(602 days)
Cell Culture for Enterovirus Detection
Not Found
No
The device description mentions "automated analysis of the resulting fluorescence signal curves and reporting of assay results" by "NucliSENS EasyQ® Director Software, in combination with NucliSENS EasyQ® Enterovirus v1.1 assav software". This suggests standard software-based analysis of predefined parameters, not AI/ML which would typically involve learning from data to make predictions or classifications. There are no mentions of AI, ML, training data, or complex algorithms indicative of AI/ML.
No
This device is an in vitro diagnostic assay used for the qualitative detection of Enterovirus RNA, providing information for diagnosis rather than directly treating or preventing a disease.
Yes
The device qualitatively detects Enterovirus RNA in CSF specimens and is used as an aid in the presumptive laboratory diagnosis of enterovirus infection in pediatric patients, indicating its role in diagnosis.
No
The device is an in-vitro diagnostic assay that includes reagents, controls, and relies on a hardware system (NucliSENS EasyQ System) for amplification and detection. While it uses software for analysis and reporting, it is not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The "Intended Use / Indications for Use" section explicitly states that the assay is an "in vitro nucleic acid amplification assay" and is used for the "qualitative detection of Enterovirus RNA in cerebral spinal fluid (CSF) specimens in patients with signs and symptoms of meningitis." This clearly indicates that the device is intended for use outside of the body to examine specimens for diagnostic purposes.
- Device Description: The "Device Description" section further reinforces this by describing the device as an "in-vitro diagnostic assay." It details how the assay works using nucleic acid amplification and detection to identify the presence of enteroviral RNA in CSF eluates.
- Performance Studies: The document includes detailed performance studies (Clinical Performance, Reproducibility, Analytical Sensitivity, Analytical Reactivity, Potentially Interfering Substances, Analytical Specificity, Specimen Stability) which are standard requirements for demonstrating the performance of an IVD.
- Intended User / Care Setting: The intended users are "Hospital laboratories associated with clinical testing sites," which are typical settings for performing in vitro diagnostic tests.
- Predicate Device: The mention of "Cell Culture for Enterovirus Detection" as a predicate device (even though it's a pre-amendment method) further confirms that this device is intended to perform a diagnostic function similar to existing methods.
All of these points align with the definition and characteristics of an In Vitro Diagnostic device.
N/A
Intended Use / Indications for Use
The NucliSens EasyQ® Enterovirus v1.1 Assay is an in vitro nucleic acid amplification assay to be used in conjunction with the NucliSens EasyQ® System for the qualitative detection of Enterovirus RNA in cerebral spinal fluid (CSF) specimens in patients with signs and symptoms of meningitis. This test, in conjunction with other laboratory results and clinical information, may be used as an aid in the presumptive laboratory diagnosis of enterovirus infection in pediatric patients with a clinical suspicion of aseptic meningitis or aseptic meningioencephalitis.
Negative results should be confirmed by cell culture.
Assay performance characteristics have not been established for adults, or for immunocompromised or immunosuppressed patients.
Caution: The results obtained with the NucliSens EasyQ Enterovirus v1.1 Assay should be used only as an adjunct to clinical observation and other information available to the physician. Positive results do not rule out other causes of meningitis, including bacteria, mycobacteria, other viruses (e.g. herpes family viruses, arboviruses, mumps virus, etc) and fungi).
Product codes
OAI
Device Description
NucliSENS EasyQ® Enterovirus v1.1 is an in-vitro diagnostic assay which uses nucleic acid amplification combined with a simultaneous detection step to detect the presence of enteroviral RNA in eluates derived from cerebrospinal fluid or appropriate control material. The assay requires extracted nucleic acid as input material, and has been validated using nucleic acid eluates extracted from clinical specimens with NucliSENS® miniMAG™. The amplification step is performed using the NucliSENS EasyQ System.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
cerebral spinal fluid (CSF)
Indicated Patient Age Range
pediatric patients
Intended User / Care Setting
Not Found
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
The NucliSENS EasyQ® Enterovirus v1.1 assay and cell culture (with identification by immunofluorescence [IFA] ) were used to evaluate cerebrospinal fluid (CSF) specimens from 520 pediatric subjects (0 to 21 years of age) who presented with signs and/or symptoms consistent with suspected aseptic meningitis (for example, fever, headache, stiff neck). Most (449/520 = 86.3%) CSF specimens were prospectively collected for this study and tested while fresh. However a minority (71/520 = 13.7%) had been previously collected and stored at -70°C prior to testing for this study. The six clinical sites were located in Ohio, Missouri, Texas (2 sites), Nebraska and California. Testing was performed at hospital laboratories associated with the testing sites in 2004-2005.
Bacteria gram stain, bacteria culture, and CSF profile (profein mg/dL, glucose mg/dL, white blood cell count, differential) were also collected for the overwhelming majority of patients. For many patients, serum glucose, white blood cell (WBC) count, complete blood cell (CBC) profile and CBC profile differential were also determined. At 5 of 6 clinical testing sites, the attending physicians ordered laboratory-developed tests for detection of enterovirus nucleic acid.
For each subject, the final diagnosis, as determined by the attending physicians based on signs and symptoms as well as laboratory testing results, was reported to the study investigator. Results from the NucliSENS EasyQ® Enterovirus v1.1 were not provided to the attending physicians, and did not influence the final diagnosis.
Summary of Performance Studies
Clinical study:
Sample size: 520 pediatric subjects (0 to 21 years of age). 449 prospectively collected CSF specimens and 71 retrospectively collected CSF specimens.
Key results:
Prospectively collected CSF specimens (n=449):
Sensitivity: EasyQ vs. Clinical Diagnosis (148/183) = 80.9%, CI = 74.4 - 86.3%
Specificity: EasyQ vs. Clinical Diagnosis (265/266) = 99.6%, CI = 97.9 - 99.9%
EasyQ Positive Predictive Value with Clinical Diagnosis (148/149) = 99.3%, CI = 96.3 - 99.9%
EasyQ Negative Predictive Value with Clinical Diagnosis (265/300) = 88.3%, CI = 84.1 - 91.7%
Positive Agreement of EasyQ and Cell Culture (114/132) = 86.4%, CI = 79.3 - 91.7%
Negative Agreement of EasyQ and Cell Culture (282/317) = 89.0%, CI = 85.0 - 92.2%
Retrospectively collected CSF specimens (n=71):
Sensitivity: EasyQ vs. Clinical Diagnosis (19/19) = 100.0%, CI = 82.4 - 100.0%
Specificity: EasyQ vs. Clinical Diagnosis (51/52) = 98.1%, CI = 89.7 - 99.9%
Positive Agreement of EasyQ and Cell Culture (18/18) = 100.0%, CI = 81.5 - 100.0%
Negative Agreement of EasyQ and Cell Culture (51/53) = 96.2%, CI = 87.0 - 99.5%
Reproducibility study:
Sample size: 48 replicates for each of the 7 panel members (48 for each serotype at LoD 95%, 48 for Cox A9 moderate, 48 for Cox A9 low, 48 for negative panel). 31 replicates for negative control and positive control.
Study type: Reproducibility study using a panel with representative strains from four Enterovirus serotypes, tested at three sites by one investigator per site, in duplicate for 4 days using two reagent kit lots.
Key results:
Variability within runs was the major source of variability. Variability between sites, between lots, and between test days contributed little additional variability.
Analytical sensitivity: Limit of Detection (LoD):
Study type: A range-finding study and verification testing for LoD 95% for 22 serotypes.
Key results: LoD 95% values determined for various serotypes ranging from 0.01 pfu to 717 pfu or 12.4 TCID50.
Analytical reactivity: Additional Enterovirus Serotypes:
Study type: Detection of additional Enterovirus Serotypes.
Key results: The assay was able to detect Enterovirus 68 and Polioviruses 1, 2, and 3 at specified concentrations, and other Coxsackie, Echovirus, and Enterovirus strains at unknown concentrations.
Potentially Interfering Substances:
Study type: Evaluation of potentially interfering substances (proteins, bilirubin, white blood cells, whole blood).
Key results: Elevated levels of tested substances did not interfere with the detection of Enterovirus RNA.
Analytical specificity: Potentially Interfering Substances:
Study type: Cross-reactivity assessment with various microorganisms known to cause central nervous system infections.
Key results: Overall specificity was 100% (28 of 28 types of interfering substances). The assay cross-reacted with 4 of 88 tested Rhinovirus strains, however, human cerebrospinal fluid is not the normal viral reservoir for rhinoviruses, and rhinoviruses are not a recognized cause of meningitis.
Key Metrics
Sensitivity:
For prospectively collected CSF specimens: 80.9% (74.4 - 86.3% CI)
For retrospectively collected CSF specimens: 100.0% (82.4 - 100.0% CI)
Specificity:
For prospectively collected CSF specimens: 99.6% (97.9 - 99.9% CI)
For retrospectively collected CSF specimens: 98.1% (89.7 - 99.9% CI)
Positive Predictive Value:
For prospectively collected CSF specimens: 99.3% (96.3 - 99.9% CI)
Negative Predictive Value:
For prospectively collected CSF specimens: 88.3% (84.1 - 91.7% CI)
Limit of Detection (LoD):
Coxsackie A9: 0.6 TCID50
Coxsackie B5: 3 pfu
Echovirus 30: 46 pfu
Enterovirus 71: 2 TCID50
And others for 18 additional serotypes ranging from 0.01 pfu to 717 pfu or 12.4 TCID50.
Predicate Device(s)
Cell Culture for Enterovirus Detection [pre-amendment test method; no 510(k) applies]
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 866.3225 Enterovirus nucleic acid assay.
(a)
Identification. An enterovirus nucleic acid assay is a device that consists of primers, probes, enzymes, and controls for the amplification and detection of enterovirus ribonucleic acid (RNA) in cerebrospinal fluid (CSF) from individuals who have signs and symptoms consistent with meningitis or meningoencephalitis. The detection of enterovirus RNA, in conjunction with other laboratory tests, aids in the clinical laboratory diagnosis of viral meningitis caused by enterovirus.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Nucleic Acid Amplification Assay for the Detection of Enterovirus RNA.” See § 866.1(e) for the availability of this guidance document.
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Image /page/0/Picture/0 description: The image shows the logo for bioMérieux. The logo consists of a stylized image of a sphere with a vertical line running through it. The text "bioMérieux" is written in all caps below the image. The font is sans-serif.
JUN 2 3 2008
510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K063261.
