The Xpert® Xpress GBS test, performed on the GeneXpert® Instrument Systems, is an automated, real-time PCR test for the qualitative detection of Group B Streptococcus (GBS) DNA from vaginal/rectal swab specimens collected from pregnant patients for intrapartum testing at term (e.g., >37 weeks) who have unknown or unavailable antepartum GBS screening test results and no additional risk factors that would warrant empiric antibiotic prophylaxis. The Xpert Xpress GBS test performed during intrapartum is intended to aid in the detection of GBS colonization in patients presenting in labor who may be candidates for antibiotic prophylaxis.

The Xpert Xpress GBS test does not provide antimicrobial susceptibility test results. Culture is necessary to obtain isolates to perform susceptibility testing as recommended for penicillin-allergic patients.

This test is conducted using direct specimen without enrichment is recommended to enhance detection of GBS colonization). In contrast to a positive test result, which can indicate colonization, a presumptive negative result cannot exclude the possibility of GBS colonization. A false negative test result at intrapartum carries a potential harm to the infant if it is used in making decisions regarding empiric antibiotic prophylaxis. Providers must use caution and default to known patient risk factors and clinical guidance regarding a role for intrapartum prophylaxis.

Device Description

The Xpert® Xpress GBS test is an automated in vitro diagnostic test for the qualitative detection of Group B Streptococcus (GBS) DNA from vaginal/rectal swab specimens collected from pregnant patients at intrapartum.

The Xpert Xpress GBS test is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx. GeneXpert Infinity-48s and GeneXpert Infinity-80 systems), which consist of an instrument, computer and preloaded software for running tests and viewing the results. The GeneXpert Instrument Systems automate and integrate sample preparation, nucleic acid extraction and amplification, and real-time detection. Depending on the instrument, the GeneXpert Instrument Systems can have from 1 and up to 80 randomly accessible modules, each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR as well as detection. The systems require the use of single-use disposable cartridges that hold the PCR reagents and host sample purification, nucleic acid amplification, and detection of the target sequences. Because the cartridges are self- contained, cross-contamination between cartridges during the testing process is minimized.

The Xpert Xpress GBS test includes reagents for the simultaneous detection of target GBS DNA from vaginal/rectal swab specimens. The primers and probes in the Xpert Xpress GBS test are designed to amplify and detect unique sequence in two conserved chromosomal targets in S. agalactiae: a) a member of the glycosysl transferase gene family, and b) a LysR transcriptional regulator. A Sample Adequacy Control (SAC), Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert instrument. The SAC is a non-target sequence naturally present in the specimen. which is amplified along with the assay target. In the Xpert Xpress GBS test, the SAC detects the presence of the human hydroxymethylbilane synthase (HMBS) gene to ensure that the sample is properly collected and contains adequate human cells from the vaginal/rectal flora. 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 GBS test is designed for use with vaginal/rectal swab specimens collected from pregnant patients at intrapartum and placed into a collection device. The ancillary specimen collection kit validated for use with the Xpert Xpress GBS test is the Cepheid Collection Device (Catalog 900-0370). The sample collection device allows dual vaginal/rectal swab specimens from patients to be collected and transported to laboratory prior to analysis with the Xpert Xpress GBS test.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the Xpert® Xpress GBS device, based on the provided text:

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of specific numeric thresholds for sensitivity, specificity, PPV, and NPV. However, it presents the clinical performance results as compared to enriched bacterial culture + MALDI-TOF MS. The implied acceptance is that the device's performance is deemed "acceptable for its intended use" and "substantially equivalent to the predicate device."

Here are the reported performance metrics from the clinical study:

Metric	Reported Device Performance (%) (95% CI)
Sensitivity	93.5% (85.7 – 97.2)
Specificity	95.5% (93.9 – 96.7)
PPV	66.1% (56.8 – 74.3)
NPV	99.4% (98.5 – 99.7)

2. Sample Size and Data Provenance for the Test Set

Sample Size for Test Set: A total of 899 intrapartum vaginal/rectal specimens were included in the performance analysis. Initially, 912 specimens were enrolled, but 13 were excluded due to non-determinate Xpert Xpress results upon retest or no culture results.
Data Provenance: The study was conducted at twelve (12) clinical sites from geographically diverse regions within the United States. This indicates the data is prospective and multi-site (US).

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number or qualifications of experts used to establish the ground truth. The ground truth was established by "enriched bacterial culture with species identification via MALDI-TOF MS." This method is considered a laboratory-based gold standard for GBS detection. The interpretation of these results would typically be done by trained laboratory personnel.

4. Adjudication Method

The document mentions that discordant results between the Xpert Xpress GBS test and the comparator method (enriched culture + MALDI-TOF MS) were investigated using an FDA-cleared nucleic acid amplification test (NAAT). However, the exact adjudication method (e.g., 2+1, 3+1, etc.) for resolving these discrepancies to establish a final ground truth is not explicitly described. The text states that the results of the FDA-cleared NAAT are "footnoted in Table 5-8, for informational purposes only," suggesting that the primary "ground truth" remained the enriched culture, and the NAAT was used for further investigation of discrepancies rather than as a tie-breaker in a formal adjudication process.

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was mentioned. This device is an automated, standalone diagnostic test and does not involve human readers for interpretation in the same way an imaging AI algorithm would.

6. Standalone Performance Study

Yes, a standalone performance study (i.e., algorithm only without human-in-the-loop performance) was performed. The clinical performance characteristics were evaluated by directly comparing the Xpert® Xpress GBS test results to an enriched bacterial culture with species identification via MALDI-TOF MS.

7. Type of Ground Truth Used

The primary ground truth used for the clinical performance study was enriched bacterial culture with species identification via MALDI-TOF MS.

8. Sample Size for the Training Set

The document does not provide information on the sample size used for the training set. The study detailed in the document focuses on the clinical performance evaluation of the finished device.

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

Since no information on the training set is provided, the method for establishing its ground truth is also not detailed in this document. Typically, for PCR-based tests like this, development and training would involve a combination of characterized GBS strains and cultured clinical samples verified by traditional microbiology methods.

Summary

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September 27, 2023

Cepheid Shilpa Kuttetira Senior Regulatory Affairs Specialist 904 Caribbean Drive Sunnyvale, California 94089

Re: K222638

Trade/Device Name: Xpert® Xpress GBS, GeneXpert® Dx System, GeneXpert® Infinity Systems Regulation Number: 21 CFR 866.3740 Regulation Name: Streptococcus Spp. Serological Reagents Regulatory Class: Class I Product Code: NJR, OOI Dated: August 31, 2022 Received: September 1, 2022

Dear Shilpa Kuttetira:

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 requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part

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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 (QS) 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 medical devices and radiation-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.

Ribhi Shawar -S

Ribhi Shawar, Ph.D. (ABMM) Chief General Bacteriology and Antimicrobial Susceptibility Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics 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) K222638

Device Name Xpert® Xpress GBS

Indications for Use (Describe)

Type of Use ( Select one or both, as applicable )
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✘ Prescription Use (Part 21 CFR 801 Subpart D)	□ Over-The-Counter Use (21 CFR 801 Subpart C)
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Traditional 510(k) Submission

510(k) Summary for Xpert Xpress GBS

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5.510(K) SUMMARY
5.1. DEVICE DESCRIPTION
5.2. DEVICE INTENDED USE/INDICATIONS FOR USE
5.3. SUBSTANTIAL EQUIVALENCE
5.4. PERFORMANCE STUDIES
5.4.1. ANALYTICAL PERFORMANCE
5.4.2. CLINICAL PERFORMANCE
5.5. CONCLUSION

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5. 510(k) Summary

As required by 21 CFR Section 807.92(c).

Submitted by:	Cepheid904 Caribbean DriveSunnyvale, CA 90489Phone Number: (408) 966-8860
Contact:	Shilpa Kuttetira
Date of Preparation:	September 18, 2023
Trade name:	Xpert® Xpress GBS
Common name:	Xpert Xpress GBS
Type of Test:	Qualitative real-time polymerase chain reaction (PCR) anddetection test
Regulation number,	21 CFR 866.3740, Streptococcus spp. serological reagents,
Classification name,	NJR; A nucleic acid amplification assay system (includingprobes, other reagents, and instrumentation) is an aid in theidentification of Group B streptococci from pre-partum andintra-partum women to establish colonization status.
Product code,	21 CFR 862.2570, Instrumentation for clinical multiplex testsystems, OOI; The system is a clinical multiplex instrumentintended to measure and sort multiple signals generated mymultiple probes, intercalating dyes, or other ligands in an assayfrom a clinical sample. Signals may be generated byfluorescence or other phenomena and may be measured usingfilters on a photodiode or other detector. It may integrate sampleand/or reagent handling, amplification, dedicated instrumentcontrol, data acquisition software, raw data storage mechanismsand other essential hardware components along with the signalreader unit. The system is used with specific assays to comprisean assay test system.
ClassificationAdvisory Panel	Microbiology (83)
Prescription Use	Yes
Predicate Device	Xpert® GBS (K060540)

CONFIDENTIAL 510(k) Summary Page 3 of 15

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5.1. Device Description

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5.2. Device Intended Use/Indications for Use

5.3. Substantial Equivalence

Table 5-1 shows the similarities and differences between Xpert Xpress GBS and the predicate device, Xpert GBS [K060540].

Attribute	Investigational Device	Predicate Device – K060540
	CepheidXpert® Xpress GBS	CepheidXpert® GBS
Regulation	Same	21 CFR 866.3740Streptococcus spp. Serological reagents
Product Code	Same	NJRNucleic Acid Amplification Assay System,Group B Streptococcus , Direct SpecimenTest
Device Class	Same	I (non-exempt)
Technology/Detection	Same	Real-Time PCR
	Investigational Device	Predicate Device – K060540
Attribute	CepheidXpert® Xpress GBS	CepheidXpert® GBS
Intended Use/Indications forUse	The Xpert® Xpress GBS test, performed onthe GeneXpert® Instrument Systems, is anautomated, real-time PCR test for thequalitative detection of Group BStreptococcus (GBS) DNA fromvaginal/rectal swab specimens collectedfrom pregnant patients for intrapartumtesting at term (e.g., >37 weeks) who haveunknown or unavailable antepartum GBSscreening test results and no additional riskfactors that would warrant empiricantibiotic prophylaxis. The Xpert XpressGBS test performed during intrapartum isintended to aid in the detection of GBScolonization in patients presenting in laborwho may be candidates for antibioticprophylaxis.The Xpert Xpress GBS test does notprovide antimicrobial susceptibility testresults. Culture is necessary to obtainisolates to perform susceptibility testing asrecommended for penicillin-allergicpatients.This test is conducted using directspecimen without enrichment (enrichmentis recommended to enhance detection ofGBS colonization). In contrast to a positivetest result, which can indicate colonization,a presumptive negative result cannotexclude the possibility of GBScolonization. A false negative test result atintrapartum carries a potential harm to theinfant if it is used in making decisionsregarding empiric antibiotic prophylaxis.Providers must use caution and default toknown patient risk factors and clinicalguidance regarding a role for intrapartumprophylaxis.	The Cepheid Xpert GBS performed on theGeneXpert Dx System is a qualitative invitro diagnostic test designed to detectGroup B Streptococcus (GBS) DNA fromvaginal/rectal swab specimens, using fullyautomated real-time polymerase chainreaction (PCR) with fluorogenic detectionof the amplified DNA.Xpert GBS Assay testing is indicated forrapid identification of antepartum andintrapartum GBS colonization.The use of the Xpert GBS forintrapartum screening should notpreclude the use of other strategies(e.g., antepartum testing). IntrapartumXpert GBS results are useful toidentify candidates for intrapartumantibiotic prophylaxis whenadministration of intravenousantibiotics is not delayed pendingresults. The Xpert GBS Assay does notprovide susceptibility results. Cultureisolates are needed for performingsusceptibility testing as recommendedfor penicillin-allergic women.
Assay Targets	Dual target assay design against twoconserved sequences in S. agalactiae :a member of the glycosysl transferasegene family and a LysR transcriptional regulator	3' region adjacent to cfb gene CAMP-factor hemolysin gene of S. agalactiae
Specimen Type	Same	Direct from vaginal/rectal swab specimens
CollectionDevice	Same	Cepheid Collection Device withLiquid Stuart Medium
Attribute	Investigational DeviceCepheidXpert® Xpress GBS	Predicate Device – K060540CepheidXpert® GBS
Single UseCartridge	Same	Yes
AutomatedNucleic AcidExtraction,Detection andResultsInterpretation	Same	Yes
Assay Results	Same	Qualitative
InternalControls	Sample Processing Control (SPC)Sample Adequacy Control (SAC)Probe Check Control (PCC)	Sample Processing Control (SPC)Internal Control (IC)Probe Check Control (PCC)
InstrumentSystems	Cepheid GeneXpert® Instrument Systems(Dx and Infinity)	Cepheid GeneXpert® Dx Systems
Early AssayTermination(EAT) Feature	YesEAT feature returns a high titer sample in~ 30 minutes	No
Time to Result	< 50 minutes	< 60 minutes

Table 5-1: Comparison of Similarities and Differences Between Xpert Xpress GBS and the Predicate Device

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Traditional 510(k) Submission

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The Xpert Xpress GBS test has the same general intended use and the same technological characteristics as the predicate device. The performance of the Xpert Xpress GBS test was evaluated in a multi-site clinical study. The differences between the Xpert Xpress GBS test and the predicate device do not raise different questions of safety and effectiveness.

The results from the clinical evaluation demonstrate that performance of the Xpert Xpress GBS test is acceptable for its intended use.

5.4. Performance Studies

5.4.1. Analytical Performance

Analytical Sensitivity (LoD) and Analytical Reactivity (Inclusivity)

The analytical limit of detection (LoD) and analytical reactivity (inclusivity) of the Xpert Xpress GBS test were determined for 12 different strains representing 12 known serotypes of GBS, 2 of which were characterized as non-hemolytic (Table 5-2). Serial dilutions of each serotype were prepared in a simulated sample matrix. Serotypes Ia. III and V were tested with 24 replicates per dilution level for each of two reagent lots across three days. Serotypes Ib, Ic, II, IV and VI-X were tested in replicates of 24 for each dilution level using one reagent lot across three days. The estimated LoD values, were verified by testing 20 replicates of each serotype diluted in simulated sample matrix to the upper limit of the 95% confidence interval determined in the probit analysis with one reagent lot across three days. Serotype Ia. III and V were also verified in clinical matrix. The result for serotypes V and VI was 85% (17/20) detected and the claimed LoD was based on the upper limit of 95% confidence interval. The verified LoD values for the GBS serotypes tested are provided in Table 5-2.

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Serotype	LoD(CFU/mL)	LoD(CFU/Swab)
Ia	663	50
Ib	40	3
Ica	301	23
IIa	173	13
III	540	41
IV	429	32
V	618b	46
VI	544b	41
VII	620	47
VIII	682	51
IX	465	35
X	677	51

Table 5-2. Xpert Xpress GBS Limit of Detection

Non-hemolytic strain a.

Claimed LoD corresponds to the upper limit of 95% CI b.

Matrix Equivalency Studies were performed to support the use of simulated sample matrix for the analytical studies.

Analytical Inclusivity of Cfb Mutants

A study was performed to evaluate the analytical reactivity (inclusivity) of Xpert Xpress GBS for strains containing different deletions ranging from 181 bp to 49 kb in or adjacent to the region of the chromosome that encodes the CAMP factor hemolysis gene cfb. Ten (10) unique, well characterized GBS clinical specimens representing different of mutations were diluted in simulated sample matrix to a concentration of 855 CFU/mL (~ 1x the highest observed LoD) and tested in the Xpert Xpress GBS test. The study was conducted over 3 days testing either 6 or 7 replicates on each day for a total of 20 replicates. All strains with cfb mutations were detected with a positivity rate of 100%.

Analytical Specificity (Cross-Reactivity/Exclusivity) and Microbial Interference

The analytical specificity and microbial interference of the Xpert Xpress GBS test was evaluated by testing a panel of 129 non-GBS organisms that can potentially cross-react and interfere with the detection of GBS both in the presence (microbial interference) and absence (cross-reactivity/exclusivity) of GBS. Challenge organisms tested included bacterial, viral, parasite and yeast strains commonly found in vaginal/rectal flora or phylogenetically related to GBS and are shown in Table 5-3.

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Bacteria and yeast were tested at concentrations of ≥ 1x106 CFU/mL, except for Staphylococcus aureus which was tested at 2x105 CFU/mL. Viruses and parasites were tested at concentrations of > 1x105 units/mL (tachyzoites, IU or copies/mL). Genomic DNA was tested at > 1x10° copies/mL. The panel of 129 organisms were tested either individually or in pools of 2 - 6 microorganisms in simulated sample matrix, both in presence of GBS at 3x LoD and in absence of GBS. Each pool was tested in replicates of 6. No cross-reactivity or microbial interference of GBS detection was observed with any of the clinically relevant pathogens tested in the study.

Organism
Arcanobacterium (Trueperella)pyogenes	Haemophilus influenzae	Serratia marcescens
Atopobium (Fannyhessea) vaginae	Hafnia alvei	Shigella flexneri
Abiotrophia defectiva	Hepatitis B virus	Shigella sonnei
Acinetobacter baumannii	Hepatitis C virus	Staphylococcus aureus a
Acinetobacter lwoffii	Human immunodeficiency virus	Staphylococcus epidermidis
Actinobacillus pleuropneumoniae	Human Papillomavirus 18 b	Staphylococcus haemolyticus
Aeromonas hydrophila	Klebsiella (Enterobacter)aerogenes	Staphylococcus intermedius
Alcaligenes faecalis	Klebsiella oxytoca	Staphylococcus lugdunensis
Anaerococcus lactolyticus	Klebsiella pneumoniae	Staphylococcus saprophyticus
Anaerococcus prevotii b	Lactobacillus acidophilus	Staphylococcus simulans
Anaerococcus tetradius	Lactobacillus casei	Stenotrophomonas maltophilia
Bacillus cereus	Lactobacillus delbrueckii lactis	Streptococcus acidominimus
Bacillus coagulans	Lactobacillus gasseri	Streptococcus anginosus
Bacteroides fragilis	Lactobacillus plantarum	Streptococcus bovis
Bifidobacteriumadolescentis Reuter	Lactobacillus reuteri	Streptococcus canis
Bifidobacterium brevis	Listeria monocytogenes	Streptococcus constellatus
BK virus	Micrococcus luteus	Streptococcus criceti
Blastocystis hominis b	Mobiluncus curtisii subsp. Curtisii b	Streptococcus cristatus
Bordetella pertussis	Moraxella atlantae	Streptococcus downei
Burkholderia cepacia	Moraxella catarrhalis	Streptococcus dysgalactiaesubsp. dysgalactiae
Campylobacter jejuni	Morganella morganii	Streptococcus dysgalactiaesubsp. equisimilis
Candida albicans	Mycoplasma genitalium b	Streptococcus equi subsp. equi

