. No additional testing was conducted.
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Image /page/18/Picture/1 description: The image shows the logo for Cepheid. The logo consists of a blue graphic element resembling stylized wings or feathers, followed by the word "Cepheid." in a sans-serif font. Below the logo is the text "Xpert® Xpress MVP", with the "®" symbol indicating a registered trademark.
5.5 Clinical Studies
Refer to the previously FDA-cleared 510(k) Premarket Notification, K212213 for clinical evaluation of the Xpert Xpress MVP test. Other than the Equivalency Study using Clinical Specimens presented in non-clinical study section, no additional clinical testing was conducted.
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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 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.
5.6 Conclusions
The results of the verification and validation studies summarized above demonstrated that the new design of the Xpert Xpress MVP test is substantially equivalent to the original design of the Xpert Xpress MVP (K212213, the predicate device).
§ 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.