TABLE OF CONTENTS
| NAME OF DEVICE | |
|---|---|
| CLASSIFICATION | |
| INTENDED USE OF THE DEVICE | |
| DEVICE TO WHICH EQUIVALENCE IS CLAIMED | |
| DESCRIPTION OF THE DEVICE | |
| Device Description: miniMAG sample preparation | |
| Device Description: EasyQ amplification and detection | |
| Device Description: Controls | |
| CLINICAL PERFORMANCE | |
| Clinical Study Design | |
| Agreement of EasyQ test with Cell Culture vs. Clinical Diagnosis | |
| NucliSENS Enterovirus Test Results by Age and Gender | |
| Expected Values | |
| PERFORMANCE CHARACTERISTICS OF THE ASSAY | |
| Reproducibility | |
| Analytical sensitivity: Limit of Detection (LoD) | |
| Analytical reactivity: Additional Enterovirus Serotypes | |
| Potentially Interfering Substances | |
| Analytical specificity: Potentially Interfering Substances | |
| Specimen Stability | |
| LIMITATIONS OF THE PROCEDURE | |
| REFERENCES |
100 Rodolphe St., Durham, NC 27712 Tel: 919-620-2000 Fax: 919-620-2548
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Name of device
NucliSENS EasyQ® Enterovirus v1.1 Assay, including the following components:
NucliSENS EasyQ® Enterovirus v1.1 NucliSENS EasyQ® Enterovirus Controls NucliSENS EasyQ® Analyzer NucliSENS EasyQ® Director Software 2.5 NucliSENS EasyQ® Incubator NucliSENS miniMAG® NucliSENS® Lysis Buffer 48T NucliSENS® Magnetic Extraction Reagents
Classification
Assay, enterovirus nucleic acid
Intended Use of the Device
The NucliSens EasyQ Enterovirus v1.1 Assay is an in vitro nucleic acid amplification assay to be used in conjunction with the NucliSens EasyQ System for the qualitative detection of Enterovirus RNA in cerebral spinal fluid (CSF) specimens in patients with signs and symptoms of meningitis. This test, in conjunction with other laboratory results and clinical information, may be used as an aid in the presumptive laboratory diagnosis of enterovirus infection in pediatric patients with a clinical suspicion of aseptic meningitis or aseptic meningioencephalitis.
Negative results should be confirmed by cell culture.
Assay performance characteristics have not been established for adults, or for immunocompromised or immunosuppressed patients.
Caution: The results obtained with the NucliSens EasyQ Enterovirus v1.1 Assay should be used only as an adjunct to clinical observation and other information available to the physician. Positive results do not rule out other causes of meningitis, including bacteria, mycobacteria, other viruses (e.g. herpes family viruses, arboviruses, mumps virus, etc.) and fungi.
Device to which equivalence is claimed
Cell Culture for Enterovirus Detection [pre-amendment test method; no 510(k) applies]
Description of the Device
NucliSENS EasyQ® Enterovirus v1.1 is an in-vitro diagnostic assay which uses nucleic acid amplification combined with a simultaneous detection step to detect the presence of enteroviral RNA in eluates derived from cerebrospinal fluid or appropriate control material. The assay requires extracted nucleic acid as input material, and has
K063261: 510(k) Summary
Prepared 17-Jun-2008
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been validated using nucleic acid eluates extracted from clinical specimens with NucliSENS® miniMAG™. The amplification step is performed using the NucliSENS EasyQ System.
Device Description: miniMAG sample preparation
NucliSENS® miniMAG™ utilizes NucliSENS® Lysis Buffer and magnetized silica beads to extract nucleic acids from lysed biological specimens, according to the operating principles initially described by Boom et al. 1 The end product of a NucliSENS® miniMAG™ extraction is an eluate containing total nucleic acid (DNA+RNA) from the specimen.
Device Description: EasyQ amplification and detection
The NucliSENS® easyQ™ System utilizes Nucleic Acid Sequence-Based Amplification (NASBA) and detection of fluorescence from specific molecular beacons to signal the presence of target nucleic acid sequences. The NASBA reaction requires the use of specific reagents, including the enzymes, primers and probes which are components of the NucliSENS EasyQ" Enterovirus v1.1 assay. Reactions are performed in closed tubes in a NucliSENS EasyQ® Analyzer in which fluorescence is measured in real-time. NucliSENS EasyQ® Director Software, in combination with NucliSENS EasyQ® Enterovirus v1.1 assav software, provides automated analysis of the resulting fluorescence signal curves and reporting of assay results.
Device Description: Controls
The NucliSENS® easyQ™ System utilizes 3 types of controls:
- Internal Control RNA, provided as a component of the NucliSENS EasyQ® . Enterovirus v1.1 kit, is used to monitor nucleic acid extraction and subsequent amplification. The Enterovirus Internal Control RNA is co-extracted and co-amplified along with any Wild Type Enterovirus RNA present in the eluted nucleic acids. This Internal Control RNA differs from the Enterovirus Wild Type RNA by only a short nucleotide sequence designed to ensure similar amplification kinetics. Primer binding sites on the Internal Control RNA and Enterovirus RNA are identical, but the probe binding sequence differs, allowing differentially labeled molecular beacons (provided in the kit) to differentially detect the amplicons from wild-type Enteroviral RNA versus the Internal Control.
- Negative and Positive Controls: NucliSENS EasyQ® Enterovirus Controls are . an external negative and external positive control (nuclease-free water and synthetic enteroviral RNA transcript, respectively) designed for use with the NucliSENS EasyQ Enterovirus v1.1 to monitor the performance of the assay. When used as directed, the positive control is present in the test at 3x LoD (95% Limit of Detection) for this transcript. The Positive Control provides quality assurance for the amplification and detection procedures of the assay, for the extraction reagents, and for the NucliSENS EasyMAG® instrument operation. The Positive Control does not provide quality assurance for viral lysis or for the efficiency of RNA extraction from virions. NucliSENS EasyQ® Enterovirus Controls are bioMérieux products which are sold separately from the NucliSENS EasyQ® Enterovirus v1.1 kit.
