(102 days)
The artus C. difficile QS-RGQ MDx Kit is an in vitro polymerase chain reaction (PCR) assay for use on the QIAsymphony RGQ MDx system for the qualitative detection of toxigenic Clostridium difficile toxin A and toxin B genes in human liquid or soft stool specimens from patients suspected of having Clostridium difficile associated disease. The test is intended to be used directly on patient samples.
The artus C. difficile QS-RGQ MDx Kit is intended to be used to aid in diagnosis of Clostridium difficile infection.
The artus C. difficile QS-RGQ MDx Kit assay uses PCR to generate an amplified product from the tcdA and tedB/tedBv genes of toxigenic C. difficile DNA in clinical specimens. Samples are extracted and prepared using the Q1Asymphony SP instrument with the QIAsymphony DSP Virus/Pathogen Mini Kit, followed by assay setup on the OIAsymphony AS. Amplification and detection are carried out using the artus C. difficile OS-RGQ MDx Kit with the Rotor-Gene Q MDx (RGQ MDx) and Rotor-Gene AssayManager software. The presence of a toxigenic C. difficile target sequence is indicated by the fluorescent signal generated through the use of fluorescently labeled oligonucleotide probes. The probes do not generate a signal unless they are specifically bound to the amplified product. The amplification cycle at which fluorescent signal is detected by the RGQ MDx is inversely proportional to the toxigenic C. difficile DNA target concentration present in the original specimen. A bacterial species unrelated to toxigenic C. difficile is introduced into each specimen during sample preparation to serve as an internal control. The internal control bacteria are lysed simultaneously with toxigenic C. difficile in the specimen. and amplified in the same reaction as the C. difficile targets using PCR, and serve to demonstrate that the entire assay process has proceeded correctly for each specimen.
Here's a summary of the acceptance criteria and study details for the QIAGEN artus® C. difficile QS-RGQ MDx Kit, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria (e.g., "Sensitivity must be >X%", "Specificity must be >Y%"). Instead, it reports the device's performance against a comparative method (enriched toxigenic culture and direct toxigenic culture) for the purpose of demonstrating substantial equivalence to a predicate device.
However, based on the provided clinical performance tables, we can present the reported performance:
| Metric | Performance vs. Enriched Toxigenic Culture (95% CI) | Performance vs. Direct Toxigenic Culture (95% CI) |
|---|---|---|
| Sensitivity | 90% (83% - 94%) | 99% (94% - 100%) |
| Specificity | 97% (96% - 98%) | 97% (95% - 98%) |
| Positive Predictive Value (PPV) | 87% (80% - 92%) | 80% (71% - 87%) |
| Negative Predictive Value (NPV) | 98% (96% - 99%) | 100% (99% - 100%) |
| Prevalence | 17% (15% - 20%) | 12% (10% - 15%) |
2. Sample Size and Data Provenance for the Test Set
- Sample Size (for clinical evaluation):
- Initially, 759 liquid or soft stool specimens were collected.
- 10 specimens were withdrawn due to missing results.
- 16 specimens reported an invalid result with the artus kit (8 became valid upon retesting as negative, 8 remained invalid).
- The final dataset for performance analysis included 741 specimens (for comparison against enriched culture).
- For comparison against direct culture, 699 specimens were available.
- Data Provenance: The specimens were collected from 5 geographically diverse locations within the United States in 2013. The study was prospective as it involved collecting specimens from patients suspected of having Clostridium difficile-associated disease for concurrent testing.
3. Number of Experts and Qualifications for Ground Truth
The document does not mention the use of "experts" in the sense of clinicians or radiologists establishing ground truth. The "ground truth" for the clinical study was established by laboratory methods: enriched toxigenic culture and direct toxigenic culture. For discordant results, alternative PCR followed by bi-directional sequencing was used to resolve discrepancies. The qualifications of the personnel performing these laboratory tests are not specified, but it can be inferred they were trained laboratory technicians.
4. Adjudication Method for the Test Set
For discordant results in the clinical comparison studies:
- Discordant Analysis: An "alternative PCR followed by bi-directional sequencing" was used.
- Enriched Culture Comparison:
- For 17 specimens that were artus Positive/Enriched Culture Negative, 12 were found positive by alternative PCR, agreeing with artus.
- For 12 specimens that were artus Negative/Enriched Culture Positive, 10 were found negative by alternative PCR, agreeing with artus. One specimen was unavailable for testing.
- Direct Culture Comparison:
- For 19 specimens that were artus Positive/Direct Culture Negative, 14 were found positive by alternative PCR, agreeing with artus. Two specimens were unavailable for testing.
- The 1 specimen that was artus Negative/Direct Culture Positive was unavailable for testing.
This method resembles a third-party arbitration/adjudication (2+1 or similar logic) where an additional, more definitive test (alternative PCR + sequencing) was used to resolve disagreements between the index test (artus kit) and the primary comparator (culture).
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. This device is an in vitro diagnostic (IVD) assay that provides a quantitative or qualitative result, not an image-based diagnostic read by human observers. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.
6. Standalone Performance
Yes, the studies reported demonstrate the standalone performance of the algorithm (the artus C. difficile QS-RGQ MDx Kit). The clinical performance tables compare the kit's results directly against culture methods, without human interpretation for the artus kit's output.
7. Type of Ground Truth Used
The primary ground truth for the clinical studies was laboratory culture results, specifically:
- Enriched Toxigenic Culture
- Direct Toxigenic Culture
- For discordant cases, a more definitive molecular method, alternative PCR followed by bi-directional sequencing, was used as a confirmatory "reference standard" to resolve discrepancies.
8. Sample Size for the Training Set
The document does not specify the sample size used for any training set. This information is typically proprietary to the manufacturer's algorithm development process and is not always disclosed in 510(k) summaries for IVD devices. The studies described are performance validation studies, not algorithm training studies.
9. How Ground Truth for the Training Set Was Established
As the sample size for a training set is not provided, the method for establishing its ground truth is also not described.
{0}------------------------------------------------
QIAGIEN artus® C. difficile QS-RGQ MDx Kit Attachment 1. Revised 510(k) Summary
510(k) Submission K 133936 Amendment Page 1 of 15
510(k) SUMMARY
General Information
| Submitted by: | QIAGEN GmbHQiagen Strasse 1Hilden, Germany D-40724 |
|---|---|
| --------------- | ------------------------------------------------------------ |
Contact Person:
Kimberly Mapp, Ph.D. Manager, Regulatory Affairs 1201 Clopper Road Gaithersburg, MD 20878
Phone: 301.944.7817 Fax: 240.686.3847 Email: kimberly.mapp(@qiagen.com
April 4, 2014 Date Prepared:
Device Name:
artus® C. difficile QS-RGQ MDx Kit
artus® C. difficile QS-RGQ MDx Kit Trade Name: Common Name: C. difficile nucleic acid amplification test assay Classification: Class II
Predicate Device
| Manufacturer | Product Name | 510(k) No. |
|---|---|---|
| Quidel | Quidel Molecular Direct C. difficile Assay | K123998 |
Device Description
The artus C. difficile QS-RGQ MDx Kit assay uses PCR to generate an amplified product from the tcdA and tedB/tedBv genes of toxigenic C. difficile DNA in clinical specimens. Samples are extracted and prepared using the Q1Asymphony SP instrument with the QIAsymphony DSP Virus/Pathogen Mini Kit, followed by assay setup on the OIAsymphony AS. Amplification and detection are carried out using the artus C. difficile OS-RGQ MDx Kit with the Rotor-Gene Q MDx (RGQ MDx) and Rotor-Gene AssayManager software. The presence of a toxigenic C. difficile target sequence is indicated by the fluorescent signal generated through the use of fluorescently labeled oligonucleotide probes. The probes do not generate a signal unless they are specifically bound to the amplified product. The amplification cycle at which fluorescent signal is
APR 0 4 2014
{1}------------------------------------------------
| QIAGEN | 510(k) Submission |
|---|---|
| artus® C. difficile QS-RGQ MDx Kit | K133936 Amendment |
| Attachment 1, Revised 510(k) Summary | Page 2 of 15 |
detected by the RGQ MDx is inversely proportional to the toxigenic C. difficile DNA target concentration present in the original specimen. A bacterial species unrelated to toxigenic C. difficile is introduced into each specimen during sample preparation to serve as an internal control. The internal control bacteria are lysed simultaneously with toxigenic C. difficile in the specimen. and amplified in the same reaction as the C. difficile targets using PCR, and serve to demonstrate that the entire assay process has proceeded correctly for each specimen.
Intended Use
The artus C. difficile QS-RGQ MDx Kit is an in vitro polymerase chain reaction (PCR) assay for use on the OlAsymphony RGO MDx system for the qualitative detection of toxigenic Clostridium difficile toxin A and toxin B genes in human liquid or soft stool specimens from patients suspected of having Clostridium difficile associated disease. The test is intended to be used directly on patient samples.
The artus C. difficile QS-RGQ MDx Kit is intended to be used to aid in diagnosis of Clostridium difficile infection.
Comparison of the artus® C. difficile QS-RGQ MDx Kit and the Predicate Device
The artus® C. difficile QS-RGQ MDx Kit is substantially equivalent to the predicate device:
- · K123998: Ouidel Molecular Direct C. difficile Assay
Similarities and differences between the artus® C. difficile QS-RGQ MDx Kit (72) and the predicate device are shown in Table 1.
{2}------------------------------------------------
Table 1: Comparison of the artus® C. difficile QS-RGQ MDx Kit with the predicate device.
| Characteristic | Device | Predicate |
|---|---|---|
| Name | artus C. difficile QS-RGQ MDx Kit | Quidel Molecular Direct C. difficile Assay |
| 510(k) No. | TBD | K123998 |
| Regulation | 866.3130 | 866.3130 |
| Product Code | OZN | OZN |
| Device Class | Class II | Class II |
| Similarities | ||
| Intended Use | The artus C. difficile QS-RGQ MDx Kit is an in vitro polymerase chain reaction (PCR) assay for use on the QIAsymphony RGQ MDx system for the qualitative detection of toxigenic Clostridium difficile toxin A and toxin B genes in human liquid or soft stool specimens from patients suspected of having Clostridium difficile associated disease. The test is intended to be used directly on patient samples. The artus C. difficile QS-RGQ MDx Kit is intended to be used to aid in diagnosis of Clostridium difficile infection. | The Quidel Molecular Direct C. difficile Assay is a qualitative, multiplexed in vitro diagnostic test for the direct detection of toxin A gene ( tcdA ) or toxin B gene ( tcdB ) sequences of toxigenic strains of Clostridium difficile from unformed (liquid or soft) stool specimens collected from patients suspected of having Clostridium difficile-Associated Disease (CDAD). The Quidel Molecular Direct C. difficile Assay is a real-time PCR test and utilizes proprietary sample preparation with fluorescently labeled primers and probes. The assay can be performed using either the Life Technologies QuantStudio® