(84 days)
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No
The summary describes a PCR-based diagnostic test with automated sample preparation and real-time detection. There is no mention of AI or ML in the device description, intended use, or performance studies. The analysis is based on detecting specific gene sequences, not on learning from data patterns.
No
This device is an in vitro diagnostic test intended to aid in the diagnosis of Clostridium difficile infection (CDI) by detecting toxin B gene sequences. It does not provide treatment or therapy.
Yes
Explanation: The "Intended Use / Indications for Use" section explicitly states that the device is a "qualitative in vitro diagnostic test for rapid detection of toxin B gene sequences" and is "intended as an aid in the diagnosis of CDI."
No
The device is an in vitro diagnostic test that utilizes a hardware system (GeneXpert Dx System) with disposable cartridges and reagents to perform automated sample preparation and real-time PCR. It is not solely software.
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 Assay... 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)."
- Device Description: The description reiterates that it is a "rapid, automated in vitro diagnostic test".
- Function: The device performs tests on biological specimens (stool) outside of the body to aid in the diagnosis of a disease (CDI). This is the core definition of an in vitro diagnostic device.
N/A
Intended Use / Indications for Use
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.
Product codes (comma separated list FDA assigned to the subject device)
LLH
Device Description
The Cepheid Xpert C. difficile Assay is a rapid, automated in vitro diagnostic test for qualitative detection of 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), and is performed on the Cepheid GeneXpert Dx System.
The Xpert C. difficile 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 gene sequences 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 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 realtime, 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 Assay includes reagents for the detection of toxin B gene (tcdB). 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
Not Found
Indicated Patient Age Range
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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
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Description of the test set, sample size, data source, and annotation protocol
A multi-center clinical comparison study was conducted on 2296 patients to evaluate the performance of the Xpert C. difficile Assay relative to the reference culture method and cytotoxin B isolate testing. Subjects included individuals whose routine care called for C. difficile testing. A portion of the leftover unformed stool specimens were obtained for testing by the Xpert C. difficile 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 cyotoxicity 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 is negative for C. difficile or the isolate was tested negative by cell cytotoxicity assay.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical Comparison Study:
A multisite prospective investigation study at seven US and Canadian institutions with 2296 specimens. Performance was compared to direct culture and reference culture.
-
Performance vs. Direct Culture:
- Sensitivity: 98.79%
- Specificity: 90.82%
- Accuracy: 91.68%
- PPV: 56.58%
- NPV: 99.83%
- Prevalence: 10.80%
-
Performance vs. Reference Culture:
- Sensitivity: 93.49%
- Specificity: 94.02%
- Accuracy: 93.95%
- PPV: 72.98%
- NPV: 98.82%
- Prevalence: 14.72%
Reproducibility Study:
Panel of 7 specimens (varying concentrations of toxigenic C. difficile, toxigenic C. difficile 027/NAP1/BI, and negative) tested in duplicate on 10 different days at each of three sites. An additional panel of 6 specimens (three negative and three toxigenic C. difficile high negative, concentration below LoD) were tested on 5 different days by two different operators at each of the three sites.
- % Total Agreement by Sample for the 7-specimen panel: Ranges from 90.0% (Toxigenic C. difficile Low Positive) to 100% (Negative, Toxigenic C. difficile High Negative, Toxigenic C. difficile Moderate Positive, 027/NAP1/BI High Negative, 027/NAP1/BI Moderate Positive, 027/NAP1/BI Low Positive).
- % Total Agreement by Site: Site 1: 100% (140/140), Site 2: 97.1% (136/140), Site 3: 97.1% (136/140). Overall: 98.1% (412/420).
- For the high negative sample in the additional reproducibility study, the % Total Agreement by Sample was 57.8% (52/90), which was expected given the concentration below LoD.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
- Performance vs. Direct Culture:
- Sensitivity: 98.79%
- Specificity: 90.82%
- Accuracy: 91.68%
- PPV: 56.58%
- NPV: 99.83%
- Prevalence: 10.80%
- Performance vs. Reference Culture:
- Sensitivity: 93.49%
- Specificity: 94.02%
- Accuracy: 93.95%
- PPV: 72.98%
- NPV: 98.82%
- Prevalence: 14.72%
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
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
Cepheid.
CONFIDENTIAL
JUL - 9 2009
510(k) Summary
As required by 21 CFR Section 807.92(c).
Submitted by:
| 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: | June 21, 2009 |
| Device: | |
| Trade name: | Xpert® C. difficile |
| Common names: | C. difficile Assay and Clostridrium difficile identification
and differentiation system |
| Type of Test: | Qualitative Nucleic Acid Amplification Test for C. difficile
toxin B gene sequences from unformed stool specimens. |
| Classification: | I |
| Classification name: | Device reagents, Clostridium difficile toxin; microorganism
differentiation and identification device. |
| Regulation number: | 866.2660 |
| Procode: | LLH |
| Classification Advisory
Committee: | Microbiology |
| Panel: | 83 |
| Predicate Device: | BD GeneOhm™ Cdiff Assay [510(k) # K081920] |
Device Description:
The Cepheid Xpert C. difficile Assay is a rapid, automated in vitro diagnostic test for qualitative detection of 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), and is performed on the Cepheid GeneXpert Dx System.
The Xpert C. difficile Assay system performs sample preparation and real-time, multiplex polymerase chain reaction (PCR) for detection of target-specific DNA.
1
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 gene sequences 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 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 realtime, 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 Assay includes reagents for the detection of toxin B gene (tcdB). 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 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 testing is necessary only if further typing or organism recovery is required.
Substantial Equivalence:
The Xpert C. difficile Assay is substantially equivalent to the BD GeneOhm Cdiff Assay, manufactured by BD Diagnostics. Both Assays qualitatively detect C. difficile toxin B gene (tcdB) in unformed (liquid or soft) stool specimens. Both Assays use real-time PCR amplification and fluorogenic target-specific hybridization detection.
Table 5.1 shows the similarities and differences between the Xpert C. difficile Assay and the BD GeneOhm Cdiff Assay.
510(k) Summary Xpert C. difficile Assay Page 2 of 11
2
The Xpert C. difficile is also substantially equivalent to the C. difficile reference culture method followed with strain identification of all C. difficile isolates as shown in a multicenter clinical comparison study.
The multi-center clinical comparison study was conducted on 2296 patients to evaluate the performance of the Xpert C. difficile Assay relative to the reference culture method and cytotoxin B isolate testing.
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.
| Item | Device | Predicate |
|---|---|---|
| Xpert C. difficile Assay | BD GeneOhm Cdiff Assay | |
| (K081920) | ||
| Intended Use | An automated test for the | |
| qualitative detection of | ||
| toxigenic C. difficile in | ||
| unformed (liquid or soft) | ||
| stool specimens. | Same | |
| Indication for | ||
| Use | Identification of C. difficile | |
| from patients suspected of | ||
| having C. difficile Infection | ||
| (CDI). | Same | |
| Technological | ||
| Principles | Fully-automated nucleic acid | |
| amplification (DNA); real-time PCR | Same | |
| Specimen Type | Unformed (liquid or soft) | |
| Stool | Same | |
| Test Cartridge | Disposable single-use, multi- | |
| chambered fluidic cartridge. | Disposable single-use PCR tube | |
| DNA Target | ||
| Sequence(s) | C. difficile toxin B | Same |
| Instrument | ||
| System | Cepheid GeneXpert Dx | |
| System | Cepheid SmartCycler Dx | |
| System | ||
| Sample | ||
| Extraction | Self-contained and automated | |
| after swab elution and two | ||
| single-dose reagent additions. | Manual | |
| Probes | TaqMan® Probes | Molecular Beacons |
Table 5.1 Similarities and Differences Between the Xpert C. difficile Assay and the BD GeneOhm Cdiff Assay
3
| Device | Predicate | |
|---|---|---|
| Item | Xpert C. difficile Assay | BD GeneOhm C.diff Assay |
| (K081920) | ||
| Sample | ||
| Extraction | Automated | Manual |
| Rapid test results | Less than 45 minutes to | |
| results. | Approximately 75-90 minutes to | |
| results. | ||
| Users | Operators with no clinical lab | |
| experience to experienced | ||
| clinical laboratory | ||
| technologists. | CLIA High Complexity | |
| Laboratory Users |
Non-Clinical Studies:
Analytical Inclusivity
The analytical inclusivity of the Xpert C. difficile 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 9000 CFU per Assay. All tested toxinotypes were correctly reported as "Toxigenic C. diff POSITIVE".
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 Assay. The fecal matrix consisted of human liquid feces (C. difficile negative by Xpert C. difficile 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.
