The Cepheid® Xpert® MRSA/SA Blood Culture test, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of Staphylococcus aureus (SA) and methicillin-resistant Staphylococus aureus (MRSA) DNA directly from positive blood cultures. The assay utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA. The assay is performed directly on positive blood culture samples from BD BACTEC™ Plus Aerobic/F, BacT/ALERT® SA (Standard Aerobic) or VersaTREK REDOX 1® (aerobic) blood culture bottles that are determined by Gram Stain as Gram Positive Cocci in Clusters (GPCC) or as Gram Positive Cocci in singles (GPC). The Xpert MRSA/SA Blood Culture test is indicated for use in conjunction with other laboratory tests, such as culture, and clinical data available to the clinician as an aid in the detection of MRSA/SA from positive blood culturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing. The Cepheid Xpert MRSA/SA Blood Culture test is not intended to monitor treatment for MRSA/SA infections.

Device Description

The Cepheid Xpert® MRSA/SA Blood Culture test is a rapid, automated DNA test for the simultaneous qualitative detection of MRSA and SA DNA directly from blood culture bottle samples that are detected as positive for microbial growth and shown to contain Gram Positive Cocci by Gram stain. The primers and probes in the Xpert MRSA/SA Blood Culture test detect nucleic acid sequences of the staphylococcal protein A (spa), the gene for methicillin/oxacillin resistance (mecA), and staphylococcal cassette chromosome (SCCmec) inserted in the SA chromosomal attB site. The test includes a Sample Processing Control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability. The sample for testing with the Xpert MRSA/SA Blood Culture test consists of an aliguot taken from a positive blood culture bottle. Using one of the disposable fixed 50 µL volume transfer pipettes provided with the test kit, an aliquot of the positive blood culture is transferred into a single-use tube of Elution Reagent, also provided with the kit. The Elution Reagent is briefly vortexed and the entire content is transferred to the sample chamber of the disposable fluidic cartridge (the Xpert MRSA/SA Blood Culture cartridge), after which the cartridge is ready to place on the instrument. The assay is performed on the Cepheid GeneXpert Systems, which automate and integrate sample purification, nucleic acid amplification and detection of the target sequences in simple or complex samples using real-time PCR. The systems consist of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The GeneXpert Instrument 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. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated. The Xpert MRSA/SA Blood Culture test performed on the GeneXpert Instrument Systems provides results in approximately 60 minutes. The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and realtime 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 and detection.

AI/ML Overview

This document describes the Xpert MRSA/SA Blood Culture test, a qualitative in vitro diagnostic test for detecting Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures. The submission is a Special 510(k) to modify the assay definition file (ADF).

Here's an analysis of the provided text for acceptance criteria and study details:

1. A table of acceptance criteria and the reported device performance

The provided document is a 510(k) summary for a Special 510(k) submission, indicating a modification to an existing cleared device (predicate device). For such submissions, the primary "acceptance criterion" is demonstrating substantially equivalent performance to the predicate device, especially considering the specific change made. In this case, the change is to the assay definition file (ADF).

The document explicitly states: "The re-analyses showed the devices were substantially equivalent." This implies that the performance after the ADF update met the previous performance standards or comparable benchmarks. However, the document does not present a table of specific numerical acceptance criteria (e.g., sensitivity, specificity thresholds) or a direct comparison of the reported device performance against those criteria in a quantitative manner for the new device. Instead, it relies on the assertion of substantial equivalence based on re-analysis of existing data.

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

The document states: "The updated Assay Definition File with rules-based algorithms and release of new GeneXpert software to support this update have been validated by the re-analyses of the original clinical performance data and a subset of the original analytical performance data, including LoD, inclusivity, exclusivity, potential interfering substances, reproducibility, and precision."

Sample Size: The document does not specify the sample size used for the re-analysis of the clinical performance data or the subset of analytical performance data. It only refers to "original clinical performance data" and "a subset of the original analytical performance data."
Data Provenance: The document does not provide information on the country of origin of the data or whether the original data was retrospective or prospective. It only mentions "original clinical performance data," implying data collected during the initial clearance of the predicate device (K130894).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

The document does not provide information on the number or qualifications of experts used to establish the ground truth for the testing. Since this is an in vitro diagnostic test for bacterial detection, the ground truth would typically be established by standard microbiological culture and identification methods, which are considered objective laboratory results rather than expert interpretation in the same way a medical image would be.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

The document does not specify any adjudication method. This is not typically relevant for in vitro diagnostic tests where ground truth is established through objective laboratory methods (like culture) rather than subjective expert consensus on complex cases.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study is designed for evaluating situations where human readers (e.g., radiologists, pathologists) interpret cases, and the technology aims to assist or replace their interpretation.

This section is not applicable to the Xpert MRSA/SA Blood Culture test. This device is an automated in vitro diagnostic test that directly detects bacterial DNA from blood cultures. It does not involve human "readers" interpreting results in the same way an imaging AI might.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

Yes, the device performs as a standalone algorithm (test kit and instrument system) without human-in-the-loop performance for its primary function of detecting MRSA/SA DNA. The device "utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA." The changes described are to the "Assay Definition File" which contains "rules-based algorithms." This indicates a standalone performance where the algorithm generates the result. While a trained technician initiates the test and reviews the output, the diagnostic decision of positive/negative for MRSA/SA is made by the device's automated analysis.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for such a molecular diagnostic test for bacterial identification is typically established through standard microbiological culture and identification methods, including phenotypic and potentially genotypic characterization of the isolates. This is considered an objective laboratory ground truth, not based on expert consensus, pathology, or outcomes data in the usual sense. The "Indications for Use" mention that "Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing," which points to culture as the gold standard for definitive identification and further characterization.

8. The sample size for the training set

The document is for a modification (Special 510(k)) to an already cleared device ("predicate device," K130894). The modification is to the "assay definition file (ADF) with rules-based algorithms." It explicitly states that this update was validated by "re-analyses of the original clinical performance data" and "a subset of the original analytical performance data."

This implies that the current submission does not involve a new "training set" for developing a new algorithm from scratch. Instead, it seems the "rules-based algorithms" were modified, and their impact was assessed using existing (original) validation data. Therefore, information about a "training set" for the modified algorithm is not provided as it's likely not applicable in the context of this specific type of submission.

9. How the ground truth for the training set was established

As inferred above (point 8), a new "training set" for the modified algorithm is not explicitly mentioned. If the "rules-based algorithms" were developed using any data, that process is not described. However, given the nature of the device (molecular detection of bacteria), any "training" or optimization data would have relied on a ground truth established by standard microbiological culture and identification methods, similar to the validation data.

Summary

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April 25, 2019

Cepheid Sudhakar Marla Senior Director, Regulatory Affairs 904 Caribbean Drive Sunnyvale, California 94089

Re: K190771

Trade/Device Name: Xpert MRSA/SA Blood Culture, GeneXpert Dx System, GeneXpert Infinity-48s System, GeneXpert Infinity-80 System Regulation Number: 21 CFR 866.1640 Regulation Name: Antimicrobial Susceptibility Test Powder Regulatory Class: Class II Product Code: NOX, OOI Dated: March 25, 2019 Received: March 26, 2019

Dear Sudhakar Marla:

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 mav, 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/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

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/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Steven R. Gitterman -S for

Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known)

K190771

Device Name

Xpert MRSA/SA Blood Culture

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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510(k) Summary

As required by 21 CFR Section 807.92(c). The purpose of this submission is to submit documentation to support a change to the assay definition file (ADF) for use with the Xpert MRSA/SA Blood Culture test.

