(87 days)
Not Found
No
The description focuses on real-time PCR technology and automated sample processing, with no mention of AI or ML algorithms for data analysis or interpretation.
No
The device is an in vitro diagnostic test used to detect Mycobacterium tuberculosis complex DNA and rifampin-resistance associated mutations. It aids in the diagnosis of pulmonary tuberculosis and in decisions regarding airborne infection isolation, but it does not treat or cure a disease, nor does it affect the structure or function of the body.
Yes
The "Intended Use / Indications for Use" section explicitly states that the Xpert MTB/RIF Assay "is intended as an aid in the diagnosis of pulmonary tuberculosis" and is an "in vitro diagnostic test."
No
The device description explicitly states that the system consists of an instrument, personal computer, and preloaded software, and requires the use of single-use disposable cartridges. This indicates the device is a hardware and software system, not software-only.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "The Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, is a qualitative, nested realtime polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA..."
The "Device Description" section also refers to it as an "in vitro diagnostic test".
N/A
Intended Use / Indications for Use
The Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, is a qualitative, nested real-time polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sputum sediment prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex is detected, the Xpert MTB/RIF Assay also detects the rifampin-resistance associated mutations of the rpoB gene.
The Xpert MTB/RIF Assay is intended for use with specimens for whom there is clinical suspicion of tuberculosis (TB) and who have received no antituberculosis therapy, or less than three days of therapy. This test is intended as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings.
An Xpert MTB/RIF Assay result of "MTB NOT DETECTED" from either one or two sputum specimens is highly predictive of the absence of M. tuberculosis complex bacilli on serial fluorescent acid-fast sputum smears from patients with suspected active pulmonary tuberculosis and can be used as an aid in the decision of whether continued airborne infection isolation (AII) is warranted in patients with suspected pulmonary tuberculosis. The determination of whether testing of either one or two sputum specimens for decisions regarding removal from AII should be based on specific clinical circumstances and institutional guidelines. Clinical decisions regarding the need for continued AII should always occur in conjunction with other clinical and laboratory evaluations and Xpert MTB/RIF Assay results should not be the sole basis for infection control practices.
The Xpert MTB/RIF Assay must always be used in conjunction with mycobacterial culture to address the risk of false negative results and to recover organisms when MTB-complex is present for further characterization and drug susceptibility testing. However, decisions regarding the removal of patients from AII need not wait for culture results. Sputum specimens for TB culture, AFB smear microscopy, and Xpert MTB/RIF Assay testing should follow CDC recommendations with regard to collection methods and time frame between specimen collection.
The Xpert MTB/RIF Assay does not provide confirmation of rifampin susceptibility since mechanisms of rifampin resistance other than those detected by this device may exist that may be associated with a lack of clinical response to treatment.
Specimens that have both MTB-complex DNA and rifampin-resistance associated mutations of the rpoB gene detected by the Xpert MTB/RIF Assay must have results confirmed by a reference laboratory. If the presence of rifampin-resistance associated mutations of the rpoB gene is confirmed, specimens should also be tested for the presence of genetic mutations associated with resistance to other drugs.
The Xpert MTB/RIF Assay should only be performed in laboratories that follow safety practices in accordance with the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories publication and applicable state or local regulations.
Product codes (comma separated list FDA assigned to the subject device)
PEU
Device Description
The Xpert MTB/RIF Assay is a qualitative, automated, in vitro diagnostic test for qualitative detection of Mycobacterium tuberculosis (MTB) complex DNA in raw sputum samples or in concentrated sputum sediments prepared from induced or expectorated sputa that are either acid-fast bacilli (AFB) smear positive or negative. The assay is performed on the Cepheid GeneXpert Instrument Systems. The Xpert MTB/RIF Assay on the GeneXpert Instrument System automates and integrates sample preparation, nucleic acid amplification, and detection of the target sequences in simple or complex samples using real-time PCR. The system consists of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The system requires 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 MTB/RIF Assay includes reagents for the detection of MTB and Rifampin (RIF) resistance from raw sputum samples and in prepared sputum sediments. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge. The SPC is present to control for adequate processing of the target bacteria and to monitor for the presence of inhibitors in the PCR reaction. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dve stability.