4
| 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)a | III | 23 | 19 | 31 |
| LUMC-5 (027/NAP1/BI)a | 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 | |||
|---|---|---|---|
By PCR-ribotyping/pulse-field gel electrophoresis/restriction endonuclease analysis
The results of this study indicate that the Xpert C. difficile Assay will produce a positive C. difficile result 95% of the time with 95% confidence for a fecal sample containing 460 CFU.
In addition to the LoD determination, eighteen C. difficile strains representing 12 variant toxinotypes, including four 027/NAP1/BI toxinotype III isolates, were tested using the Xpert C. difficile 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 Assay correctly identified all 18 toxinotypes 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 Assay. All four 027/NAP1/BI isolates representing toxinotype III were correctly identified as "Toxigenic C. diff POSITIVE".
Linearitv
A study was conducted to define the reportable range of the Xpert C. difficile Assay and demonstrated a linear relationship.
Analytical Specificity
Fifty-five (55) strains were collected, quantitated and tested using the Xpert C. difficile 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).
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
5
either Gram positive (37) or Gram negative (18). The organisms were further classified as aerobic (24), anaerobic (29) or microaerophillic (2).
Each strain was tested in triplicate from cultures adjusted to 0.5 - 4.7 McFarland units. Positive and negative controls were included in the study. Under the conditions of the study, all isolates were reported "Toxigenic C. diff NEGATIVE". The analytical specificity was 100%.
Interfering Substances
Twenty-one (21) biological and chemical substances occasionally used or round in stool specimens were tested for interference with the Xpert C. difficile 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 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
6
Clinical Studies
Clinical Comparison Study
Performance characteristics of the Xpert C. difficile Assay were determined in a multisite prospective investigation study at seven US and Canadian institutions by comparing the Xpert C. difficile Assay to reference culture followed by cell cytotoxicity testing on the isolates.
Subjects included individuals whose routine care called for C. difficile testing. A portion of the leftover unformed stool specimens were obtained for testing by the Xpert. C. difficile 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 cyotoxicity 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 is negative for C. difficile or the isolate was tested negative by cell cytotoxicity assay.
Performance of the Xpert C. difficile Assay was calculated relative to the results of direct culture and reference culture.
Overall Results
A total of 2296 specimens were tested by Xpert C. difficile Assay and culture.
Performance vs. Direct Culture
Relative to direct culture with REA strain typing, the Xpert C. difficile Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 98.79% and 90:82%, respectively (Table 5.4).
510(k) Summary Xpert C. difficile Assay Page 7 of 11
7
| Direct Culture | ||||
|---|---|---|---|---|
| C. diff | NEG | Total | ||
| Xpert C. difficile | Toxin B+ | 245 (240) | 188 (183) | 433 (423) |
| NEG | 3 (3) | 1860 (1795) | 1863 (1798) | |
| Total | 248 (243) | 2048 (1978) | 2296 (2221) | |
| Sensitivity: 98.79% | ||||
| Specificity: 90.82% | ||||
| Accuracy: 91.68% | ||||
| PPVa: 56.58% | ||||
| NPVb: 99.83% | ||||
| Prevalence: 10.80% |
Table 5.4 - Xpert C. difficile Assay Performance vs. Direct Culture
()Xpert C. difficile results on first attempt
4Positive predictive value
Negative predictive value
Performance vs. Reference Culture
ﺎ ﺗﻌﻠﻴ . ..
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 lost of viability due to specimen transport.
Relative to reference culture, the Xpert C. difficile Assay demonstrated a sensitivity and specificity for toxigenic C. difficile of 93.49% and 94.02%, respectively (Table 5.5).
| Table 5.5 - Xpert C. difficile Assay Performance vs. Reference Culture | |||
|---|---|---|---|
| ------------------------------------------------------------------------ | -- | -- | -- |
| Reference Culture | ||||
|---|---|---|---|---|
| C. diff | NEG | Total | ||
| Xpert C. difficile | Toxin B+ | 316 (310) | 117 (113) | 433 (423) |
| NEG | 22 (22) | 1841 (1776) | 1863 (1798) | |
| Total | 338 (332) | 1958 (1889) | 2296 (2221) | |
| Sensitivity: | ||||
| Specificity: | ||||
| Accuracy: | ||||
| PPVa: | ||||
| NPVb: | ||||
| Prevalence | 93.49% | |||
| 94.02% | ||||
| 93.95% | ||||
| 72.98% | ||||
| 98.82% | ||||
| 14.72% |
()Xpert C. difficile results on first attempt
4Positive predictive value
6Negative predictive value
8
Antibiotic Usage
Among the 2296 cases included in the main dataset, antibiotic use within the 2 months prior to sample collection was reported for 1633 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.