Submitted by:	Cepheid904 Caribbean DriveSunnyvale, CA 90489Phone number: (847) 228-3299Fax number: (847) 890-6589
Contact:	Sudhakar Marla, Ph.D.
Date of Preparation:	April 25, 2019
Proprietary/Trade name:	Xpert® MRSA/SA Blood Culture
Common name:	Xpert MRSA/SA Blood Culture
Type of Test:	Nucleic Acid Amplification Test, DNA, Methicillin-resistantStaphylococcus aureus (MRSA) and Staphylococcus aureus(SA), qualitative
Regulation number:	21 CFR 866.1640
Classification name:	Antimicrobial susceptibility test powder
Primary Product code:	NQX; Class II
Secondary Product code:	OOI; Class II
Classification AdvisoryPanel	Microbiology (83)
Prescription Use	Yes
Predicate Device Assay:	Cepheid Xpert MRSA/SA Blood Culture[510(k) #K130894]

DEVICE DESCRIPTION

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The test includes a Sample Processing Control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The sample for testing with the Xpert MRSA/SA Blood Culture test consists of an aliguot taken from a positive blood culture bottle. Using one of the disposable fixed 50 µL volume transfer pipettes provided with the test kit, an aliquot of the positive blood culture is transferred into a single-use tube of Elution Reagent, also provided with the kit. The Elution Reagent is briefly vortexed and the entire content is transferred to the sample chamber of the disposable fluidic cartridge (the Xpert MRSA/SA Blood Culture cartridge), after which the cartridge is ready to place on the instrument.

The assay is performed on the Cepheid GeneXpert Systems, which automate and integrate sample purification, nucleic acid amplification and detection of the target sequences in simple or complex samples using real-time PCR. The systems consist of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The GeneXpert Instrument 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. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated. The Xpert MRSA/SA Blood Culture test performed on the GeneXpert Instrument Systems provides results in approximately 60 minutes.

The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and realtime 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 and detection.

INTENDED USE

The Intended Use is identical to the predicate device with the exception of the device name changed from Xpert® MRSA/SA Blood Culture Assay to Xpert® MRSA/SA Blood Culture.

Device Intended Use

The Cepheid® Xpert® MRSA/SA Blood Culture test, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of

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Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures. The assay utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA. The assay is performed directly on positive blood culture samples using BD BACTECTM Plus Aerobic/F, BacT/ALERT® SA (Standard Aerobic) or VersaTREK REDOX 1® (aerobic) blood culture bottles that are determined as Gram Positive Cocci in Clusters (GPCC) or as Gram Positive Cocci in singles (GPC) by Gram stain. The Xpert MRSA/SA Blood Culture test is indicated for use in conjunction with other laboratory tests, such as culture, and clinical data available to the clinician as an aid in the detection of MRSA/SA from positive blood cultures. Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing. The Cepheid Xpert MRSA/SA Blood Culture test is not intended to monitor treatment for MRSA/SA infections.

TECHNOLOGICAL CHARACTERISTICS

The Xpert MRSA/SA Blood Culture test has the same intended use as the predicate device and the same technological characteristics as the predicate device.

DEVICE COMPARISON

The purpose of this Special 510(k) submission is to request a modification of the assay definition file (ADF) for use with the Xpert MRSA/SA Blood Culture test. The updated Assay Definition File with rules-based algorithms and release of new GeneXpert software to support this update have been validated by the re-analyses of the original clinical performance data and a subset of the original analytical performance data, including LoD, inclusivity, exclusivity, potential interfering substances, reproducibility, and precision. The re-analyses showed the devices were substantially equivalent.

Table 8-1 shows the similarities and differences between the Xpert MRSA/SA Blood Culture test and predicate assay. The differences between Xpert MRSA/SA Blood Culture test and the predicate device do not raise different questions of safety and effectiveness.