The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems, the GeneXpert Infinity-48 System, the GeneXpert Infinity-48s, and the GeneXpert Infinity-80 System, have 1 to 80 randomly accessible modules, depending upon the instrument, that are 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 and detection.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
The Xpert MTB/RIF Assay should only be performed in laboratories that follow safety practices in accordance with the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories publication and applicable state or local regulations.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
A prospective multi-center study (Study 2) was conducted at multiple sites in the United States, as well as South Africa and Brazil. Performance of the MTB/RIF Assay was assessed as an alternative to fluorescent stained AFB-smear microscopy as an aid in determining the need for continued airborne infection isolation in patients with suspected active pulmonary tuberculosis. The clinical data demonstrated that a single negative Xpert MTB/RIF result predicted the absence of AFB smear-positive pulmonary tuberculosis with an overall negative predictive value (NPV) of 99.7% (99.6% in the U.S. and 100% in non-U.S.). Two serial negative Xpert MTB/RIF Assay results predicted the absence of AFB smear-positive pulmonary tuberculosis with an overall NPV of 100%.
Overall performance of one Xpert MTB/RIF Assay result compared to the results of MTB culture, stratified by AFB smear result (Table 5.5). Overall sensitivity of one Xpert MTB/RIF Assay in AFB smear-positive and AFB smear-negative subjects (based on two AFB smears) was 98.5% (95% CI: 94.6%,99.6%) and 54.8% (95% CI: 44.1%, 65.0%) respectively, and overall specificity was 98.7% (95% CI: 97.5%, 99.3%). One Xpert MTB/RIF Assay result of MTB Not Detected was associated with a probability of MTB culture-positive/AFB smear-positive results of 0.4% for U.S. subjects and 0.0% for non-U.S. subjects.
One Xpert MTB/RIF Assay was associated with a sensitivity of 81.4% (95% CI: 75.7%, 86.0%) for identifying MTB culture-positive subjects compared to a sensitivity of 60.9% (95% CI: 54.3%, 67.2%) for two AFB smears.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Sensitivity: 98.5% (129/131), 95% CI: 94.6%,99.6% (for Smear Positive)
Specificity: 94.4% (17/18), 95% CI: 74.2%, 99.0% (for Smear Positive)
Sensitivity: 54.8% (46/84), 95% CI: 44.1%, 65.0% (for Smear Negative)
Specificity: 98.8% (718/727), 95% CI: 97.7%, 99.4% (for Smear Negative)
Overall Probability of MTB Culture Positive among subjects with an Xpert MTB/RIF Negative Result: 5.2% (40/775), 95% CI: 3.8%, 7.0%
Probability of MTB Culture Positive among subjects with an Xpert MTB/RIF Negative Result (U.S. subjects): 2.4% (13/539), 95% CI: 1.4%, 4.1%
Probability of MTB Culture Positive among subjects with an Xpert MTB/RIF Negative Result (non-U.S. subjects): 11.4% (27/236), 95% CI: 8.0%, 16.1%
Overall Probability of MTB Culture Positive and AFB smear positive among subjects with an Xpert MTB/RIF Negative Result: 0.3% (2/775), 95% CI:
§ 866.3373 Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex (MTB-complex) and the genetic mutations associated with MTB-complex antibiotic resistance in respiratory specimens.
(a)
Identification. Nucleic acid-based in vitro diagnostic devices for the detection ofMycobacterium tuberculosis complex (MTB-complex) and the genetic mutations associated with MTB-complex antibiotic resistance in respiratory specimens are qualitative nucleic acid-based devices that detect the presence of MTB-complex-associated nucleic acid sequences in respiratory samples. These devices are intended to aid in the diagnosis of pulmonary tuberculosis and the selection of an initial treatment regimen when used in conjunction with clinical findings and other laboratory results. These devices do not provide confirmation of antibiotic susceptibility since other mechanisms of resistance may exist that may be associated with a lack of clinical response to treatment other than those detected by the device.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The FDA document entitled “Class II Special Controls Guideline: Nucleic Acid-Based In Vitro Diagnostic Devices for the Detection of
Mycobacterium tuberculosis Complex and Genetic Mutations Associated with Antibiotic Resistance in Respiratory Specimens,” which addresses the mitigation of risks specific to the detection of MTB-complex. For availability of the document, see § 866.1(e).(2) The following items, which address the mitigation of risks specific to the detection of the genetic mutations associated with antibiotic resistance of MTB-complex:
(i) The device must include an external positive assay control as appropriate. Acceptable positive assay controls include MTB-complex isolates containing one or more antibiotic-resistance associated target sequences detected by the device.
(ii) The device must include internal controls as appropriate. An acceptable internal control may include human nucleic acid co-extracted with MTB-complex containing nucleic acid sequences associated with antibiotic resistance and primers amplifying human housekeeping genes (e.g., RNaseP, β-actin).
(iii) The device's intended use must include a description of the scope of antibiotic resistance targeted by the assay, i.e., the specific drugs and/or drug classes.
(iv) The specific performance characteristics section of the device's labeling must include information regarding the specificity of the assay oligonucleotides for detecting mutations associated with antibiotic resistance of MTB-complex, and any information indicating the potential for non-specific binding (e.g., BLAST search).
(v) In demonstrating device performance you must perform:
(A) Pre-analytical studies that evaluate:
(
1 )Frozen samples. If there is use of any frozen samples in the device performance studies, or if there is a device claim for the use of frozen samples for testing, the effect of freezing samples prior to testing and the effect of multiple freeze/thaw cycles on both antibiotic susceptible and antibiotic resistant strains of MTB-complex.(
2 )Nucleic acid extraction methods. Extraction methods must parallel those used in devices for the detection of MTB-complex nucleic acid and confirm that the detection of the genetic mutations associated with antibiotic resistance is not affected.(B) Analytical studies that analyze:
(
1 )Limit of Detection. Limit of Detection must be determined in the most challenging matrix (e.g., sputum) claimed for use with the device. The Limit of Detection must be determined using both antibiotic susceptible and antibiotic resistant strains of MTB-complex. The antibiotic resistant strains must be those with well characterized genetic mutations associated with antibiotic resistance.(
2 )Analytical Reactivity (Inclusivity). Testing must be conducted to evaluate the ability of the device to detect genetic mutations associated with antibiotic resistance in a diversity of MTB-complex strains. Isolates used in testing must be well characterized. Isolate strain characterization must be determined using standardized reference methods recognized by a reputable scientific body and appropriate to the strain lineage.(
3 )Within-Laboratory (Repeatability) Precision Testing. Within-laboratory precision studies, if appropriate, must include at least one antibiotic resistant and one antibiotic susceptible strain of MTB-complex.(
4) Between Laboratory Reproducibility Testing. The protocol for the reproducibility study may vary slightly depending on the assay format; however, the panel must include at least one antibiotic resistant and one antibiotic susceptible strain of MTB-complex.(C) Clinical Studies. Clinical performance of the device must be established by conducting prospective clinical studies that include subjects with culture confirmed active tuberculosis. Studies must attempt to enroll subjects at risk for antibiotic-resistant MTB-complex; however, it may be necessary to include supplemental antibiotic resistant retrospective and contrived samples. Clinical studies must compare device results to both phenotypic drug susceptibility testing and genotypic reference methods. The genotypic reference method must be a polymerase chain reaction based method that uses primers different from those in the experimental device and confirmed by bidirectional sequencing.
0
Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized image of a human figure, represented by three overlapping profiles facing to the right. The profiles are rendered in a dark color, contrasting with the white background of the seal.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
CEPHEID PAMELA JOHNSON EXECUTIVE DIRECTOR, CLINICAL AFFAIRS 904 CARIBBEAN DRIVE SUNNYVALE CA 94089-1189
February 19. 2015
Re: K143302
Trade/Device Name: Xpert® MTB/RIF Regulation Number: 21 CFR 866.3373 Regulation Name: Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex and the genetic mutations associated with Mycobacterium tuberculosis complex antibiotic resistance in respiratory specimens
Regulatory Class: Class II Product Code: PEU Dated: November 13, 2014 Received: November 19, 2014
Dear Ms. Johnson:
This letter corrects our substantially equivalent letter of February 12, 2015.
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. 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.
