(73 days)
This document does not contain Reference Device(s) K/DEN numbers.
No
The summary describes a PCR-based diagnostic test and automated system, with no mention of AI or ML in the device description, intended use, or performance studies.
No.
Explanation: This device is an in vitro diagnostic test designed to detect specific gene sequences of Clostridium difficile, which aids in the diagnosis of C. difficile infection (CDI). It does not provide any therapeutic intervention or treatment.
Yes
The "Intended Use / Indications for Use" section explicitly states that the assay "is a qualitative in vitro diagnostic test" and "is intended as an aid in the diagnosis of CDI."
No
The device description clearly states that the system includes hardware components such as the GeneXpert instrument, personal computer, and disposable fluidic cartridges, which perform sample preparation, PCR, and detection.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The very first sentence explicitly states: "The Cepheid Xpert® C. difficile/Epi Assay is a qualitative in vitro diagnostic test..." This directly identifies the device as an IVD.
- Device Description: The description further reinforces this by stating it is a "rapid, automated in vitro diagnostic test".
- Function: The device performs tests on biological specimens (stool) outside of the body ("in vitro") to aid in the diagnosis of a disease (CDI).
- Regulatory Context: The document provides performance data compared to reference methods and lists predicate devices, which are typical requirements for regulatory submissions of IVD devices.
N/A
Intended Use / Indications for Use
The Cepheid Xpert® C. difficile/Epi Assay is a qualitative in vitro diagnostic test for rapid detection of toxin B gene sequences and for presumptive identification of 027/NAP1/BI strains of toxigenic Clostridium difficile from unformed (liquid or soft) stool specimens collected from patients suspected of having C. difficile infection (CDI). Presumptive identification of 027/NAP1/BI strains of C. difficile is by detection of binary toxin (CDT) gene sequences and the single base pair deletion at nucleotide 117 in the tedC gene. The tcdC gene encodes for a negative regulator in C. difficile toxin production. The test is performed on the Cepheid GeneXpert® Dx System and utilizes automated real-time polymerase chain reaction (PCR) to detect toxin gene sequences associated with toxin producing C. difficile. The Xpert C. difficile/Epi Assay is intended as an aid in the diagnosis of CDI. Detection of 027/NAP1/BI strains of C. difficile by the Xpert C. difficile/Epi Assay is presumptive and is solely for epidemiological purposes and is not intended to guide or monitor treatment for C. difficile infections. Concomitant culture is necessary only if further typing or organism recovery is required.
Product codes
LLH, OMN
Device Description
The Cepheid Xpert C. difficile/Epi Assay is a rapid, automated in vitro diagnostic test for qualitative detection of toxin producing Clostridium difficile directly from unformed (liquid or soft) stool specimens of patients suspected of having Clostridium difficile infection (CDI). The assay detects the toxin B gene (tcdB), the binary toxin gene (CDT), and the single base pair deletion at nucleotide 117 within the gene encoding a negative regulator of toxin production (tedCA117). The combined presence of the genes encoding toxin B and binary toxin and the tcdCA117 deletion have been associated with a hypervirulent C. difficile strain known as 027/NAP1/BI, which has been associated with severe disease outbreaks in healthcare facilities worldwide. The assay is performed on the Cepheid GeneXpert Dx System.
The Xpert C. difficile/Epi Assay system performs sample preparation and real-time, multiplex polymerase chain reaction (PCR) for detection of target-specific DNA.
The GeneXpert Dx System consists of a GeneXpert® instrument, personal computer, and disposable fluidic cartridges. Each instrument contains 1-16 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests for detection of C. difficile toxin B and binary toxin gene sequences, and the tcdCA117 deletion, in less than 45 minutes. Each module contains a syringe drive for dispensing fluids, an ultrasonic horn for lysing cells or spores, and I-CORE® thermocycler for performing real-time PCR and detection.
A swab is inserted into the stool specimen and then is placed in a tube containing elution reagent. Following brief vortexing, the eluted material and two single-use reagents (Reagent 1 and Reagent 2) that are provided with the Assay are transferred to different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert C. difficile/Epi cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert Dx System instrument platform, which performs hands-off real-time, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated.
The Xpert C. difficile/Epi Assay includes reagents for the detection of toxigenic C. difficile and the presumptive detection of sequences found in 027/NAP1/B1 strains. In addition, the assay reagents include an internal sample processing control (SPC) to ensure adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR Assay. The SPC also ensures that the PCR conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Stool (unformed/liquid or soft)
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Operators with no clinical lab experience to experienced clinical laboratory technologists.
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
Clinical Comparison Study:
A total of 2293 specimens were tested by Xpert C. difficile/Epi Assay, culture, and strain typing.
The study was a multi-site prospective investigation at seven US and Canadian institutions.
The Xpert C. difficile/Epi Assay was compared to reference culture followed by cell cytotoxicity testing on the isolates and strain typing on the toxigenic strains by restriction endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and PCR ribotyping methods.
Subjects included individuals whose routine care called for C. difficile testing. A portion of each leftover unformed stool specimen was obtained for testing by the Xpert C. difficile/Epi Assay.
The remaining excess specimen was sent to a central laboratory for reference culture and cytotoxin B isolate testing.
Each stool specimen was inoculated onto pre-reduced CCFA-D (cycloserine-cefoxitin-fructose agar -direct plate) and Cycloserine cefoxitin mannitol broth with taurocholate lysozyme cysteine (CCMB-TAL). After 24 hours the CCMB-TAL was subcultured on to a second CCFA-E plate (CCFA-Enriched). This direct-enriched culture method is referred to hereafter as "reference culture".
If C. difficile was isolated from the CCFA-D plate and the isolate was positive by cell cytotoxicity assay, the specimen was classified as "toxigenic C. difficile positive" and CCFA-E plate was not further analyzed.
If no C. difficile was isolated from the CCFA-D plate or if the isolate was negative by cell cytotoxicity assay, the CCFA-E plate was further analyzed.
If CCFA-E was positive for C. difficile and the isolate was positive for cell cytotoxicity assay, the specimen was classified as "toxigenic C. difficile positive". The specimen was reported as "negative" if CCFA-E was negative for C. difficile or the isolate was tested negative by cell cytotoxicity assay.
Following central culture testing, the toxigenic C. difficile positive isolates were sent to a second set of central laboratories for strain identification by REA, PFGE and PCR ribotyping.
Reproducibility Study:
A panel of 7 specimens with varying concentrations of a toxigenic C. difficile strain, a toxigenic C. difficile 027/NAP1/BI strain and a negative were tested in duplicate on 10 different days at each of three sites (7 specimens x 2 times/ day x 10 days x 3 sites = 420 total tests).
One lot of Xpert C. difficile kit was used at each of the 3 testing sites.