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of Xpert MRSA/SA Blood Culture with the Predicate Device
Similarities
Item	New DeviceXpert MRSA/SA Blood Culture	PredicateCurrent Xpert MRSA/SA BloodCulture510(k) #K130894
Intended Use	The Cepheid® Xpert® MRSA/SA BloodCulture test, performed on theGeneXpert® Instrument Systems, is aqualitative in vitro diagnostic testintended for the detection ofStaphylococcus aureus (SA) andmethicillin-resistant Staphylococcusaureus (MRSA) DNA directly frompositive blood cultures. The assayutilizes automated real-time polymerasechain reaction (PCR) for theamplification of MRSA/SA specificDNA targets and fluorogenic target-specific hybridization probes for thereal-time detection of the amplifiedDNA. The assay is performed directlyon positive blood culture samples usingBD BACTECTTM Plus Aerobic/F,BacT/ALERT® SA (Standard Aerobic)or VersaTREK REDOX 1® (aerobic)blood culture bottles that are determinedas Gram Positive Cocci in Clusters(GPCC) or as Gram Positive Cocci insingles (GPC) by Gram stain. The XpertMRSA/SA Blood Culture test isindicated for use in conjunction withother laboratory tests, such as culture,and clinical data available to theclinician as an aid in the detection ofMRSA/SA from positive blood cultures.Subculturing of positive blood culturesis necessary to recover organisms forsusceptibility testing or forepidemiological typing. The CepheidXpert MRSA/SA Blood Culture test isnot intended to monitor treatment forMRSA/SA infections.	Same
Similarities
	New Device	Predicate
Item	Xpert MRSA/SA Blood Culture	Current Xpert MRSA/SA BloodCulture510(k) #K130894
Specimen Type	Positive Blood Culture	Same
Technological Principles	Fully automated nucleic acidamplification (DNA); real-time PCR	Same
DNA Target Sequence	Sequence incorporating the insertion site(attB) of Staphylococcal CassetteChromosome mec (SCC mec ) fordetection of MRSA.	Same
Test Cartridge	Disposable single-use, multi-chamberedfluidic cartridge.	Same
Sample Preparation	Self-contained and automated aftermixed specimen is added to cartridge.All other reagents are contained in thecartridge.	Same
Probes	TaqMan® Probes	Same
Internal Controls	Sample processing control (SPC) andprobe check control (PCC).	Same
DNA Target Sequence	Sequence specific tomethicillin/oxacillin resistance ( mecAgene)	Same
DNA Target Sequence	Sequence specific to Staphylococcus aureus species ( spa gene)	Same
Ability to identifycorrectly "EmptyCassette Variants"	Yes, sequence specific toStaphylococcus aureus species ( mecAgene)	Same
Time to Results	Approximately 60 minutes to result.	Same

Table 8-1: Comparison of Similarities and Differences of Xpert MRSA/SA Blood Culture with the Predicate Device

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Differences
	New Device	Predicate
Item	Xpert MRSA/SA Blood Culture	Current Xpert MRSA/SA Blood Culture510(k) # K130894
Instrument System	Cepheid GeneXpert Dx Systems andGeneXpert Infinity-48s and Infinity-80Systems	Cepheid GeneXpert Dx Systems,GeneXpert Infinity-48 System, andGeneXpert Infinity-48s and Infinity-80Systems
Minimum softwarerequirements	GeneXpert Dx software version 5.3 andhigher, GeneXpert Infinity-48s andInfinity-80 Xpertise software version 6.8and higher	GeneXpert Dx software version 4.3 andhigher, GeneXpert Infinity-48 Xpertise4.3 and higher, GeneXpert Infinity-48sand Infinity-80 Xpertise softwareversion 6.0 and higher
Assay Definition File	Rules-based algorithms incorporatingdelta Ct values between targets within avalid Ct range and algorithms based onthe Ct value for the targets falling withina valid Ct range	Algorithms based on the Ct value forthe targets falling within a valid Ctrange

Conclusion

The Xpert MRSA/SA Blood Culture test is substantially equivalent to the predicate device.

Regulation Number and Section

§ 866.1640 Antimicrobial susceptibility test powder.

(a)
Identification. An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).