1
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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If vou desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21CFR 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 the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours, Uwe Sonerf -S for
Sally A. Hojvat, M. Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known)
Device Name
Xpert® MTB/RIF
Indications for Use (Describe)
The Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, is a qualitative, nested realtime polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sputum sediment prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex) is detected, the Xpert MTB/RIF Assay also detects the rifampin-resistance associated mutations of the rpoB gene.
The Xpert MTB/RIF Assay is intended for use with specimens for whom there is clinical suspicion of tuberculosis (TB) and who have received no antituberculosis therapy, or less than three days of therapy. This test is intended as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings.
An Xpert MTB/RIF Assay result of "MTB NOT DETECTED" from either one or two sputum specimens is highly predictive of the absence of M. tuberculosis complex bacilli on serial fluorescent acid-fast sputum smears from patients with suspected active pulmonary tuberculosis and can be used as an aid in the decision of whether continued airborne infection isolation (AII) is warranted in patients with suspected pulmonary tuberculosis. The determination of whether testing of either one or two sputum specimens for decisions regarding removal from AII should be based on specific clinical circumstances and institutional guidelines. Clinical decisions regarding the need for continued AII should always occur in conjunction with other clinical and laboratory evaluations and Xpert MTB/RIF Assay results should not be the sole basis for infection control practices.
The Xpert MTB/RIF Assay must always be used in conjunction with mycobacterial culture to address the risk of false negative results and to recover organisms when MTB-complex is present for further characterization and drug susceptibility testing. However, decisions regarding the removal of patients from AII need not wait for culture results. Sputum specimens for TB culture, AFB smear microscopy, and Xpert MTB/RIF Assay testing should follow CDC recommendations with regard to collection methods and time frame between specimen collection.
The Xpert MTB/RIF Assay does not provide confirmation of rifampin susceptibility since mechanisms of rifampin resistance other than those detected by this device may exist that may be associated with a lack of clinical response to treatment.
Specimens that have both MTB-complex DNA and rifampin-resistance associated mutations of the rpoB gene detected by the Xpert MTB/RIF Assay must have results confirmed by a reference laboratory. If the presence of rifampin-resistance associated mutations of the rpoB gene is confirmed, specimens should also be tested for the presence of genetic mutations associated with resistance to other drugs.
The Xpert MTB/RIF Assay should only be performed in laboratories that follow safety practices in accordance with the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories publication and applicable state or local regulations.
3
Type of Use (Select one or both, as applicable)
X Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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4
5.0 510(k) Summary
As required by 21 CFR Section 807.92(c).
| Submitted by: | Cepheid®
904 Caribbean Drive
Sunnyvale, CA 90489
Phone number: (408) 400-8460
Fax number: (847) 510-0539
E-mail: kerry.flom@cepheid.com |
|---------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Kerry J. Flom, Ph.D. |
| Date of Preparation: | November 13, 2014 |
| Device: | |
| Trade name: | Xpert® MTB/RIF |
| Common name: | Xpert MTB/RIF Assay |
| Type of Test: | Qualitative, nested real-time polymerase chain reaction (PCR) |
| Regulation number/ | 866.3373/ |
| Classification name/
Product code: | System, nucleic acid-based, mycobacterium tuberculosis
complex, resistance marker, direct specimen/
PEU |
| Classification
Advisory Panel | Microbiology (83) |
| Predicate Devices
Name(s): | Xpert MTB/RIF |
Device Description:
The Xpert MTB/RIF Assay is a qualitative, automated, in vitro diagnostic test for qualitative detection of Mycobacterium tuberculosis (MTB) complex DNA in raw sputum samples or in concentrated sputum sediments prepared from induced or expectorated sputa that are either acid-fast bacilli (AFB) smear positive or negative. The assay is performed on the Cepheid GeneXpert Instrument Systems. The Xpert MTB/RIF Assay on the GeneXpert Instrument System automates and integrates sample preparation, nucleic acid amplification, and detection of the target sequences in simple or complex samples using real-time PCR. The system consists of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The system requires 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 MTB/RIF Assay includes reagents for the detection of MTB and Rifampin (RIF) resistance from raw sputum samples and in prepared sputum sediments. A Sample
5
Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge. The SPC is present to control for adequate processing of the target bacteria and to monitor for the presence of inhibitors in the PCR reaction. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dve stability.