Xpert C. difficile/Epi Assays were performed according to the Xpert C. difficile/Epi procedure (2 operators/day x 10 days x 3 sites).
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Non-Clinical Studies:
- Analytical Inclusivity: 13 Clostridium difficile strains of different toxinotypes (0, I, III. IV, V, VI, VIII, IX, X, XII, XIV, XXI, XXII) were tested in triplicate with 900 CFU/swab. All strains were correctly reported as Toxigenic C. difficile positive. All strains were reported either as 027/NAP1/BI presumptive negative or presumptive positive. In three toxinotypes (X, IV, XIV), one to three replicates were incorrectly reported as 027/NAP1/BI presumptive positive. All other strains were correctly identified as 027/NAP1/BI presumptive positive or negative.
- Analytical Sensitivity (Limit of Detection - LoD): 20 replicates were evaluated at each C. difficile concentration tested (CFU/swab) for 7 different C. difficile strains (toxinotypes 0 (two strains), III (two strains), IV, V and VIII (one of each strain)). The LoD point estimates for C. difficile toxinotype ranged from 23 CFU/swab (LUMC-1) to 460 CFU/swab (90556-M6S). The Xpert C. difficile/Epi Assay will produce a positive C. difficile result 95% of the time for a fecal sample containing 460 CFU/swab and a presumptive positive 027/NAP1/BI result 95% of the time for a swab containing 75 CFU.
Additionally, 18 C. difficile strains (including 8 CDT positive and four 027/NAP1/BI toxinotype III isolates) were tested at approximately 900 CFU/swab in triplicate. All 18 strains were correctly identified as "Toxigenic C. diff POSITIVE". All 8 CDT positive strains were CDT positive. All four 027/NAP1/BI isolates were correctly identified as "Toxigenic C. diff POSITIVE; 027-NAP1-BI PRESUMPTIVE POSITIVE". - Linearity: A study was conducted to define the reportable range and demonstrated a linear relationship.
- Analytical Specificity: 55 strains (10 non-toxigenic C. difficile, 11 non C. difficile Clostridium species, others: Gram positive, Gram negative, aerobic, anaerobic, microaerophilic) were tested in triplicate at concentrations ranging from 1.1x10^8 to 2.2x10^0 CFU. All isolates were reported "Toxigenic C. diff NEGATIVE; 027/NAP1/BI PRESUMPTIVE NEG". The analytical specificity was 100%.
- Interfering Substances: 21 biological and chemical substances were tested for interference. 19 substances showed no detectable interference.
Clinical Studies:
- Clinical Comparison Study:
- Study type: Multi-site prospective investigation study.
- Sample size: 2293 specimens.
- Performance vs. Direct Culture & REA:
- Toxigenic C. difficile: Sensitivity: 98.72% (232/235), Specificity: 90.86% (1860/2047), Accuracy: 91.67% (2092/2282).
- 027/NAP1/BI: Positive Agreement: 98.55% (68/69), Negative Agreement: 97.65% (2161/2213), Accuracy: 97.68% (2229/2282).
- Performance vs. Direct Culture & PFGE:
- Toxigenic C. difficile: Sensitivity: 98.76% (238/241), Specificity: 90.86% (1860/2047), Accuracy: 91.70% (2098/2288).
- 027/NAP1/BI: Positive Agreement: 100% (71/71), Negative Agreement: 97.61% (2163/2216), Accuracy: 97.68% (2234/2288).
- Performance vs. Direct Culture & PCR Ribotyping:
- Toxigenic C. difficile: Sensitivity: 98.78% (242/245), Specificity: 90.86% (1860/2047), Accuracy: 91.71% (2102/2292).
- 027/NAP1/BI: Positive Agreement: 100% (74/74), Negative Agreement: 97.70% (2167/2218), Accuracy: 97.77% (2241/2292).
- Performance vs. Reference Culture & REA:
- Toxigenic C. difficile: Sensitivity: 93.35% (295/316), Specificity: 94.02% (1841/1958), Accuracy: 93.93% (2136/2274).
- 027/NAP1/BI: Positive Agreement: 96.51% (83/86), Negative Agreement: 98.31% (2151/2188), Accuracy: 98.24% (2234/2274).
- Performance vs. Reference Culture & PFGE:
- Toxigenic C. difficile: Sensitivity: 93.60% (307/328), Specificity: 94.02% (1841/1958), Accuracy: 93.96% (2148/2286).
- 027/NAP1/BI: Positive Agreement: 97.73% (86/88), Negative Agreement: 98.27% (2160/2198), Accuracy: 98.25% (2246/2286).
- Performance vs. Reference Culture & PCR Ribotyping:
- Toxigenic C. difficile: Sensitivity: 93.39% (311/333), Specificity: 94.02% (1841/1958), Accuracy: 93.93% (2152/2291).
- 027/NAP1/BI: Positive Agreement: 98.89% (89/90), Negative Agreement: 98.36% (2165/2201), Accuracy: 98.38% (2254/2291).
- Antibiotic Usage: Antibiotic use did not cause a statistically significant difference in assay performance.
- Reproducibility:
- Study type: Multi-site reproducibility study (3 sites, 2 operators/day, 10 days).
- Sample size: 7 specimens tested in duplicate on 10 different days at each of the three sites (total 420 tests).
- Total Agreement by Sample ranged from 90.0% to 100%. Overall total agreement by site was 100% at Site 1, 97.1% at Site 2, and 97.1% at Site 3. Overall total agreement was 98.1% (412/420).