Reproducibility
Reproducibility of the Xpert C. difficile 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 Assays were performed according to the Xpert C. difficile 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 Assay was used at each of the 3 testing sites. Xpert C. difficile Assays were performed according to the Xpert C. difficile Assay procedure. Results are summarized in Table 5.6.
| 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 5.6 - Summary of Reproducibility Results (all)
9
| SPC | |||
|---|---|---|---|
| Level | Ave | StdDev | CV |
| Toxigenic C. diff high neg | 32.17 | 0.59 | 1.83% |
| Toxigenic C. diff low pos | 32.14 | 0.53 | 1.66% |
| Toxigenic C. diff mod pos | 31.98 | 0.47 | 1.47% |
| 027/NAP1/BI high neg | 32.11 | 0.65 | 2.03% |
| 027/NAP1/BI low pos | 31.93 | 0.72 | 2.26% |
| 027/NAP1/BI mod pos | 31.96 | 0.61 | 1.90% |
| Neg | 32.26 | 0.72 | 2.22% |
| Table 5.7 - Summary of Ct Value Results by Sample Level and Probe | ||||
|---|---|---|---|---|
| tcdB | |||||||
|---|---|---|---|---|---|---|---|
| Level | Ave | StdDev | CV | ||||
| Toxigenic C. diff high neg | 39.59 | 0.70 | 1.77% | ||||
| Toxigenic C. diff low pos | 35.88 | 0.81 | 2.24% | ||||
| Toxigenic C. diff mod pos | 32.17 | 0.45 | 1.39% | ||||
| 027/NAP1/BI high neg | 39.11 | 0.98 | 2.50% | ||||
| 027/NAP1/BI low pos | 35.49 | 0.58 | 1.65% | ||||
| 027/NAP1/BI mod pos | 32.10 | 0.63 | 1.97% |
An additional panel of 6 specimens, three negative and three toxigenic C. difficile high negative, were tested on 5 different days by two different operators at each of the three sites (6 specimens x 2 operators/ day x 5 days x 3 sites). The high negative specimens were prepared at a concentration below LoD such that they were expected to give a negative result 20 to 80% of the time. One lot of Xpert C. difficile Assay was used at each of the 3 testing sites. Xpert C. difficile Assays were performed according to the Xpert C. difficile Assay procedure. Results are summarized in Table 5.8.
| Specimen ID | Site 1 | Site 2 | Site 3 | % Total
Agreement
by Sample |
|------------------------------------------|-------------------|-------------------|-------------------|-----------------------------------|
| Negative | 100%
(30/30) | 100%
(30/30) | 100%
(30/30) | 100%
(90/90) |
| Toxigenic C. difficile High
Negativea | 60.0%
(18/30)b | 60.0%
(18/30)b | 53.3%
(16/30)b | 57.8%
(52/90)b |
| Table 5.8 - Summary of Additional Reproducibility Specimen Results | |
|---|---|
| -------------------------------------------------------------------- | -- |
20-80% agreement expected for high negative sample
6(# negative results / total high negative samples run)
510(k) Summary Xpert C. difficile Assay Page 10 of 11
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Conclusions
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The results of the nonclinical analytical and clinical performance studies summarized above demonstrate that the Xpert C. difficile Assay is as safe, as effective, and performs as well as or better than the predicate device.
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510(k) Summary Xpert C. difficile Assay
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Image /page/11/Picture/0 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three stripes representing the department's mission. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the eagle.
DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993
JUL - 9 2009
Cepheid Russel K. Enns, Ph.D. Senior Vice President 904 Caribbean Drive Sunnyvale, CA 94089-1189
Re: K091109
Trade/Device Name: Xpert® C. difficile Regulation Number: 21 CFR 866.2660 Regulation Name: Microorganism differentiation and detection device Regulatory Class: Class I Product Code: LLH Dated: June 22, 2009 Received: June 23, 2009
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 either class II (Special Controls) or class III (PMA), 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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Page 2 .
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 proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at 240-276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at 240-276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at 240-276-3464. 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 (240) 276-3150 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours.
Sally attayma
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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4.0 Indications for Use Statement
510(k) Number (if known): K091109
Device Name: Xpert® C. difficile
Indications for Use:
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.
Prescription Use X (Part 21 CFR 801 Subpart D)
Over-The-Counter Use AND/OR (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE
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Office of In Vitro Diagnos Device Evaluation and Safety
NO 4110 510(k)