The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems, the GeneXpert Infinity-48 System, the GeneXpert Infinity-48s, and the GeneXpert Infinity-80 System, have 1 to 80 randomly accessible modules, depending upon the instrument, that are 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 and detection.
Device Intended Use:
The Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, is a qualitative, nested real-time polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sputum sediment prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex (MTB-complex) is detected, the Xpert MTB/RIF Assay also detects the rifampin-resistance associated mutations of the rpoB gene.
The Xpert MTB/RIF Assay is intended for use with specimens from patients for whom there is clinical suspicion of tuberculosis (TB) and who have received no antituberculosis therapy, or less than three days of therapy. This test is intended as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings.
An Xpert MTB/RIF Assay result of "MTB NOT DETECTED" from either one or two sputum specimens is highly predictive of the absence of M. tuberculosis complex bacilli on serial fluorescent acid-fast sputum smears from patients with suspected active pulmonary tuberculosis and can be used as an aid in the decision of whether continued airborne infection isolation (AII) is warranted in patients with suspected pulmonary tuberculosis. The determination of whether testing of either one or two sputum specimens is appropriate for decisions regarding removal from AII should be based on specific clinical circumstances and institutional guidelines. Clinical decisions regarding the need for continued AII should always occur in conjunction with other clinical and laboratory evaluations and Xpert MTB/RIF Assay results should not be the sole basis for infection control practices.
The Xpert MTB/RIF Assay must always be used in conjunction with mycobacterial culture to address the risk of false negative results and to recover organisms when MTB-complex is present for further characterization and drug susceptibility testing. However, decisions regarding the removal of patients from AII need not wait for culture
6
results. Sputum specimens for TB culture, AFB smear microscopy, and Xpert MTB/RIF Assay testing should follow CDC recommendations with regard to collection methods and time frame between specimen collection.
The Xpert MTB/RIF Assay does not provide confirmation of rifampin susceptibility since mechanisms of rifampin resistance other than those detected by this device may exist that may be associated with a lack of clinical response to treatment.
Specimens that have both MTB-complex DNA and rifampin-resistance associated mutations of the rpoB gene detected by the Xpert MTB/RIF Assay must have results confirmed by a reference laboratory. If the presence of rifampin-resistance associated mutations of the rpoB gene is confirmed, specimens should also be tested for the presence of genetic mutations associated with resistance to other drugs.
The Xpert MTB/RIF Assay should only be performed in laboratories that follow safety practices in accordance with the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories publication and applicable state or local regulations.
Substantial Equivalence:
Predicate device name(s): Cepheid Xpert® MTB/RIF Assay
Predicate 510(k) number(s): K131706
Comparison with predicate:
The Xpert MTB/RIF Assay is substantially equivalent to the current Xpert MTB/RIF Assay [510(k) #K131706].
Similarities and differences between the Cepheid Xpert MTB/RIF Assay and the predicate device are shown in Table 5.1.
A prospective multi-center study (Study 2) was conducted at multiple sites in the United States, as well as South Africa and Brazil. Performance of the MTB/RIF Assay was assessed as an alternative to fluorescent stained AFB-smear microscopy as an aid in determining the need for continued airborne infection isolation in patients with suspected active pulmonary tuberculosis. The clinical data demonstrated that a single negative Xpert MTB/RIF result predicted the absence of AFB smear-positive pulmonary tuberculosis with an overall negative predictive value (NPV) of 99.7% (99.6% in the U.S. and 100% in non-U.S.). Two serial negative Xpert MTB/RIF Assay results predicted the absence of AFB smear-positive pulmonary tuberculosis with an overall NPV of 100%.