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Performance vs. Direct Culture & REA:
- Toxigenic C. difficile:
- Sensitivity: 98.72% (232/235)
- Specificity: 90.86% (1860/2047)
- Accuracy: 91.67% (2092/2282)
- PPV: 55.37% (232/419)
- NPV: 99.84% (1860/1863)
- 027/NAP1/BI:
- Positive Agreement: 98.55% (68/69)
- Negative Agreement: 97.65% (2161/2213)
- Accuracy: 97.68% (2229/2282)
- PPV: 56.67% (68/120)
- NPV: 99.95% (2161/2162)
Performance vs. Direct Culture & PFGE:
- Toxigenic C. difficile:
- Sensitivity: 98.76% (238/241)
- Specificity: 90.86% (1860/2047)
- Accuracy: 91.70% (2098/2288)
- PPV: 56.00% (238/425)
- NPV: 99.84% (1860/1863)
- 027/NAP1/BI:
- Positive Agreement: 100% (71/71)
- Negative Agreement: 97.61% (2163/2216)
- Accuracy: 97.68% (2234/2288)
- PPV: 57.26% (71/124)
- NPV: 100% (2164/2164)
Performance vs. Direct Culture & PCR Ribotyping:
- Toxigenic C. difficile:
- Sensitivity: 98.78% (242/245)
- Specificity: 90.86% (1860/2047)
- Accuracy: 91.71% (2102/2292)
- PPV: 56.41% (242/429)
- NPV: 99.84% (1860/1863)
- 027/NAP1/BI:
- Positive Agreement: 100% (74/74)
- Negative Agreement: 97.70% (2167/2218)
- Accuracy: 97.77% (2241/2292)
- PPV: 59.20% (74/125)
- NPV: 100% (2218/2218)
Performance vs. Reference Culture & REA:
- Toxigenic C. difficile:
- Sensitivity: 93.35% (295/316)
- Specificity: 94.02% (1841/1958)
- Accuracy: 93.93% (2136/2274)
- PPV: 71.60% (295/412)
- NPV: 98.87% (1841/1862)
- 027/NAP1/BI:
- Positive Agreement: 96.51% (83/86)
- Negative Agreement: 98.31% (2151/2188)
- Accuracy: 98.24% (2234/2274)
- PPV: 69.17% (83/120)
- NPV: 99.86% (2151/2154)
Performance vs. Reference Culture & PFGE:
- Toxigenic C. difficile:
- Sensitivity: 93.60% (307/328)
- Specificity: 94.02% (1841/1958)
- Accuracy: 93.96% (2148/2286)
- PPV: 72.41% (307/424)
- NPV: 98.87% (1841/1862)
- 027/NAP1/BI:
- Positive Agreement: 97.73% (86/88)
- Negative Agreement: 98.27% (2160/2198)
- Accuracy: 98.25% (2246/2286)
- PPV: 69.35% (86/124)
- NPV: 99.91% (2160/2162)
Performance vs. Reference Culture & PCR Ribotyping:
- Toxigenic C. difficile:
- Sensitivity: 93.39% (311/333)
- Specificity: 94.02% (1841/1958)
- Accuracy: 93.93% (2152/2291)
- PPV: 72.66% (311/428)
- NPV: 98.82% (1841/1863)
- 027/NAP1/BI:
- Positive Agreement: 98.89% (89/90)
- Negative Agreement: 98.36% (2165/2201)
- Accuracy: 98.38% (2254/2291)
- PPV: 71.20% (89/125)
- NPV: 99.95% (2165/2166)
Reproducibility (Total Agreement by Sample):
- Negative: 100% (60/60)
- Toxigenic C. difficile High Negative: 100% (60/60)
- Toxigenic C. difficile Low Positive: 90.0% (54/60)
- Toxigenic C. difficile Moderate Positive: 100% (60/60)
- 027/NAP1/BI High Negative: 100% (60/60)
- 027/NAP1/BI Low Positive: 96.7% (58/60)
- 027/NAP1/BI Moderate Positive: 100% (60/60)
- % Total Agreement by Site: Site 1: 100% (140/140), Site 2: 97.1% (136/140), Site 3: 97.1% (136/140)
- Overall Total Agreement: 98.1% (412/420)
Predicate Device(s)
Cepheid Xpert® C. difficile [510(k) #K001109], BD GeneOhm™ Cdiff Assay [510(k) #K081920]
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 866.2660 Microorganism differentiation and identification device.
(a)
Identification. A microorganism differentiation and identification device is a device intended for medical purposes that consists of one or more components, such as differential culture media, biochemical reagents, and paper discs or paper strips impregnated with test reagents, that are usually contained in individual compartments and used to differentiate and identify selected microorganisms. The device aids in the diagnosis of 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.
0
5.0 510(k) Summary
As required by 21 CFR Section 807.92(c).
APR - 7 2011
| Submitted by: | Cepheid
904 Caribbean Drive
Sunnyvale, CA 90489
Phone number: (408) 400-8230
Fax number: (408) 541-6439 |
|---------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Russel K. Enns, Ph.D. |
| Date of Preparation: | April 6, 2011 |
| Device: | |
| Trade name: | Xpert® C. difficile/Epi |
| Common names: | C. difficile/Epi Assay, C. diff/Epi Assay, and Clostridium
difficile identification and differentiation system |
| Type of Test: | Qualitative Nucleic Acid Amplification Test for C. difficile
toxin B and binary toxin gene sequences and the single base
pair deletion at nucleotide 117 in tcdC from unformed stool
specimens. |
| Classification: | I |
| Classification name: | Device reagents, Clostridium difficile toxin; microorganism
differentiation and identification device. |
| Regulation number: | 866.2660 |
| Procode: | LLH, OMN |
| Classification Advisory
Committee: | Microbiology |
| Panel: | 83 |
| Predicate Devices: | Cepheid Xpert® C. difficile [510(k) #K001109]
BD GeneOhm™ Cdiff Assay [510(k) #K081920] |
Device Description:
The Cepheid Xpert C. difficile/Epi Assay is a rapid, automated in vitro diagnostic test for qualitative detection of toxin producing Clostridium difficile directly from unformed (liquid or soft) stool specimens of patients suspected of having Clostridium difficile infection (CDI). The assay detects the toxin B gene (tcdB), the binary toxin gene (CDT), and the single base pair deletion at nucleotide 117 within the gene encoding a negative regulator of toxin production (tedCA117). The combined presence of the genes encoding toxin B and binary toxin and the tcdCA117 deletion have been associated with a
1
hypervirulent C. difficile strain known as 027/NAP1/BI, which has been associated with severe disease outbreaks in healthcare facilities worldwide. The assay is performed on the Cepheid GeneXpert Dx System.
The Xpert C. difficile/Epi Assay system performs sample preparation and real-time, multiplex polymerase chain reaction (PCR) for detection of target-specific DNA.
The GeneXpert Dx System consists of a GeneXpert® instrument, personal computer, and disposable fluidic cartridges. Each instrument contains 1-16 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests for detection of C. difficile toxin B and binary toxin gene sequences, and the tcdCA117 deletion, in less than 45 minutes. Each module contains a syringe drive for dispensing fluids, an ultrasonic horn for lysing cells or spores, and I-CORE® thermocycler for performing real-time PCR and detection.
A swab is inserted into the stool specimen and then is placed in a tube containing elution reagent. Following brief vortexing, the eluted material and two single-use reagents (Reagent 1 and Reagent 2) that are provided with the Assay are transferred to different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert C. difficile/Epi cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert Dx System instrument platform, which performs hands-off real-time, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated.
The Xpert C. difficile/Epi Assay includes reagents for the detection of toxigenic C. difficile and the presumptive detection of sequences found in 027/NAP1/B1 strains. In addition, the assay reagents include an internal sample processing control (SPC) to ensure adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR Assay. The SPC also ensures that the PCR conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.
Device Intended Use:
The Cepheid Xpert® C. difficile/Epi Assay is a qualitative in vitro diagnostic test for rapid detection of toxin B gene sequences and for presumptive identification of 027/NAP1/BI strains of toxigenic Clostridium difficile from unformed (liquid or soft) stool specimens collected from patients suspected of having C. difficile infection (CDI). Presumptive identification of 027/NAP1/BI strains of C. difficile is by detection of binary toxin (CDT) gene sequences and the single base pair deletion at nucleotide 117 in the tedC gene. The tcdC gene encodes for a negative regulator in C. difficile toxin production. The test is performed on the Cepheid GeneXpert® Dx System and utilizes automated real-time polymerase chain reaction (PCR) to detect toxin gene sequences associated with toxin producing C. difficile. The Xpert C. difficile/Epi Assay is intended
2
as an aid in the diagnosis of CDI. Detection of 027/NAP1/BI strains of C. difficile by the Xpert C. difficile/Epi Assay is presumptive and is solely for epidemiological purposes and is not intended to guide or monitor treatment for C. difficile infections. Concomitant culture is necessary only if further typing or organism recovery is required.
Substantial Equivalence:
The Xpert C. difficile/Epi Assay is substantially equivalent to the Cepheid Xpert C. difficile Assay and the BD Diagnostics GeneOhm Cdiff Assay. All three assays qualitatively detect C. difficile toxin B gene (tcdB) in unformed (liquid or soft) stool specimens and use real-time PCR amplification and fluorogenic target-specific hybridization detection.
Table 5.1 shows the similarities and differences between the Xpert C. difficile/Epi Assay and the predicate devices.
The Xpert C. difficile/Epi is also substantially equivalent to the C. difficile reference culture method followed with strain identification of all C. difficile isolates as shown in a multi-center clinical comparison study.
The multi-center clinical comparison study was conducted on 2293 patients to evaluate the performance of the Xpert C. difficile Assay relative to the reference culture method and cytotoxin B isolate testing. Following culture testing, the toxigenic C. difficile isolates were sent to three central laboratories for strain typing by PCR Ribotyping, PFGE and REA methods for the identification of 027/NAP1/BI hypervirulent strains.
The test results showed the Xpert C. difficile Assay to be substantially equivalent to the current standard of care, the C. difficile reference culture method followed with strain identification of all toxigenic C. difficile isolates.
3
| Device | Predicate | Predicate | |
|---|---|---|---|
| Xpert C. difficile/Epi Assay | Xpert C. difficile | ||
| Assay (K091109) | BD GeneOhm | ||
| Cdiff Assay | |||
| (K081920) | |||
| Intended | |||
| Use | The Cepheid Xpert® C. | ||
| difficile/Epi Assay is a qualitative | |||
| in vitro diagnostic test for rapid | |||
| detection of toxin B gene | |||
| sequences and for presumptive | |||
| identification of 027/NAP1/BI | |||
| strains of toxigenic Clostridium | |||
| difficile from unformed (liquid or | |||
| soft) stool specimens collected | |||
| from patients suspected of having | |||
| C. difficile infection (CDI). | |||
| Presumptive identification of | |||
| 027/NAP1/BI strains of C. difficile | |||
| is by detection of binary toxin | |||
| (CDT) gene sequences and the | |||
| single base pair deletion at | |||
| nucleotide 117 in the tcdC gene. | |||
| The tcdC gene encodes for a | |||
| negative regulator in C. difficile | |||
| toxin production. The test is | |||
| performed on the Cepheid | |||
| GeneXpert® Dx System and | |||
| utilizes automated real-time | |||
| polymerase chain reaction (PCR) | |||
| to detect toxin gene sequences | |||
| associated with toxin producing C. | |||
| difficile . The Xpert C. difficile/Epi | |||
| Assay is intended as an aid in the | |||
| diagnosis of CDI. Detection of | |||
| 027/NAP1/BI strains of C. difficile | |||
| by the Xpert C. difficile/Epi Assay | |||
| is presumptive and is solely for | |||
| epidemiological purposes and is | |||
| not intended to guide or monitor | |||
| treatment for C. difficile | |||
| infections. Concomitant culture is | |||
| necessary only if further typing or | |||
| organism recovery is required. | The Cepheid Xpert C. | ||
| difficile Assay, | |||
| performed on the | |||
| Cepheid GeneXpert® | |||
| Dx System, is a | |||
| qualitative in vitro | |||
| diagnostic test for | |||
| rapid detection of | |||
| toxin B gene | |||
| sequences from | |||
| unformed (liquid or | |||
| soft) stool specimens | |||
| collected from | |||
| patients suspected of | |||
| having Clostridium | |||
| difficile infection | |||
| (CDI). The test | |||
| utilizes automated | |||
| real-time polymerase | |||
| chain reaction (PCR) | |||
| to detect toxin gene | |||
| sequences associated | |||
| with toxin producing | |||
| C. difficile . The Xpert | |||
| C. difficile Assay is | |||
| intended as an aid in | |||
| the diagnosis of CDI. | |||
| Concomitant culture | |||
| is necessary only if | |||
| further typing or | |||
| organism recovery is | |||
| required. | The BD GeneOhm | ||
| Cdiff Assay is a | |||
| rapid in vitro | |||
| diagnostic test for | |||
| the direct, | |||
| qualitative | |||
| detection of C. | |||
| difficile toxin B | |||
| gene ( tcdB ) in | |||
| human liquid or | |||
| soft stool | |||
| specimens from | |||
| patients suspected | |||
| of having | |||
| Clostridium | |||
| difficile -associated | |||
| disease (CDAD). | |||
| The test, based on | |||
| real-time PCR, is | |||
| intended for use as | |||
| an aid in diagnosis | |||
| of CDAD. The test | |||
| is performed | |||
| directly on the | |||
| specimen, utilizing | |||
| polymerase chain | |||
| reaction (PCR) for | |||
| the amplification of | |||
| specific targets and | |||
| fluorogenic target- | |||
| specific | |||
| hybridization | |||
| probes for the | |||
| detection of the | |||
| amplified DNA. | |||
| Device | Predicate | Predicate | |
| Item | Xpert C. difficile/Epi Assay | Xpert C. difficile | |
| Assay (K091109) | BD GeneOhm | ||
| Cdiff Assay | |||
| (K081920) | |||
| Indication | |||
| for Use | Identification of C. difficile from | ||
| patients suspected of having C. | |||
| difficile Infection (CDI). | Same | Same | |
| Techno- | |||
| logical | |||
| Principles | Fully-automated nucleic acid | ||
| amplification (DNA); real-time | |||
| PCR | Same | Same | |
| Specimen | |||
| Type | Unformed (liquid or soft) Stool | Same | Same |
| Test | |||
| Cartridge | Disposable single-use, multi- | ||
| chambered fluidic cartridge. | Same as Xpert C. | ||