K063261: 510(k) Summary
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- Lysis and Viral Extraction Controls: The NucliSENS EasyQ® Enterovirus � Positive Control does not provide quality assurance for viral lysis or for the efficiency of RNA extraction from virions therefore we recommend the use of any one of 4 viral strains, available from ATCC, which have been shown to be appropriate for use as a control for lysis and extraction of virions in the NucliSENS EasyQ Enterovirus v1.1 test, as described in the Instructions for Use provided with the NucliSENS EasyQ® Enterovirus v1.1 test.
Clinical Performance
Clinical Study Design
At six clinical sites, the NucliSENS EasyQ® Enterovirus v1.1 assay and cell culture (with identification by immunofluorescence [IFA] ) were used to evaluate cerebrospinal fluid (CSF) specimens from 520 pediatric subjects (0 to 21 years of age) who presented with signs and/or symptoms consistent with suspected aseptic meningitis (for example, fever, headache, stiff neck). Most (449/520 = 86.3%) CSF specimens were prospectively collected for this study and tested while fresh. However a minority (71/520 = 13.7%) had been previously collected and stored at -70°C prior to testing for this study. The six clinical sites were located in Ohio, Missouri, Texas (2 sites), Nebraska and California. Testing was performed at hospital laboratories associated with the testing sites in 2004-2005.
Bacteria gram stain, bacteria culture, and CSF profile (profein mg/dL, glucose mg/dL, white blood cell count, differential) were also collected for the overwhelming majority of patients. For many patients, serum glucose, white blood cell (WBC) count, complete blood cell (CBC) profile and CBC profile differential were also determined. At 5 of 6 clinical testing sites, the attending physicians ordered laboratory-developed tests for detection of enterovirus nucleic acid.
For each subject, the final diagnosis, as determined by the attending physicians based on signs and symptoms as well as laboratory testing results, was reported to the study investigator. Results from the NucliSENS EasyQ® Enterovirus v1.1 were not provided to the attending physicians, and did not influence the final diagnosis.
Agreement of EasyQ test with Cell Culture vs. Clinical Diagnosis
Results from the clinical study are presented below. Results from the NucliSENS EasyQ Enterovirus v1.1 are compared against results from cell culture (coupled with immunofluorescent detection), and against the clinical diagnoses assigned by the attending physicians. Among 449 prospectively collected specimens, the NucliSENS EasyQ Enterovirus v1.1 displayed 80.9% sensitivity and 99.6% specificity versus clinical diagnosis. Additional data and analyses of the agreement between the NucliSENS EasyQ® Enterovirus v1.1, cell culture, and clinical diagnosis are presented in Table 1 and Table 2 below.
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Table 1 Prospectively collected CSF specimens: EasyQ vs. Cell Culture and Clinical Diagnosis
| NucliSENS EasyQ
Enterovirus v1.1 | CSF
Cell Culture + IFA | Total
Patients | Clinical Diagnosis | |
|-------------------------------------|---------------------------|-------------------|--------------------|----------|
| | | | Positive | Negative |
| + | + | 114 | 114 | 0 |
| + | - | 35 | 34 | 1 |
| - | + | 18 | 17 | 1 |
| - | - | 282 | 18 | 264 |
| Total | | 449 | 183 | 266 |
| Agreement of tests or of EasyQ/Clinical Diagnosis
(Prospectively collected CSF specimens, n=449) | Percent
Agreement | Confidence
Interval‡ |
|-----------------------------------------------------------------------------------------------------|----------------------|-------------------------|
| Sensitivity: EasyQ vs. Clinical Diagnosis (148/183) | 80.9% | 74.4 - 86.3% |
| Specificity: EasyQ vs. Clinical Diagnosis (265/266) | 99.6% | 97.9 - 99.9% |
| EasyQ Positive Predictive Value with Clinical Diagnosis (148/149) | 99.3% | 96.3 - 99.9% |
| EasyQ Negative Predictive Value with Clinical Diagnosis (265/300) | 88.3% | 84.1 - 91.7% |
| Positive Agreement of EasyQ and Cell Culture (114/132) | 86.4% | 79.3 - 91.7% |
| Negative Agreement of EasyQ and Cell Culture (282/317)‡ | 89.0% | 85.0 - 92.2% |
*Confidence interval for the percent agreement noted in the previous column
Retrospectively collected CSF specimens: EasyQ vs. Cell Culture Table 2 and Clinical Diagnosis
| NucliSENS EasyQ
Enterovirus v1.1 | CSF
Cell Culture + IFA | Total
Patients | Clinical Diagnosis | |
|-------------------------------------|---------------------------|-------------------|--------------------|----|
| + | + | 18 | 18 | 0 |
| + | - | 2 | 1 | 1 |
| - | + | 0 | 0 | 0 |
| - | - | 51 | 0 | 51 |
| Total | | 71 | 19 | 52 |
| Agreement of tests or of EasyQ/Clinical Diagnosis
(Retrospectively collected CSF specimens, n=71) | Percent
Agreement | Confidence
Interval‡ |
|------------------------------------------------------------------------------------------------------|----------------------|-------------------------|
| Sensitivity: EasyQ vs. Clinical Diagnosis (19/19) | 100.0% | 82.4 - 100.0% |
| Specificity: EasyQ vs. Clinical Diagnosis (51/52) | 98.1% | 89.7 - 99.9% |
| Positive Agreement of EasyQ and Cell Culture (18/18) | 100.0% | 81.5 - 100.0% |
| Negative Agreement of EasyQ and Cell Culture (51/53) | 96.2% | 87.0 - 99.5% |
*Confidence interval for the percent agreement noted in the previous column
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NucliSENS Enterovirus Test Results by Age and Gender
The performance of the NucliSENS EasyQ Enterovirus v1.1 test as compared to clinical diagnosis was assessed for newborns, infants, children and adolescents. Results are shown in Table 3 below. Results for prospectively collected (fresh) specimens are presented separately from retrospectively collected (banked) specimens.
| Prospective (Fresh) | Retrospective (Banked) | |||
|---|---|---|---|---|
| Age Group* | Sensitivity | Specificity | Sensitivity | Specificity |
| Newborn | ||||
| (0-27 days) | 80.0% | |||
| (40/50) | ||||
| CI = 66.3-90.0% | 100.0% | |||
| (62/62) | ||||
| CI = 94.2-100.0% | 100.0% | |||
| (8/8) | ||||
| CI = 63.1-100.0% | 94.7% | |||
| (18/19) | ||||
| CI = 74.0-99.9% | ||||
| Infant/Toddler | ||||
| (28 days-23 months) | 70.9% | |||
| (61/86) | ||||
| CI = 60.1-80.2% | 99.3% | |||
| (143/144) | ||||
| CI = 96.2-99.9% | 100.0% | |||
| (10/10) | ||||
| CI = 69.2-100.0% | 100.0% | |||
| (21/21) | ||||
| CI = 83.9-100.0% | ||||
| Child | ||||
| (2-11 years) | 100.0% | |||
| (37/37) | ||||
| CI = 90.5-100.0% | 100.0% | |||
| (46/46) | ||||
| CI = 92.3-100.0% | 100.0% | |||
| (1/1) | ||||
| CI = 2.5-100.0% | 100.0% | |||
| (12/12) | ||||
| CI = 73.5-100.0% | ||||
| Adolescent | ||||
| (12-21 years) | 100.0% | |||
| (10/10) | ||||
| CI = 69.2-100.0% | 100.0% | |||
| (14/14) | ||||
| CI = 76.8-100.0% | NA | NA |
Table 3 Clinical Performance of EasyQ Enterovirus v1.1 by subject age groups
*Pediatric age groups as defined by ICH E11: International Conference on Harmonization, Guidance E11: Clinical Investigation of Medicinal Products in the Pediatric Population
NOTE: Each data cell shows:
(1) % agreement between EasyQ and Clinical Diagnosis
(2) # specimens in agreement / total # positive by Clinical Diagnosis (for sensitivity) OR
specimens in agreement / total # negative by Clinical Diagnosis (for specificity) (3) 95% confidence interval
Expected Values
Five-hundred twenty pediatric specimens from 6 clinical trial sites were tested with the NucliSENS EasyQ Enterovirus v1.1. Of these samples, 449 were prospectively collected clinical samples. Seventy-one specimens were previously collected at a single trial site. There was no statistically significant different between performance characteristics for prospectively versus retrospectively collected specimens. For each age and gender group listed, the number and percentage of specimens yielding positive results with the NucliSENS EasyQ Enterovirus v1.1 test are shown in Table 4 below.
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| Age Group* | Gender | Prospective
Positive n (%) | Prospective
Total | Retrospective
Positive n (%) | Retrospective
Total |
|---------------------------------------|--------|-------------------------------|----------------------|---------------------------------|------------------------|
| Newborn
(0-27 days) | M | 24 (41%) | 59 | 5 (31%) | 16 |
| Newborn
(0-27 days) | F | 16 (30%) | 53 | 4 (36%) | 11 |
| Infant/Toddler
(28 days-23 months) | M | 34 (27%) | 124 | 7 (35%) | 20 |
| Infant/Toddler
(28 days-23 months) | F | 28 (26%) | 106 | 3 (27%) | 11 |
| Child
(2-11 years) | M | 22 (45%) | 49 | 1 (8%) | 12 |
| Child
(2-11 years) | F | 15 (44%) | 34 | 0 (0%) | 1 |
| Adolescent
(12-21 years) | M | 5 (45%) | 11 | 0 (0%) | 0 |
| Adolescent
(12-21 years) | F | 5 (38%) | 13 | 0 (0%) | 0 |
| Total | both | 149 | 449 | 20 | 71 |
Table 4 NucliSENS EasyQ Enterovirus v1.1 Test Results by Age and Gender
*Pediatric age groups as defined by ICH E11: International Conference on Harmonization, Guidance E11: Clinical Investigation of Medicinal Products in the Pediatric Population
Performance Characteristics of the Assay
Reproducibility
A reproducibility study was conducted using a panel with representative strains from four Enterovirus serotypes: Coxsackie A9, Coxsackie B5, Echovirus 30, and Enterovirus 71. Titered stocks were diluted to the estimated 95 % Limit of Detection for each strain. Two additional panel members were prepared to detect reproducibility at lower hit rates, using using lower concentrations of Coxsackie A9 (these samples were 0.1 TCIDso and 0.02 TCID30, versus LoD 95% = 0.4 TCIDg). Testing was performed at three sites. At each evaluation site, one investigator conducted the evaluation. Each panel member was tested in duplicate for four (4) days by each investigator using two reagent kit lots. Each of the 7 panel members was tested in duplicate in each of 4 days (one run per day) with 2 lots at each of 3 sites. Each of the controls was tested in singlicate in each day (one run per day) with 2 lots at each of 3 sites.
Fluorescence values in the EasyQ system are not reported to users as part of the test output. However for this analysis, fluorescence values were retrieved from the instrument memory and were subjected to variance components analysis. For each panel member and for each control, variance components analysis was used to estimate total variability and variability due to site, lot, run within lot (test day), and (for panel members only) duplicates within run. For the sources of variability with estimates of zero for the standard deviation (SD) and zero for the coefficient of variation (CV%), the zeros indicate instances of negative variance components. Variation due to these sources was negligible relative to the other sources of variation.
Variance components analysis indicated that variability within runs (i.e., between replicates for single specimens) was the major source of variability in this precision experiment. Variability between sites, between lots, and between test days contributed little additional variability to the total.
Table 5 below presents qualitative results from this experiment based on positive versus neqative result output. The table also shows the mean fluorescence values obtained for testing with different panel specimens, and variance components analysis of the variability in these fluorescence values. Relative contributions to variability in
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fluorescence signals from variability within runs, between test days, between lots and between sites are shown.
| | N | Total
Positive | 95%
CI | Mean
Value* | Within Run | | Between
Days | | Between
Lots | | Between
Sites | | Total | |
|----------------------|----|-------------------|----------------|----------------|------------|------|-----------------|------|-----------------|------|------------------|------|-------|------|
| | | | | | SD | CV% | SD | CV% | SD | CV% | SD | CV% | SD | CV% |
| Cox A9
LoD 95% | 48 | 100%
(48/48) | 92.6-
100% | 3.56 | 0.81 | 22.9 | 0.48 | 13.5 | 0.60 | 16.8 | 0.26 | 7.3 | 1.06 | 29.7 |
| Cox A9
moderate | 48 | 85%
(41/48) | 72.2-
93.9% | 1.98 | 0.51 | 25.8 | 0.36 | 18.4 | 0 | 0 | 0.25 | 12.6 | 0.66 | 33.3 |
| Cox A9
low | 48 | 23%
(11/48) | 12.0-
37.3% | 1.36 | 0.37 | 27.0 | 0 | 0 | 0 | 0 | 0 | 0 | 0.37 | 27.0 |
| Cox B5
LoD 95% | 48 | 94%
(45/48) | 82.8-
98.7% | 2.81 | 1.04 | 37.1 | 0 | 0 | 0 | 0 | 0 | 0 | 1.04 | 37.1 |
| Echo 30
LoD 95% | 48 | 98%
(47/48) | 88.9-
99.9% | 2.68 | 0.65 | 24.3 | 0 | 0 | 0.04 | 1.6 | 0.67 | 24.8 | 0.85 | 31.8 |
| Entero 71
LoD 95% | 48 | 88%
(42/48) | 74.8-
95.3% | 2.18 | 0.47 | 21.5 | 0.61 | 28.0 | 0 | 0 | 0 | 0 | 0.75 | 34.5 |
| Negative
Panel | 48 | 0%
(0/48) | 0-
7.4% | 1.17 | 0.03 | 2.4 | 0.03 | 2.8 | 0 | 0 | 0.02 | 1.3 | 0.04 | 3.8 |
| Negative
Control | 31 | 0%
(0/31) | 0-
11.2% | 1.17 | N/A | N/A | 0.04 | 3.4 | 0.02 | 1.9 | 0.00 | 0.2 | 0.04 | 3.7 |
| Positive
Control | 31 | 100%
(31/31) | 88.8-
100% | 4.91 | N/A | N/A | 1.30 | 26.5 | 0.91 | 18.5 | 0 | 0 | 1.45 | 29.6 |
Table 5 Reproducibility results: panel with four Enterovirus serotype strains
- Mean background corrected fluorescence values (recorded on instrument but not reported in user output) SD = standard deviation
CV% = coefficient of variation; 100xSD/mean
Cl = confidence interval
Cox A9 = Coxsackie A9
Cox A9 moderate = 0.1 TCID50 (versus 0.4 TCID50 at LoD 95%)
Cox A9 low = 0.02 TCID50 (versus 0.4 TCID50 at LoD 95%)
Cox B5 = Coxsackie B5
Echo 30 = Echovirus 30
Entero 71 = Enterovirus 71
N/A = not applicable (neqative and positive controls were run in singlicate)
Analytical sensitivity: Limit of Detection (LoD)
One representative serotype from each of the four major serotype groups was evaluated with multiple tests over a concentration range (12 replicates per level) to derive an LoD value for 95% detection. This estimate was then used to conduct additional verification testing at the presumed LoD 95% value (20 replicates per level). LoD 95% values were calculated using Probit regression analysis.
The results of this study are summarized in Table 6.
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| Table 6 95 % LoD values for representative clinically relevant serotypes from |
|---|
| each of the major serotype groups |
| Group | Serotype | Strain | LoD 95 %(a) |
|---|---|---|---|
| Coxsackie A | 9 | P.B. (Bozek) | 0.6 TCID50 |
| Coxsackie B | 5 | Faulkner | 3 pfu |
| Echovirus | 30 | Bastianni | 46 pfu |
| Enterovirus | 71 | BrCr | 2 TCID50 |
pfu = plaque forming unit, TCID50 = Tissue Culture Infectious Dose 50 % (a)
For the remaining 18 serotypes, the LoD 95% values derived in a range-finding study were used as the basis for a more limited verification testing approach by testing two dilutions (20 replicates at each level) near the estimated LoD 95% value. The results of this study are summarized in Table 7.
| Group | Serotype | Strain | LoD 95 %(a) |
|---|---|---|---|
| Coxsackie A | 16 | G-10 | 0.3 TCID50 |
| Coxsackie B | 1 | Conn-5 | 717 pfu |
| Coxsackie B | 2 | Ohio-1 | 2.6 pfu |
| Coxsackie B | 3 | Nancy | 2.5 pfu |
| Coxsackie B | 4 | J.V.B (Benschoten) | 29.3 pfu |
| Echovirus | 3 | Morrisey | 10 pfu |
| Echovirus | 4 | Pesascek | 0.9 pfu |
| Echovirus | 5 | Noyce | 933 pfu |
| Echovirus | 6 | D'Amori | 15.4 pfu |
| Echovirus | 7 | Wallace | 45 pfu |
| Echovirus | 9 | Hill | 0.3 pfu |
| Echovirus | 11 | Gregory | 40 pfu |
| Echovirus | 13 | DelCarmen | 12.4 TCID50 |
| Echovirus | 14 | TOW | 0.2 TCID50 |
| Echovirus | 16 | Harrington | 135 TCID50 |
| Echovirus | 17 | CHHE-29 | 0.02 pfu |
| Echovirus | 18 | D3; Metcalf | 0.01 pfu |
| Echovirus | 25 | JV-4 | 0.3 pfu |
Table 7 Estimated 95 % LoD values for Clinically Relevant Enterovirus serotypes
(a) pfu = plaque forming unit, TCIDso = Tissue Culture Infectious Dose 50 %
Analytical reactivity: Additional Enterovirus Serotypes
An additional study, summarized in Table 8 below, determined that the NucliSENS EasyQ® Enterovirus v1.1 assay was able to detect Enterovirus 68 and Polioviruses 1, 2, and 3 at the concentrations indicated below. The LoD's for these serotypes were not determined. This study also indicated that the NucliSENS EasyQ® Enterovirus v1.1 assay was able to detect a number of other enterovirus strains, listed below. The concentrations of these additional strains was not known.
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| Group | Serotype | TCID50 input |
|---|---|---|
| Enterovirus | 68 | 77 |
| Poliovirus | 1 | 1 |
| Poliovirus | 2 | 1 |
| Poliovirus | 3 | 100 |
| Coxsackie | A2, A3, A4, A6, A7, A8, A10, A11, A12, | |
| A15, A17, A18, A20, A21, A24, B6 | unknown | |
| Echovirus | 1, 2, 12, 15, 19, 20, 21, 24, 26, 27, 29, | |
| 31, 32, 33 | unknown | |
| Enterovirus | 69, 70 | unknown |
Table 8 Detection of Additional Enterovirus Serotypes
Potentially Interfering Substances
A study was conducted with potentially interfering substances encountered in CSF, Substances tested were proteins (albumin, gammaglobulin), bilirubin, white blood cells, and whole blood.
The interferent was tested at different concentration levels with negative CSF. Each interferent was tested at a concentration above that normally seen in clinical cases of enteroviral meningitis. Specimens were spiked with Echovirus 30 virions (100 pfu, approx, 2x LoD) to mimic positive clinical specimens. All unspiked specimens gave valid negative results. The Enterovirus-spiked specimens consistently vielded valid positive results. Elevated levels of the tested substances did not interfere with the detection of Enterovirus RNA by the NucliSENS EasyQ® Enterovirus v1.1 assay even at the highest tested level.
Analytical specificity: Potentially Interfering Substances
Cross-reactivity of various micro-orqanisms known to cause central nervous system infections was assessed. Each potential cross-reacting agent was tested with and without an Enterovirus spike (Echovirus 30 at 2-3x LoD; viral cross-reacting agents at ≥10 TCIDsoj bacterial cross-reacting agents at ≥10 cfu/mL ). Results indicated that the NucliSENS EasyQ® Enterovirus v1.1 assay accurately detected the added Enteroviral RNA in the presence of the potential interfering substances, while vielding no false positives in unspiked specimens. Therefore the overall specificity in this study was 100% (i.e. 28 of 28 types of interfering substances). Microorganisms tested in this study were:
| Haemophilus influenza type b |
|---|
| Streptococcus pneumoniae |
| Neisseria meningitides |
| Escherichia coli |
| Streptococcus agalactiae |
| Klebsiella pneumoniae |
| Staphylococcus aureus |
| Enterobacter sp. |
| Citrobacter sp. |
Proteus sp. Salmonella sp. Pseudomonas sp. Staphylococcus epidermidis Herpes Simplex Virus Type 1 Herpes Simplex Virus Type 2 Varicella Zoster Cytomegalovirus Rotavirus
Rubella Parvovirus B19 West Nile Virus Mumps Measles Cryptococcus neoformans Naegleria fowleri Rhinovirus Encephalomyocarditis virus
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Because of the structural and genetic similarities between enteroviruses and rhinoviruses, cross-reactivity with Rhinoviruses was further assessed with 88 rhinovirus strains, including 13 strains at defined levels of viral input between 100-10,000 TCIDso. The NucliSENS EasyQ® Enterovirus v1.1 assay cross-reacted with 4 of the tested Rhinovirus strains. However, human cerebrospinal fluid is not the normal viral reservoir for rhinoviruses, and rhinoviruses are not a recognized cause of meningitis.23
Specimen Stability
Testing with the NucliSENS EasyQ® Enterovirus v1.1 assay demonstrated that for purposes of detection using this assay, Enterovirus in CSF samples is stable for at least 4 days at 2 - 8°C or for at least 2 months at ≤ -70°C (+/- Lysis Buffer) CSF specimens can be frozen and thawed (freeze/thaw cvcle -70°C / 37°C ) up to two times without measurable loss of Enterovirus RNA.