7
| Device | Predicate | |
|---|---|---|
| Item | Cepheid Xpert MTB/RIF | Current Cepheid Xpert MTB/RIF |
| 510(k) Number | To be assigned | #K131706 |
| Regulation | Same | 866.3373 |
| Product Code | Same | PEU |
| Device Class | Same | II |
| Technology/ | ||
| Detection | Same | Multiplex real time RT/PCR |
| Indication for Use | Same | Patients for whom there is clinical |
| suspicion of tuberculosis (TB) and whohave received no antituberculosis | ||
| therapy, or less than 3 days of therapy | ||
| Assay Targets | Same | MTB-complex DNA and Rif resistance |
| associated mutations | ||
| Specimen Types | Same | Raw sputum samples or concentrated |
| sputum sediments | ||
| Technological | ||
| Principles | Same | Real-time PCR |
| Nucleic Acid | ||
| Extraction | Same | Yes |
| Extraction | ||
| Methods | Same | Sample preparation integrated in |
| GeneXpert Cartridge and GeneXpert | ||
| Instrumentation System | ||
| Assay Results | Same | Qualitative |
| Instrument System | Same | Cepheid GeneXpert Instrument Systems |
| Assay Controls | Same | Sample Processing Control (SPC) and |
| Probe Check Control (PCC). | ||
| Failures result in single sample repeat. | ||
| Rapid test results | Same | Total 120 minutes for sample preparation |
| and real-time PCR | ||
| Laboratory Users | Same | CLIA Moderate or High Complexity |
| Differences | ||
| Device | Predicate | |
| Item | Cepheid Xpert MTB/RIF | Current Cepheid Xpert MTB/RIF |
| Intended | ||
| Use | The Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, is a qualitative, nested real-time polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sputum sediment prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex (MTB-complex) is detected, the Xpert MTB/RIF Assay also detects the rifampin-resistance associated mutations of the rpoB gene. | |
| The Xpert MTB/RIF Assay is intended for use with specimens from patients for whom there is clinical suspicion of tuberculosis (TB) and who have received no antituberculosis therapy, or less than three days of therapy. This test is intended as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings. | The Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, is a qualitative, nested real-time polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sediments prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex (MTB-complex) is detected, the Xpert MTB/RIF Assay also detects the rifampin-resistance associated mutations of the rpoB gene. | |
| The Xpert MTB/RIF Assay is intended for use with specimens from patients for whom there is clinical suspicion of tuberculosis (TB) and who have received no antituberculosis therapy, or less than 3 days of therapy. This test is intended as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings. | ||
| The Xpert MTB/RIF Assay does not provide confirmation of rifampin susceptibility since mechanisms of | ||
| An Xpert MTB/RIF Assay result of "MTB NOT DETECTED" from either one or two sputum specimens is highly predictive of the absence of M. tuberculosis complex bacilli on serial fluorescent acid-fast sputum smears from patients with suspected active pulmonary tuberculosis and can be used as an aid in the decision of whether continued airborne infection isolation (AII) is warranted in patients with suspected pulmonary tuberculosis. The determination of whether testing of either one or two sputum specimens is appropriate for decisions regarding | rifampin resistance other than those detected by this device may exist that may be associated with a lack of clinical response to treatment. | |
| Specimens that have both MTB-complex DNA and rifampin-resistance associated mutations of the rpoB gene detected by the Xpert MTB/RIF Assay must have results confirmed by a reference laboratory. If the presence of rifampin-resistance associated mutations of the rpoB gene is confirmed, specimens should also be tested for the presence of genetic mutations associated with resistance to other drugs. | ||
| Differences | ||
| Device | Predicate | |
| Item | Cepheid Xpert MTB/RIF | Current Cepheid Xpert MTB/RIF |
| removal from AII should be based on | ||
| specific clinical circumstances and | ||
| institutional guidelines. Clinical | ||
| decisions regarding the need for | ||
| continued AII should always occur in | ||
| conjunction with other clinical and | ||
| laboratory evaluations and Xpert | ||
| MTB/RIF Assay results should not be | ||
| the sole basis for infection control | ||
| practices. |
The Xpert MTB/RIF Assay must
always be used in conjunction with
mycobacterial culture to address the
risk of false negative results and to
recover organisms when MTB-
complex is present for further
characterization and drug
susceptibility testing. However,
decisions regarding the removal of
patients from AII need not wait for
culture results. Sputum specimens for
TB culture, AFB smear microscopy,
and Xpert MTB/RIF Assay testing
should follow CDC recommendations
with regard to collection methods and
time frame between specimen
collection. | The Xpert MTB/RIF Assay must be used
in conjunction with mycobacterial
culture to address the risk of false
negative results and to recover the
organisms for further characterization
and drug susceptibility testing.