Table 5-3: Analytical Specificity of Xpert Xpress GBS

CONFIDENTIAL

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Traditional 510(k) Submission

Organism
Candida glabrata	Neisseria gonorrhoeae	Streptococcus gordonii
Candida tropicalis	Norovirus	Streptococcus intermedius
Chlamydia trachomatis	Pantoea agglomerans	Streptococcus mitis
Citrobacterfreundii	Pasteurellaaerogenes	Serratia liquefaciens
Clostridiumdifficile	Peptoniphilus asaccharolyticus	Streptococcus mutans
Cytomegalovirus	Peptostreptococcus anaerobius	Streptococcus oralis
Corynebacterium accolens	Porphyromonas asaccharolytica	Streptococcus parasanguinis
Corynebacterium sp. (genitalium)	Prevotella bivia	Streptococcus pneumoniae
Corynebacterium urealyticum	Prevotella melaninogenica	Streptococcus pseudoporcinus
Cryptococcus neoformans	Prevotella oralis	Streptococcus pyogenesb
Enterobacter cloacae	Propionibacterium acnes	Streptococcus ratti
Enterococcus durans	Proteus mirabilis	Streptococcus salivarius
Enterococcus faecalis	Proteus vulgaris	Streptococcus sanguinis
Enterococcus faecium	Providencia stuartiib	Streptococcus sobrinus
Enterococcus gallinarum	Providencia sp.	Streptococcus suis
Epstein-Barr virus	Pseudomonas aeruginosa	Streptococcus uberis
Escherichia coli	Pseudomonas fluorescens	Streptococcus vestibularis
Finegoldia magna	Rhodococcus equi	Toxoplasma gondii
Fusobacterium nucleatum	Rubella virus	Trichomonas vaginalis
Gardnerella vaginalis	Salmonella enterica subsp. entericaser. Dublin (group D)	Vibrio cholerae
Giardia lambliab	Salmonella enterica subp.typhimurium	Yersinia enterocolitica subsp.palearctica

Tested < 1x106 (2x105 CFU/mL) a.

Evaluated with DNA b.

Potentially Interfering Substances

Substances that may be present in vaginal/rectal specimens with the potential to interfere with the Xpert Xpress GBS test were evaluated. Potentially interfering endogenous and exogenous substances include human amniotic fluid, meconium, urine, fecal material, human blood, lubricating gel, vaginal anti-itch medications, vaginal antifungal medications, antidiarrheal medications, laxatives, stool softeners, topical hemorrhoid ointments, body oil, body powder, deodorant sprays, enema solutions, and spermicidal foam. These substances are listed in Table 5-4.

Potentially interfering substances were tested according to a liquid, solid or tablet workflow. Liquid substances were added directly to the swab. Solid substances were added to the swab

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by dipping three fourths (3/4) of the swab head into the substance. Tablets were first dissolved in simulated sample matrix and the liquid added directly to the swab.

Negative samples consisting of simulated matrix only were tested in replicates of 6 in the presence of each substance to determine the effect on the performance of the sample processing control (SPC) and Sample Adequacy Control (SAC). Positive samples were prepared using GBS serotype Ia in simulated matrix at 3x LoD and were tested in replicates of 6 per substance. The negative and positive controls were prepared in the absence of potentially interfering substances and consisted of simulated sample matrix only and GBS spiked at 3x LoD into simulated sample matrix, respectively.

For substances that resulted in an INVALID test result, the concentration of the substance was reduced by dilution in simulated sample matrix and re-tested. Five exogenous substances (Aquasonic® gel, Floraplus, Pepto Bismol®, Body oil and Xyloproct) showed interference at the concentration initially tested and were subsequently tested at a lower concentration to determine the highest concentration at which no interference was observed. A list of the endogenous and exogenous substances along with their forms and the highest concentrations at which all GBS positive and negative samples were correctly identified by the Xpert Xpress GBS test (i.e., no observed interference) is shown in Table 5-4.

Substance	Substance Form	Highest Concentration on Swab Resulting in No Interference
Human Amniotic Fluid	Liquid	60% (v/v)
Human Urine	Liquid	60% (v/v)
Human Whole Blood - EDTA	Liquid	80% (v/v)
Human Whole Blood - Na Citrate	Liquid	80% (v/v)
Leukocytes, Buffy coat, 2x107 WBCs/mL	Liquid	80% (v/v)
Meconium	Solid	100% a
Mucus - mucin from porcine stomach	Solid	30% (w/v)
Human Feces - Pool of 10 donors	Solid	100% a
Anti-Diarrheal Medication - Pepto Bismol	Liquid b	40% (v/v)
Anti-Diarrheal Medication - Dimor Comp [Dimeticone]	Tablet	0.03% loperamid +1.7% dimetikon (w/v)
Lubricant - RFSU Klick Ultra Glide	Solid	100% a
Lubricant - Sense Me Aqua Glide	Solid	100% a
Lubricant - KY-Jelly	Solid	100% a
Body Oil - ACO Repairing Skin Oil	Liquid c	100% a
Dialon Baby - Dialon Baby Powder	Solid	100% a
Deodorant Powder - Vagisil® Deodorant Powder	Solid	100% a
Deodorant Spray - LN Intimate Deo	Liquid	60% (v/v)
Deodorant Suppositories - Norforms Feminine DeodorantSuppositories	Tablet	46.4% (w/v)

Table 5-4: Potentially Interfering Substances

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Traditional 510(k) Submission

Substance	Substance Form	Highest Concentration on Swab Resulting in No Interference
Enema solution – Microlax mikrolavemang	Solid	100% a
Oral Laxative – Mylan	Solid	25% (w/v)
Oral Laxative – Phillips Milk of Magnesia	Liquid	60% (v/v)
Oral Laxative – Pursennid Ex-Lax	Tablet	0.64% (w/v)
Spermicidal Foam – Caya preventivgel	Solid	100% a
Stool Softener – Laktulos Meda	Liquid	60% (v/v)
Stool Softener – Movicol	Tablet	9% (w/v)
Topical Hemorrhoid Ointment – Xyloproct Rectal Ointment	Solid d	8% (v/v)
Topical Hemorrhoid Ointment – Scheriproct rektalsalva /Prednisolone Ointment	Solid	100% a
Ultrasound Transmission Gel – Aquasonic Gel	Solid d	20% (v/v)
Vaginal Antifungal Gel – Multi-Gyn Actigel	Solid	100% a
Vaginal Antifungal Gel – Multi-Gyn Floraplus	Solid d	75% (w/v)
Vaginal Anti-itch Cream – Ellen Probiotisk Utvärtes Intim Creme	Solid	100% a
Vaginal Antifungal Cream – Canesten	Solid	100% a
Vaginal Antifungal Cream – Daktar	Solid	100% a

100% represents undiluted solid substances used directly by dipping the upper 3/4 of the swab head into the substance. a. The amount tested was regarded as well above the typical concentrations found in clinical specimens.

b. Pepto Bismol diluted to 40% in simulated background matrix and no interference observed.

Skin oil was tolerated when tested as a solid by dipping 2/3 of the swab head into the substance. C.

Substances were diluted into a simulated background matrix prior to testing: Xyloproct Rectal Ointment was tested at d. 8%, Aquasonic Gel was tested at 20% and MultiGyn Floraplus was tested at 75%. No interference was detected after dilution.

Carryover Contamination

A study was conducted to assess whether the single-use, self-contained Xpert Xpress GBS cartridge prevents specimen and amplicon carryover by testing a negative sample immediately after testing a very high positive sample in the same GeneXpert module. The negative sample used in this study consisted of simulated vaginal/rectal matrix and the positive sample consisted of high GBS serotype Ia positive sample spiked at 1.00E+07 CFU/mL (7.50E+05 CFU/swab) into simulated vaginal/rectal matrix. The negative sample was tested in a GeneXpert module at the start of the study. Following the initial testing of the negative sample, the high GBS positive sample was processed in the same GeneXpert module immediately followed by another negative sample. This was repeated 10 times in the same modules, resulting in 10 positives and 11 negatives for the module. The study was repeated using a second GeneXpert module for a total of 20 positive and 22 negative samples. All 20 positive samples were correctly reported as GBS POSITIVE. All 22 negative samples were correctly reported as GBS PRESUMPTIVE NEGATIVE.

Reproducibility and Precision

The reproducibility and precision of the Xpert Xpress GBS test was evaluated in a multicenter, blinded study using two panels totaling ten members that consisted of simulated vaginal/rectal matrix as negative sample as well as low positive (~1 – 1.5xLoD) and

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Image /page/15/Picture/0 description: The image shows the Cepheid logo. The logo features a stylized blue wing-like design above the company name. The company name "Cepheid" is written in a modern, sans-serif font, with a small circle to the right of the name.

moderate positive (~3x LoD) samples prepared by spiking GBS strain into simulated vaginal/rectal matrix at the respective target levels. Three strains of GBS representing hemolytic phenotypes (serotypes Ia. III, IV) and one strain (Serotype Ic) representing a nonhemolytic phenotype were used in the study. Testing was performed at three sites (one internal, two external) using the GeneXpert Instrument Systems. Each panel member was tested in triplicate each day (one run/day) by two operators on six different days at three different sites (10 members x 2 operators x 3 replicates/day x 6 days x 3 sites). Three lots of the Xpert Xpress GBS cartridges were used, with each lot tested on two days.

The percent agreement of the qualitative results for GBS detection for each panel member analyzed by each of the six operators and by each site is shown in Table 5-5. In addition, the overall percent agreement for each sample (total agreement) and the 95% two-sided Wilson Score confidence interval are presented in the last column.

PanelMember	Sample	Level	Site 1			Site 2			Site 3			Total Agreement(95% CI)
1	Negative	Negative	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	94.1%(16/17)	100.0%(18/18)	97.1%(34/35)	99.1% (106/107)(94.9% - 100.0%)
2	GBS serotype IaLow Pos	~1xLoD	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0% (108/108)(96.6% - 100.00%)
3	GBS serotype IIILow Pos	~1xLoD	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	83.3%(15/18)	100.0%(17/17)	91.4%(32/35)	97.2% (104/107)(92.1% - 99.0%)
4	GBS serotype IVLow Pos	~1xLoD	94.4%(17/18)	88.9%(16/18)	91.7%(33/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	88.9%(16/18)	94.4%(34/36)	95.4% (103/108)(89.6% - 98.0%)
5	GBS serotype IaMod Pos	~3xLoD	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0% (108/108)(96.6% - 100.0%)
6	GBS serotype IIIMod Pos	~3xLoD	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100% (108/108)(96.6% - 100.0%)
7	GBS serotype IVMod Pos	~3xLoD	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100% (108/108)(96.6% - 100.0%)
8	Negative 2	Negative	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0% (108/108)(96.6% - 100.0%)
9	GBS Serotype IcLow Pos	~1.5xLoD	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0% (108/108)(96.6% - 100.0%)
10	GBS Serotype IcMod Pos	~3xLoD	94.4%(17/18)	100.0%(18/18)	97.2%(35/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	100.0%(18/18)	100.0%(18/18)	100.0%(36/36)	99.1% (107/108)(94.9% - 100.0%)

Table 5-5. Summary of Reproducibility Results - % Agreement

Evaluation of repeatability and the within-laboratory precision of the underlying Ct values obtained in the Xpert Xpress GBS test was analyzed. The mean, standard deviation (SD), and coefficient of variation (CV) between-sites, between-days, between-days, between-operators and within-assay for each panel member are shown in Table 5-6.

Table 5-6. ANOVA Summary of Reproducibility Data by the Coefficient of Variance

			Site		Op		Lot		Day		Within Assay		Total
Panel Member	Na	Mean	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Negativeb	107c	32.4	0.1	0.2	0.0	0	0.5	1.5	0.2	0.7	0.8	2.4	1.0	2.9
Low Pos GBS serotype Ia~1xLoD	108	34.7	0.0	0	0.0	0	0.3	0.9	0.2	0.5	1.2	3.3	1.2	3.5
Low Pos GBS serotype III~1xLoD	104d	34.8	0.0	0	0.0	0	0.4	1.1	0.0	0	1.3	3.8	1.4	3.9
Low Pos GBS serotype IV~1xLoD	103e	35.2	0.2	0.4	0.0	0	0.5	1.4	0.0	0	1.0	2.7	1.1	3.1

CONFIDENTIAL

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Traditional 510(k) Submission

Mod Pos GBS serotype Ia~3xLoD	108	33	0.3	1	0.0	0	0.0	0	0.0	0	1.0	3.1	1.1	3.3
Mod Pos GBS serotype III~3xLoD	108	33.1	0.0	0	0.0	0	0.3	1	0.3	1	0.8	2.5	1.0	2.9
Mod Pos GBS serotype IV~3xLoD	108	33.7	0.0	0	0.3	1	0.3	0.9	0.1	0.3	0.8	2.3	0.9	2.7
Negative 2b	108	32.5	0.2	0.5	0.0	0	0.5	1.4	0.2	0.7	0.6	2	0.8	2.6
Low Pos GBS serotype Ic~1.5xLoD	108	34.7	0.1	0.3	0.0	0	0.2	0.6	0.5	1.3	1.1	3.2	1.2	3.5
Mod Pos GBS serotype Ic~3xLoD	107f	33.8	0.0	0	0.2	0.5	0.1	0.3	0.4	1.2	0.7	2	0.8	2.4

Three samples with GBS Ct value = 0 and one non-determinate sample were excluded from ANOVA analysis

e Five samples with GBS Ct value = 0 were excluded from ANOVA analysis

1 One sample with a GBS Ct value = 0 was excluded from ANOVA analysis

5.4.2. Clinical Performance

Clinical performance characteristics of the Xpert Xpress GBS test were evaluated in a multisite, observational, method comparison study using vaginal/rectal swab specimens collected from pregnant patients. The study was conducted at twelve (12) clinical sites from geographically diverse regions within the United States between July 2020 and November 2021.

The clinical performance of the Xpert Xpress GBS test was compared to enriched bacterial culture with species identification via MALDI-TOF MS. Eligible participants provided two sets of dual vaginal/rectal swabs. The first set of swabs was divided - one swab was used for Xpert Xpress GBS testing; the other was used for culture, if the Xpert Xpress GBS test gave a valid result. If the Xpert Xpress GBS test resulted in a non-determinate result, the second set of marked swabs was divided - one swab was used for repeat Xpert Xpress GBS testing; the other was used for culture testing.

Discordant results between the Xpert Xpress GBS test and the comparator method were investigated using an FDA-cleared nucleic acid amplification test (NAAT); the results of which are footnoted in Table 5-8, for informational purposes only.

Performance of the Xpert Xpress GBS Test vs. Enriched Culture + MALDI-TOF MS

Nine hundred and twelve (912) vaginal/rectal swab specimens were enrolled from eligible participants. Age distribution of vaginal/rectal specimens collected at Intrapartum are represented in Table 5-7.

Age Group	Intrapartum Vaginal/Rectal (ABX-)N (%)
14-17	2 (0.2%)
18-24	285 (31.3%)
25-34	507 (55.6%)
≥35	118 (12.9%)
Total	912 (100.0%)

Table 5-7: Age Distribution of Specimens Included

CONFIDENTIAL

510(k) Summary

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Of the 912, 13 were excluded from the analysis of performance due to non-determinate Xpert Xpress results upon retest or no culture results. A total of 899 intrapartum vaginal/ rectal specimens were included in the performance analyses. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the Xpert Xpress GBS test as compared to enriched culture with species identification via MALDI-TOF MS are presented in Table 5-8. The Xpert Xpress GBS demonstrated a sensitivity of 93.5% and specificity of 95.5% in vaginal/rectal swab specimens collected at intrapartum, and a PPV of 66.1% and NPV of 99.4%. respectively.

Table 5-8. Xpert Xpress GBS Performance Results vs. Enriched Culture + MALDI-TOF MS - Intrapartum Specimens

Results	CulturePositive	CultureNegative	Total	Sensitivity(95%CI)	Specificity(95%CI)	PPV(95%CI)	NPV(95%CI)
Xpert Xpress GBSPositive	72	37a	109
Xpert Xpress GBSPresumptiveNegative	5b	785	790	93.5%(85.7 – 97.2)	95.5%(93.9 – 96.7)	66.1%(56.8 – 74.3)	99.4%(98.5 – 99.7)
Total	77	822	899

a. Discrepant test results based on an FDA-cleared NAAT: 13/37 GBS negative; 9/37 no valid result

b. Discrepant test results based on an FDA-cleared NAAT: 4/5 GBS positive; 1/5 GBS negative

Non-Determinate Rate

Of the 912 Xpert Xpress GBS tests performed in the clinical study, 55 resulted in nondeterminate results (ERROR, INVALID or NO RESULT) on the first attempt. Upon retest, 12 specimens remained non-determinate. The initial non-determinate rate was 6.0% (55/912). Upon retest, the final non-determinate rate was 1.3% (12/912).

5.5. Conclusion

The results of the non-clinical and clinical performance studies summarized above demonstrated that the Xpert Xpress GBS test is substantially equivalent to the predicate device.

Regulation Number and Section

§ 866.3740

Streptococcus spp. serological reagents.(a)
Identification. Streptococcus spp. serological reagents are devices that consist of antigens and antisera (excluding streptococcal exoenzyme reagents made from enzymes secreted by streptococci) used in serological tests to identifyStreptococcus spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genusStreptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

1. Acceptance Criteria and Reported Device Performance

2. Sample Size and Data Provenance for the Test Set

3. Number of Experts and Qualifications for Ground Truth

4. Adjudication Method

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

6. Standalone Performance Study

7. Type of Ground Truth Used

8. Sample Size for the Training Set

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

Re: K222638

Dear Shilpa Kuttetira:

Ribhi Shawar -S

Indications for Use

Indications for Use (Describe)

510(k) Summary for Xpert Xpress GBS

TABLE OF CONTENTS

5. 510(k) Summary

5.1. Device Description

5.2. Device Intended Use/Indications for Use

5.3. Substantial Equivalence

Traditional 510(k) Submission

5.4. Performance Studies

5.4.1. Analytical Performance

Analytical Sensitivity (LoD) and Analytical Reactivity (Inclusivity)

Analytical Inclusivity of Cfb Mutants

Analytical Specificity (Cross-Reactivity/Exclusivity) and Microbial Interference

Table 5-3: Analytical Specificity of Xpert Xpress GBS

Traditional 510(k) Submission

Potentially Interfering Substances

Carryover Contamination

Reproducibility and Precision

Traditional 510(k) Submission

5.4.2. Clinical Performance

Performance of the Xpert Xpress GBS Test vs. Enriched Culture + MALDI-TOF MS

Table 5-7: Age Distribution of Specimens Included

Table 5-8. Xpert Xpress GBS Performance Results vs. Enriched Culture + MALDI-TOF MS - Intrapartum Specimens

Non-Determinate Rate

5.5. Conclusion

§ 866.3740