| difficile/Epi Assay | Disposable single- | ||
| use PCR tube | |||
| DNA | |||
| Target | |||
| Sequences | C. difficile toxin B, binary toxin | ||
| and the tcdC deletion nt 117 | |||
| (tcdCA117) | C. difficile toxin B | ||
| only | C. difficile toxin B | ||
| only | |||
| Instrument | |||
| System | Cepheid GeneXpert Dx System | Same as Xpert C. | |
| difficile/Epi Assay | Cepheid | ||
| SmartCycler Dx | |||
| System | |||
| Sample | |||
| Extraction | Self-contained and automated after | ||
| swab elution and two single-dose | |||
| reagent additions. | Same as Xpert C. | ||
| difficile/Epi Assay | Manual | ||
| Probes | TaqMan® Probes | Same as Xpert C. | |
| difficile/Epi Assay | Molecular Beacons | ||
| Sample | |||
| Extraction | Automated | Same as Xpert C. | |
| difficile/Epi Assay | Manual | ||
| Rapid test | |||
| results | Less than 45 minutes to results. | Same as Xpert C. | |
| difficile/Epi Assay | Approximately 75- | ||
| 90 minutes to | |||
| results. | |||
| Users | Operators with no clinical lab | ||
| experience to experienced clinical | |||
| laboratory technologists. | Same/ CLIA | ||
| Moderate Complexity | |||
| Laboratory Users | CLIA High | ||
| Complexity | |||
| Laboratory Users |
Table 5.1: Similarities and Differences Between the Xpert C. difficile/Epi Assay and the Predicate Devices
4
5
Non-Clinical Studies:
Analytical Inclusivity
The analytical inclusivity of the Xpert C. difficile/Epi Assay was determined using 13 Clostridium difficile strains of different toxinotypes selected to represent the range of genetic diversity found in C. difficile. Toxinotypes 0, I, III. IV, V, VI, VIII, IX, X, XII, XIV, XXI, and XXII were tested. All strains were tested in triplicate with 900 CFU/swab. All tested toxinotypes were correctly reported as Toxigenic C. difficile positive. In addition, all strains were reported either as 027/NAP1/BI presumptive negative or presumptive positive. In three toxinotypes X, IV and XIV, one to three replicates were incorrectly reported as 027/NAP1/BI presumptive positive, respectively. All other strains were correctly identified as 027/NAP1/BI presumptive positive or negative.
Analytical Sensitivity (Limit of Detection)
Studies were performed to determine the 95% confidence intervals for the analytical limit of detection (LoD) of C. difficile diluted into a fecal matrix of human origin that can be detected by the Xpert C. difficile/Epi Assay. The fecal matrix consisted of human liquid feces (C. difficile negative by Xpert C. difficile/Epi Assay) diluted in PBS with 15% glycerol. The LoD is defined as the lowest number of colony forming units (CFU) per swab that can be reproducibly distinguished from negative samples with 95% confidence.
Replicates of 20 were evaluated at each C. difficile concentration tested (CFU/swab) for 7 different C. difficile strains representing toxinotypes 0 (two strains), III (two strains), IV, V and VIII (one of each strain).
The estimate and confidence intervals were determined using logistic regression with data (number of positive results per number of replicates at each level) over the range of CFU loadings. The confidence intervals were determined using maximum likelihood estimates on the logistic model parameters using the large sample variance-covariance matrix. The LoD point estimates and 95% upper and lower confidence intervals for each C. difficile toxinotype tested are summarized in Table 5.2.
6
| Strain ID | Toxinotype | LoD95%
(CFU/swab) | Lower
95% CI | Upper
95% CI |
|-----------------------|------------|----------------------|-----------------|-----------------|
| VPI 10463 (CCUG19126) | 0 | 255 | 190 | 632 |
| 90556-M6S (ATCC9689) | 0 | 460 | 419 | 587 |
| LUMC-1 (027/NAP1/BI) | III | 23 | 19 | 31 |
| LUMC-5 (027/NAP1/BI) | III | 75 | 45 | 176 |
| LUMC-7 | V | 45 | 34 | 104 |
| LUMC-6 | VIII | 60 | 50 | 74 |
| 9101 | XII | 41 | 34 | 49 |
| Table 5.2: 95% Confidence Intervals for Analytical LoD – C. difficile | ||
|---|---|---|
| -- | ------------------------------------------------------------------------------ | -- |
The results of this study indicate that the Xpert C, difficile/Epi Assay will produce a positive C. difficile result 95% of the time for a fecal sample containing 460 CFU/swab and a presumptive positive 027/NAP1/BI result 95% of the time for a swab containing 75 CFU.
In addition to the LoD determination, eighteen C. difficile strains representing toxinotypes 0 plus 12 variant toxinotypes, including four 027/NAP1/BI toxinotype III isolates, were tested using the Xpert C. difficile/Epi Assay. C. difficile strains were selected to broadly represent the majority of C. difficile toxinotypes encountered in practice. Stock cultures were prepared by suspending the bacterial growth from agar plates in PBS buffer containing 15% glycerol. The concentration of each stock was adjusted to 1.4-5.9 McFarland units. All strains were serially diluted to approximately 900 CFU/swab and tested in triplicate.
Under the conditions of this study, the Xpert C. difficile/Epi Assay correctly identified all 18 strains tested as "Toxigenic C. diff POSITIVE". Included in the panel were 8 toxinotypes reported to be positive for binary toxin (CDT) production as well. All were CDT positive using the Xpert C. difficile/Epi Assay. All four 027/NAP1/BI isolates representing toxinotype III were correctly identified as "Toxigenic C. diff POSITIVE; 027-NAP1-BI PRESUMPTIVE POSITIVE".
Linearity
A study was conducted to define the reportable range of the Xpert C. difficile/Epi Assay and demonstrated a linear relationship.
Analytical Specificity
Fifty-five (55) strains were collected, quantitated and tested using the Xpert C. difficile/Epi Assay. The strains originated from the American Type Culture Collection (ATCC), Culture Collection University of Göteborg (CCUG), German Collection of Microorganisms and Cell Cultures (DSMZ), the Centers for Disease Control and Prevention (CDC), the Institute of Public Health, Maribor, Slovenia and Swedish Institute for Infectious Disease Control (SMI).
7
Of the tested species, ten (10) non-toxigenic C. difficile strains and eleven (11) non C. difficile Clostridium species were included. The organisms tested were identified as either Gram positive (37) or Gram negative (18). The organisms were further classified as aerobic (24), anaerobic (29) or microaerophilic (2).
Each strain was tested in triplicate at concentrations ranging from 1.1x108 to 2.2x1000 Positive and negative controls were included in the study. Under the conditions of the study, all isolates were reported "Toxigenic C. diff NEGATIVE; 027/NAP1/BI PRESUMPTIVE NEG". The analytical specificity was 100%.
Interfering Substances
Twenty-one (21) biological and chemical substances occasionally used or found in stool specimens were tested for interference with the Xpert C. difficile/Epi Assay. Potentially interfering substances include, but are not limited to, Vagisil cream and zinc oxide paste. The 19 substances listed in Table 5.3 showed no detectable interference with the Xpert C. difficile/Epi Assay.
| Substance | Substance |
|---|---|
| Whole Blood | K-Y Jelly/Gelée® |
| Karolinska University Hospital | McNeil-PPC |
| Mucin (porcine) | Vaseline |
| Sigma | Unilever |
| Kaopectate® | Dulcolax® |
| Chattem | Boehringer Ingelheim Pharmaceuticals |
| Imodium® | Preparation H Portable Wipes |
| McNeil-PPC | Wyeth Consumer Healthcare |
| Pepto-Bismol® | Vaginal Contraceptive Film (VCF) |
| Procter & Gamble | Apothecus Pharmaceutical |
| Preparation H® | Vancomycin |
| Wyeth Consumer Healthcare | Fluka |
| Fleet® | Metronidazole |
| CB Fleet Company | Actavis |
| Fecal fats | Anusol® Plus |
| Karolinska University Hospital | TM Warner-Lambert Company |
| Monistat® | E-Z-HD™ High Density Barium Sulfate |
| for suspension | |
| McNeil-PPC | E-Z-EM Canada |
| Hydrocortisone Cream | |
| Longs Drugs |
Table 5.3: Substances Tested and Showing No Assay Interference
8
Clinical Studies
Clinical Comparison Study
Performance characteristics of the Xpert C. difficile/Epi Assay were determined in a multi-site prospective investigation study at seven US and Canadian institutions by comparing the Xpert C. difficile/Epi Assay to reference culture followed by cell cytotoxicity testing on the isolates and strain typing on the toxigenic strains by restriction endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and PCR ribotyping methods.
Subjects included individuals whose routine care called for C. difficile testing. A portion of each leftover unformed stool specimen was obtained for testing by the Xpert C. difficile/Epi Assay. The remaining excess specimen was sent to a central laboratory for reference culture and cytotoxin B isolate testing, Each stool specimen was inoculated onto pre-reduced CCFA-D (cycloserine-cefoxitin-fructose agar -direct plate) and Cycloserine cefoxitin mannitol broth with taurocholate lysozyme cysteine (CCMB-TAL). After 24 hours the CCMB-TAL was subcultured on to a second CCFA-E plate (CCFA-Enriched). This direct-enriched culture method is referred to hereafter as "reference culture".
If C. difficile was isolated from the CCFA-D plate and the isolate was positive by cell cytotoxicity assay, the specimen was classified as "toxigenic C. difficile positive" and CCFA-E plate was not further analyzed. If no C. difficile was isolated from the CCFA-D plate or if the isolate was negative by cell cytotoxicity assay, the CCFA-E plate was further analyzed.
If CCFA-E was positive for C. difficile and the isolate was positive for cell cytotoxicity assay, the specimen was classified as "toxigenic C. difficile positive". The specimen was reported as "negative" if CCFA-E was negative for C. difficile or the isolate was tested negative by cell cytotoxicity assay.
Following central culture testing, the toxigenic C. difficile positive isolates were sent to a second set of central laboratories for strain identification by REA, PFGE and PCR ribotyping.
Performance of the Xpert C. difficile/Epi Assay was calculated relative to the results of direct culture with strain typing, for each of the three strain typing methods, and reference culture with strain typing, for each of the three strain typing methods.
9
Overall Results
A total of 2293 specimens were tested by Xpert C. difficile/Epi Assay, culture, and strain typing.
Performance vs. Direct Culture
Relative to direct culture with REA strain typing, the Xpert C. difficile/Epi Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 98.72% and 90.86%, respectively. The Xpert C. difficile/Epi Assay also demonstrated 98.55% positive agreement and 97.65% negative agreement for BI (Table 5.4).
| Direct Culture & REA | ||||
|---|---|---|---|---|
| Xpert C. diff/Epia | Toxin B + | |||
| BI + | Toxin B + | |||
| BI – | NEG | Totalb | ||
| Toxin B + | ||||
| 027/NAP1/BI + | 68 | 5 | 47 | 120 |
| Toxin B + | ||||
| 027/NAP1/BI– | 1 | 158 | 140 | 299 |
| NEG | 0 | 3 | 1860 | 1863 |
| Total | 69 | 166 | 2047 | 2282 |
| Toxigenic C. difficile | Toxigenic C. difficile / 027/NAP1/BI | |||
| Sensitivity: | 98.72% (232/235) | Pos Agreement: 98.55% (68/69) | ||
| Specificity: | 90.86% (1860/2047) | Neg Agreement: 97.65% (2161/2213) | ||
| Accuracy: | 91.67% (2092/2282) | Accuracy: 97.68% (2229/2282) | ||
| PPVc: | 55.37% (232/419) | PPV: 56.67% (68/120) | ||
| NPVd: | 99.84% (1860/1863) | NPV: 99.95% (2161/2162) |
Table 5.4: Xpert C. difficile/Epi Assay Performance vs. Direct Culture & REA
a Xpert results shown are for first or second attempt. Approximately 3.2% of the specimens were indeterminate on the first attempt.
6 11 specimens were culture positive but were not strain typed for the following reasons: incomplete restriction endonuclease digestion; or the isolate was not sent. These 11 specimens are not included in the performance characteristics above.
6 Positive predictive value
d Negative predictive value
10
Relative to direct culture with PFGE strain typing, the Xpert C. difficile/Epi Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 98.76% and 90.86%, respectively. The Xpert C. difficile/Epi Assay also demonstrated 100% positive agreement and 97.61% negative agreement for NAP1 (Table 5.5).
| Direct Culture & PFGE | |||||
|---|---|---|---|---|---|
| Toxin B + | |||||
| NAP1 + | Toxin B + | ||||
| NAP1 - | NEG | Totalb | |||
| Xpert C. diff/Epia | Toxin B +; | ||||
| 027/NAP1/BI + | 71 | 6 | 47 | 124 | |
| Toxin B +; | |||||
| 027/NAP1/BI- | 0 | 161 | 140 | 301 | |
| NEG | 0 | 3 | 1860 | 1863 | |
| Total | 71 | 169 | 2047 | 2288 | |
| Toxigenic C. difficile | Toxigenic C. difficile / 027/NAP1/BI | ||||
| Sensitivity: | |||||
| Specificity: | |||||
| Accuracy: | |||||
| PPVc: | 98.76% (238/241) | ||||
| 90.86% (1860/2047) | |||||
| 91.70% (2098/2288) | |||||
| 56.00% (238/425) | Pos Agreement: | ||||
| Neg Agreement: | |||||
| Accuracy: | |||||
| PPV: | 100% (71/71) | ||||
| 97.61% (2163/2216) | |||||
| 97.68% (2234/2288) | |||||
| 57.26% (71/124) |
Table 5.5: Xpert C. difficile/Epi Assav Performance vs. Direct Culture & PFGE
4 Xpert results shown are for first or second attempt. Approximately 3.2% of the specimens were indeterminate on the first attempt.
99.84% (1860/1863)
6 5 specimens were culture positive but were not strain typed for the following reasons: incomplete restriction endomuclease digestion: no growth; or contamination. These 5 specimens are not included in the performance characteristics above.
NPV:
·Positive predictive value
NPV4:
dNegative predictive value
100% (2164/2164)
11
Relative to direct culture with PCR ribotyping, the Xpert C. difficile/Epi Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 98.78% and 90.86%, respectively. The Xpert C. difficile/Epi Assay also demonstrated 100% positive agreement and 97.70% negative agreement for 027 (Table 5.6).
| Table 5.6: Xpert C. difficile/Epi Assay Performance vs. Direct Culture & | |||
|---|---|---|---|
| Compression, consisted consistent comes and to control and charges and charges and charges and charges and charges and charges and charges and charges and charges and constru | PCR Ribotyping |
| Direct Culture & PCR-Ribotyping | |||||
|---|---|---|---|---|---|
| Xpert C. diff/Epia | Toxin B + | ||||
| 027+ | Toxin B + | ||||
| 027 - | NEG | Totalb | |||
| Toxin B +; | |||||
| 027/NAP1/BI + | 74 | 4 | 47 | 125 | |
| Toxin B +; | |||||
| 027/NAP1/BI - | 0 | 164 | 140 | 304 | |
| NEG | 0 | 3 | 1860 | 1863 | |
| Total | 74 | 171 | 2047 | 2292 | |
| Toxigenic C. difficile | Toxigenic C. difficile / 027/NAP1/BI | ||||
| Sensitivity: 98.78% (242/245) | Pos Agreement: 100% (74/74) | ||||
| Specificity: 90.86% (1860/2047) | Neg Agreement: 97.70% (2167/2218) | ||||
| Accuracy: 91.71% (2102/2292) | Accuracy: 97.77% (2241/2292) | ||||
| PPVc: 56.41% (242/429) | PPV: 59.20% (74/125) | ||||
| NPVd: 99.84% (1860/1863) | NPV: 100% (2218/2218) |
4 Xpert results shown are for first or second attempt. Approximately 3.2% of the specimens were indeterminate on the first attempt.
One isolate was not typeable due to contamination; this specimen is not included in the performance statistics.
"Positive predictive value
ªNegative predictive value
12
Performance vs. Reference Culture
Reference (enriched) culture is a more sensitive method for detection of C. difficile in symptomatic patients, for example it allows detection of low number of organism due to prior antibiotic treatment and potential loss of viability due to specimen transport.
Relative to reference culture with REA strain typing, the Xpert C. difficile/Epi Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 93.35% and 94.02%, respectively. The Xpert C. difficile/Epi Assay also demonstrated 96.51% positive agreement and 98.31% negative agreement for BI (Table 5.7).
| Reference Culture & REA | |||||
|---|---|---|---|---|---|
| Toxin B + | |||||
| BI + | Toxin B + | ||||
| BI - | NEG | Totalb | |||
| Xpert C. diff/Epra | Toxin B +; | ||||
| 027/NAP1/BI + | 83 | 6 | 31 | 120 | |
| Toxin B +; | |||||
| 027/NAP1/BI - | 2 | 204 | 86 | 292 | |
| NEG | 1 | 20 | 1841 | 1862 | |
| Total | 86 | 230 | 1958 | 2274 | |
| Toxigenic C. difficile | Toxigenic C. difficile / 027/NAP1/BI | ||||
| Sensitivity: | 93.35% (295/316) | Pos Agreement: | 96.51% (83/86) | ||
| Specificity: | 94.02% (1841/1958) | Neg Agreement: | 98.31% (2151/2188) | ||
| Accuracy: | 93.93% (2136/2274) | Accuracy: | 98.24% (2234/2274) | ||
| PPVc: | 71.60% (295/412) | PPV: | 69.17% (83/120) | ||
| NPVd: | 98.87% (1841/1862) | NPV: | 99.86% (2151/2154) |
| Table 5.7: Xpert C. difficile/Epi Assay Performance vs. Reference Culture & REA | ||
|---|---|---|
4 Xpert results shown are for first or second attempt. Approximately 3.3% of the specimens were indeterminate on the first attempt.
b 19 specimens were culture positive but were not strain typed for the following reasons: incomplete restriction endonuclease digestion; or the isolate was not sent. These 19 specimens are not included in the performance characteristics above.
Positive predictive value
dNegative predictive value
13
Relative to reference culture with PFGE strain typing, the Xpert C. difficile/Epi Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 93.60% and 94.02%, respectively. The Xpert C. difficile/Epi Assay also demonstrated 97.73% positive agreement and 98.27% negative agreement for NAP1 (Table 5.8).
| Reference Culture & PFGE | |||||
|---|---|---|---|---|---|
| Toxin B + | |||||
| NAP1 + | Toxin B +- | ||||
| NAP1 - | NEG | Totalb | |||
| Xpert C. diff/Epia | Toxin B +; | ||||
| 027/NAP1/BI + | 86 | 7 | 31 | 124 | |
| Toxin B +; | |||||
| 027/NAP1/BI - | 1 | 213 | 86 | 300 | |
| NEG | 1 | 20 | 1841 | 1862 | |
| Total | 88 | 240 | 1958 | 2286 | |
| Toxigenic C. difficile | Toxigenic C. difficile / 027/NAP1/BI | ||||
| Sensitivity: | 93.60% (307/328) | Pos Agreement: | 97.73% (86/88) | ||
| Specificity: | 94.02% (1841/1958) | Neg Agreement: | 98.27% (2160/2198) | ||
| Accuracy: | 93.96% (2148/2286) | Accuracy: | 98.25% (2246/2286) | ||
| PPVc: | 72.41% (307/424) | PPV: | 69.35% (86/124) | ||
| NPVd: | 98.87% (1841/1862) | NPV: | 99.91% (2160/2162) |
Table 5.8: Xpert C. difficile/Epi Assay Performance vs. Reference Culture & PFGE
4 Xpert results shown are for first or second attempt. Approximately 3.2% of the specimens were indeterminate on the first attempt.
6 7 specimens were culture positive but were not strain typed for the following reasons: incomplete restriction endomiclease digestion; no growth; or contamination. These 11 specimens are not included in the performance characteristics above.