The Xpert MTB/RIF Assay should only
be performed in laboratories that follow
safety practices in accordance with the
CDC/NIH Biosafety in Microbiological
and Biomedical Laboratories publication
and applicable state or local regulations. |
| | The Xpert MTB/RIF Assay does not
provide confirmation of rifampin
susceptibility since mechanisms of
rifampin resistance other than those
detected by this device may exist that
may be associated with a lack of
clinical response to treatment.
Specimens that have both MTB-
complex DNA and rifampin-resistance
associated mutations of the rpoB gene | |
| | detected by the Xpert MTB/RIF Assay
must have results confirmed by a | |
| Differences | | |
| | Device | Predicate |
| Item | Cepheid Xpert MTB/RIF | Current Cepheid Xpert MTB/RIF |
| | reference laboratory. If the presence of
rifampin-resistance associated mutations
of the rpoB gene is confirmed,
specimens should also be tested for the
presence of genetic mutations associated
with resistance to other drugs.
The Xpert MTB/RIF Assay should only
be performed in laboratories that follow
safety practices in accordance with the
CDC/NIH Biosafety in Microbiological
and Biomedical Laboratories publication
and applicable state or local regulations. | |
Table 5.1. Comparison of Similarities and Differences of the proposed Xpert MTB/RIF Assay with the Predicate Device
8
9
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Non-Clinical Studies:
Analytical Sensitivity
Please refer to the previously FDA-cleared 510(k) #K131706.
Analytical Reactivity (Inclusivity)
Please refer to the previously FDA-cleared 510(k) #K131706.
Analytical Specificity (Exclusivity)
Potential cross-reactivity of eight microorganisms was evaluated by in silico analysis. All eight microorganisms tested revealed no potential for cross-reactivity. See Table 5.2 below.
Table 5.2. Microorganisms Predicted to be Non-Cross Reactive by In Silico Analysis
| Mycobacterium chimaera | Mycobacterium immunogenum |
|---|---|
| Mycobacterium avium subsp. | |
| paratuberculosis | Mycobacterium massiliense |
| Mycobacterium avium subsp. | |
| silvaticum | Mycobacterium bolletii |
| Mycobacterium avium subsp. | |
| hominissuis | |
| Mycobacterium franklinii |
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Please refer to the previously FDA-cleared 510(k) #K131706 for a description of additional analytical specificity testing performed.
Interfering Substances
Please refer to the previously FDA-cleared 510(k) #K131706.
Carry-Over Contamination Study
Please refer to the previously FDA-cleared 510(k) #K131706.
RIF Resistance Study
Please refer to the previously FDA-cleared 510(k) #K131706.
Linearity
Not applicable, the Xpert MTB/RIF Assay is a qualitative assay.
Clinical Performance Characteristics:
Reproducibility
Please refer to the previously FDA-cleared 510(k) #K131706.
Instrument System Precision
Please refer to the previously FDA-cleared 510(k) #K131706.
Clinical Performance Study
Xpert MTB/RIF Assay Performance in an HIV Population
To compare performance of the Xpert MTB/RIF Assay in HIV-infected and HIVuninfected subjects, data from Study 2 were analyzed by smear status of specimens and HIV status of the population. Tables 5.3 and 5.4 compare the sensitivities and specificities of one Xpert MTB/RIF Assay result in specimens obtained from HIVinfected and HIV-uninfected subjects stratified by AFB smear-positive and AFB smearnegative results, respectively. For both HIV-infected and HIV-uninfected subjects, the sensitivity of the Xpert MTB/RIF Assay for detection of MTB-complex was higher in AFB smear-positive specimens (100.0% and 97.8%, respectively) than in AFB smearnegative specimens (52.1% and 58.3%. respectively). These data are summarized in Table 5.4.