Limitations of the Procedure
- . Positive results do NOT rule out other non-EV causes of meningitis. Positive results should be interpreted in conjunction with other laboratory findings (e.g., CSF glucose, CSF Gram stains, CSF protein, CSF leukocytes, etc.), and clinical signs or symptoms. In rare instances, meningitis can be caused by co-infection of a viral and bacterial or other agent.
- . False positive test results are more likely when prevalence of disease due to enterovirus is low or non-existent in a community, or outside the enteroviral season.
- . A negative result does not preclude the possibility of the presence of Enterovirus RNA in a sample. For example, only 54% of the cell-culture positive specimens with Coxsackie B5 were detected with the NucliSENS EasyQ® Enterovirus v1.1 assay.
- . Cross-reactivity of this assay with human rhinoviruses does occur. However, human cerebrospinal fluid is not the normal viral reservoir for rhinoviruses, and rhinoviruses are not a recognized cause of meningitis. 2,3
- NucliSENS EasyQ Enterovirus v1.1 has been shown to detect numerous Enterovirus � serotypes (Coxsackie A2, A3, A4, A6, A7, A8, A9, A10, A11, A12, A15, A16, A17, A18, A20, A21, A24; Coxsackie B1, B2, B3, B4, B5; Echovirus 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 24, 25, 26, 27, 29, 30, 31, 32, 33; Enterovirus 68, 69, 70, 71; Poliovirus 1, 2, 3). The ability to detect other diverse Enterovirus serotypes has not been established.
- Results that are positive for enterovirus RNA do not identify a specific enteroviral serotype. .
- The performance of the NucliSENS EasyQ® Enterovirus v1.1 assay was established using . human cerebral spinal fluid. The use of the device with other specimen types (e.g., stool) has not been established.
- Test results from the NucliSENS EasyQ® Enterovirus v1.1 assay should be evaluated in . relation to patient symptoms and clinical history to establish a diagnosis.
- Testing of clinical specimens showed an initial invalid rate of 9%. All invalid results were . resolved using the instructions for retesting as outlined in the Instructions for Use.
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References
1 Boom R, Sol CJ, Saliman MM, Jansen CL, Wertheim-van Dillen PM and Van der Noordaa J (1990). Rapid and simple method for purification of nucleic acids. J. Clin. Microbiol., 28, 495-503.
2 Couch RB. Rhinoviruses. In Fields Virology 4th ed. 2002, D.M. Knipe and P. M Howley, eds, pp. 777-798, Lippincott Williams & Wilkens, Philadelphia.
3 Booss J and Esiri MM Viral Encephalitis in Humans. 2003, p.26, ASM Press, Washington, DC.
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Public Health Service
Food and Druq Administration 2098 Gaither Road Rockville MD 20850
JUN 2 3 2008
Sandra Perreand Senior Director, North American Regulatory Affair bioMerieux, Inc. 595 Anglum Road St. Louis, MO 63042
Re: K063261
Trade/Device Name: NucliSens EasyQ® Enterovirus v1.1 Regulation Number: 21 CFR 866.3225 Regulation Name: Nucleic acid amplification assay system, enterovirus (EV) RNA Regulatory Class: Class II Product Code: OAI Dated: April 30, 2008 Received: May 1, 2008
Dear Ms. Perreand:
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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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 attaym
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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INDICATIONS FOR USE STATEMENT
510(k) Number (if known): K063261
Device Name: NucliSENS EasyQ® Enterovirus v1.1
Indications For Use: The NucliSens EasyQ® Enterovirus v1.1 Assay is an in vitro nucleic acid amplification assay to be used in conjunction with the NucliSens EasyQ® System for the qualitative detection of Enterovirus RNA in cerebral spinal fluid (CSF) specimens in patients with signs and symptoms of meningitis. This test, in conjunction with other laboratory results and clinical information, may be used as an aid in the presumptive laboratory diagnosis of enterovirus infection in pediatric patients with a clinical suspicion of aseptic meningitis or aseptic meningioencephalitis.
Negative results should be confirmed by cell culture.
Assay performance characteristics have not been established for adults, or for immunocompromised or immunosuppressed patients.
Caution: The results obtained with the NucliSens EasyQ Enterovirus v1.1 Assay should be used only as an adjunct to clinical observation and other information available to the physician. Positive results do not rule out other causes of meningitis, including bacteria, mycobacteria, other viruses (e.g. herpes family viruses, arboviruses, mumps virus, etc) and fungi).
Prescription Use X Prescription Use _____________________________________________________________________________________________________________________________________________________________
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Uve Schif
Division Sign Off
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Office of In Vitro Diagnostic Device Evaluation and Safety
12063261 510(k)_