°Positive predictive value
"Negative predictive value
14
Relative to reference culture with PCR ribotyping, the Xpert C. difficile Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 93.39% and 94.02%, respectively. The Xpert C. difficile Assay also demonstrated 98.89% positive agreement and 98.36% negative agreement for 027 (Table 5.9).
| Ribotyping | |||||
|---|---|---|---|---|---|
| Reference Culture & PCR-Ribotyping | |||||
| Xpert C. diff/Epia | Toxin B + | ||||
| 027+ | Toxin B + | ||||
| 027 – | NEG | Totalb | |||
| Toxin B +; | |||||
| 027/NAP1/BI + | 89 | 5 | 31 | 125 | |
| Toxin B +; | |||||
| 027/NAP1/BI - | 0 | 217 | 86 | 303 | |
| NEG | 1 | 21 | 1841 | 1863 | |
| Total | 90 | 243 | 1958 | 2291 | |
| Toxigenic C. difficile | Toxigenic C. difficile / 027/NAP1/BI | ||||
| Sensitivity: | 93.39% (311/333) | Pos Agreement: | 98.89% (89/90) | ||
| Specificity: | 94.02% (1841/1958) | Neg Agreement: | 98.36% (2165/2201) | ||
| Accuracy: | 93.93% (2152/2291) | Accuracy: | 98.38% (2254/2291) | ||
| PPVc: | 72.66% (311/428) | PPV: | 71.20% (89/125) | ||
| NPVd: | 98.82% (1841/1863) | NPV: | 99.95% (2165/2166) |
| Table 5.9: Xpert C. difficile Assay Performance vs. Reference Culture & PCR- | |||
|---|---|---|---|
| Ribotyping |
4 Xpert results shown are for first or second attempt. Approximately 3.2% of the specimens were indeterminate on the first attempt.
6 2 specimens were culture positive but were not strain typeable due to contamination and are not included in the performance characteristics above.
Positive predictive value
·Negative predictive value
Antibiotic Usage
Among the 2293 cases included in the main dataset, antibiotic use within the 2 months prior to sample collection was reported for 1630 and no antibiotic use was confirmed for 570; for 93 cases, antibiotic status was unknown. Antibiotic use did not cause a statistically significant difference in assay performance.
15
Reproducibility
Reproducibility of the Xpert C. difficile/Epi Assay was demonstrated using a panel of 7 specimens with varying concentrations of a toxigenic C. difficile strain, a toxigenic C. difficile 027/NAP1/BI strain and a negative that were tested in duplicate on 10 different days at each of the three sites (7 specimens x 2 times/ day x 10 days x 3 sites). One lot of Xpert C. difficile kit was used at each of the 3 testing sites. Xpert C. difficile/Epi Assays were performed according to the Xpert C. difficile/Epi procedure.
A panel of 7 specimens with varying concentrations of C. difficile and C. difficile. 027/NAP1/BI were tested on 10 different days by two different operators at each of the three sites (7 specimens x 2 operators/ day x 10 days x 3 sites). One lot of Xpert C. difficile/Epi Assay was used at each of the 3 testing sites. Xpert C. difficile/Epi Assays were performed according to the Xpert C. difficile/Epi Assay procedure. Results are summarized in Table 5.10.
| Specimen ID | Site 1 | Site 2 | Site 3 | % Total
Agreement by
Sample |
|---------------------------------------------|-------------------|--------------------|--------------------|-----------------------------------|
| Negative | 100%
(20/20) | 100%
(20/20) | 100%
(20/20) | 100%
(60/60) |
| Toxigenic C. difficile High Negative | 100%
(20/20) | 100%
(20/20) | 100%
(20/20) | 100%
(60/60) |
| Toxigenic C. difficile Low Positive | 100%
(20/20) | 85%
(17/20) | 85%
(17/20) | 90.0%
(54/60) |
| Toxigenic C. difficile Moderate
Positive | 100%
(20/20) | 100%
(20/20) | 100%
(20/20) | 100%
(60/60) |
| 027/NAP1/BI High Negative | 100%
(20/20) | 100%
(20/20) | 100%
(20/20) | 100%
(60/60) |
| 027/NAP1/BI Low Positive | 100%
(20/20) | 95%
(19/20) | 95%
(19/20) | 96.7%
(58/60) |
| 027/NAP1/BI Moderate Positive | 100%
(20/20) | 100%
(20/20) | 100%
(20/20) | 100%
(60/60) |
| % Total Agreement by Site | 100%
(140/140) | 97.1%
(136/140) | 97.1%
(136/140) | 98.1%
(412/420) |
Table 5.20: Summary of Reproducibility Results (all)
Conclusions
The results of the nonclinical and clinical performance studies summarized above demonstrate that the Xpert C. difficile/Epi Assay is as safe, as effective, and performs as well as or better than the predicate devices.
16
Image /page/16/Picture/0 description: The image shows the logo for the Department of Health & Human Services (HHS) in the USA. The logo features a stylized depiction of an eagle or bird with three curved lines forming its body and wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the bird symbol.
DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993
Cepheid c/o Russel K. Enns. Ph.D. Senior Vice President, Chief Regulatory Officer 904 Caribbean Drive Sunnyvale. CA 94089-1189
APR 0 7 2011
Re: K110203
Trade/Device Name: Regulation Number: Regulation Name: Regulatory Class: Product Code: Dated: Received:
Xpert® C. difficile/Epi 21 CFR 8866.2660 Microorganism differentiation and identification device Class I OMN January 21, 2011 January 24, 2011
Dear Dr. Enns:
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.
If your device is classified (see above) into class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to
17
Page 2 - Russel K. Enns, Ph.D.
proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. 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 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 Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrl/industry/support/index.html.
Sincerely yours.
Saliaotypica
Sally A. Hojvat, M.Sc., Ph Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
18
4.0 Indications for Use Form
510(k) Number (if known): K110203
Device Name: Xpert® C. difficile/Epi Assay
Indications for Use:
The Cepheid Xpert® C. difficile/Epi Assay is a qualitative in vitro diagnostic test for rapid detection of toxin B gene sequences and for presumptive identification of 027/NAP1/BI strains of toxigenic Clostridium difficile from unformed (liquid or soft) stool specimens collected from patients suspected of having C. difficile infection (CDI). Presumptive identification of 027/NAP1/BI strains of C. difficile is by detection of binary toxin (CDT) gene sequences and the single base pair deletion at nucleotide 117 in the tedC gene. The tcdC gene encodes for a negative regulator in C. difficile toxin production. The test is performed on the Cepheid GeneXpert® Dx System and utilizes automated real-time polymerase chain reaction (PCR) to detect toxin gene sequences associated with toxin producing C. difficile. The Xpert C. difficile/Epi Assay is intended as an aid in the diagnosis of CDI. Detection of 027/NAP 1/BI strains of C. difficile by the Xpert C. difficile/Epi Assay is presumptive and is solely for epidemiological purposes and is not intended to guide or monitor treatment for C. difficile infections. Concomitant culture is necessary only if further typing or organism recovery is required.
| Prescription Use X | AND/OR Over-The-Counter Use _ |
|---|---|
| (Part 21 CFR 801 Subpart D) | (21 CFR 801 Subpart C) |
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE OF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Freddie W. Cooke
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K110203
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