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| Xpert
MTB/RIF | Overall | HIV-
infected | HIV-uninfected | Difference
(95% CI) |
|------------------|--------------------|------------------|------------------|------------------------|
| Sensitivity | 98.5%
(129/131) | 100%
(39/39) | 97.8%
(90/92) | 2.2%
(-0.8%, 5.2%) |
| Specificity | 94.4%
(17/18) | 100%
(7/7) | 90.9%
(10/11) | 9.1%
(-7.9%, 26.1%) |
Table 5.3. Comparison of Sensitivity and Specificity of One Xpert MTB/RIF Assay Result in HIV-Infected and HIV-Uninfected Subjects - AFB Smear Positive Only
Table 5.4. Comparison of Sensitivity and Specificity of One Xpert MTB/RIF Assay Result in HIV-Infected and HIV-Uninfected Subjects - AFB Smear Negative Only
| Xpert
MTB/RIF | Overall | HIV-infected | HIV-uninfected | Difference
(95% CI) |
|------------------|--------------------|--------------------|--------------------|--------------------------|
| Sensitivity | 54.8%
(46/84) | 52.1%
(25/48) | 58.3%
(21/36) | -6.3%
(-27.7%, 15.2%) |
| Specificity | 98.8%
(718/721) | 98.2%
(332/338) | 99.2%
(386/389) | -1.0%
(-2.7%, 0.7%) |
Xpert MTB/RIF Assay Performance as Basis for Removal of Patients from Respiratory Isolation
Tables 5.5 and 5.6 present the overall performance of one Xpert MTB/RIF Assay result compared to the results of MTB culture, stratified by AFB smear result (Table 5.5). Table 5.6 is a side-by-side comparison of the performance of one Xpert MTB/RIF Assay result versus the composite result of two AFB smears in U.S. and non-U.S. subjects (N=960). Overall sensitivity of one Xpert MTB/RIF Assay in AFB smear-positive and AFB smearnegative subjects (based on two AFB smears) was 98.5% (95% CI: 94.6%,99.6%) and 54.8% (95% CI: 44.1%, 65.0%) respectively, and overall specificity was 98.7% (95% CI: 97.5%, 99.3%). One Xpert MTB/RIF Assay result of MTB Not Detected was associated with a probability of MTB culture-positive/AFB smear-positive results of 0.4% for U.S. subjects and 0.0% for non-U.S. subjects.
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Table 5.5. Performance of One Xpert MTB/RIF Assay Result Stratified by Two AFB Smears Relative to MTB Culture in U.S. and non-U.S. Subjects
| Culture | Total | |||||||
|---|---|---|---|---|---|---|---|---|
| Positive | Negative | |||||||
| Xpert | ||||||||
| MTB/RIF | ||||||||
| Assay | AFB | |||||||
| Smear |
- | AFB
Smear
- | Overall
Culture
- | AFB
Smear - | AFB
Smear
- | Overall
Culture - | |
| | Positive | 129 | 46 | 175 | 1 | 9 | 10a | 185 |
| | Negative | 2 | 38 | 40 | 17 | 718 | 735 | 775 |
| | Total | 131 | 84 | 215 | 18b | 727 | 745 | 960 |
Performance of Xpert MTB/RIF Assay for Smear Positive:
Sensitivity: 98.5% (129/131), 95% CI: 94.6%,99.6% Specificity: 94.4% (17/18), 95% CI: 74.2%, 99.0%
Performance of Xpert MTB/RIF Assay for Smear Negative:
Sensitivity: 54.8% (46/84), 95% CI: 44.1%, 65.0% Specificity: 98.8% (718/727), 95% CI: 97.7%, 99.4%
Prevalence of MTB Culture Positive: 22.4% (215/960) Prevalence of MTB Culture Positive in U.S. subjects: Prevalence of MTB Culture positive in non-U.S. subjects: 37.1% (127/342)
Percent of AFB smear positive subjects among subjects with MTB Culture Positive: 60.9% (131/215)
Overall Probability of MTB Culture Positive among subjects with an Xpert MTB/RIF Negative Result: 5.2% (40/775), 95% CI: 3.8%, 7.0%
Probability of MTB Culture Positive among subjects with an Xpert MTB/RIF Negative Result (U.S. subjects): 2.4% (13/539), 95% CI: 1.4%, 4.1%
Probability of MTB Culture Positive among subjects with an Xpert MTB/RIF Negative Result (non-U.S. subjects): 11.4% (27/236), 95% CI: 8.0%, 16.1%
Overall Probability of MTB Culture Positive and AFB smear positive among subjects with an Xpert MTB/RIF Negative Result: 0.3% (2/775), 95% CI: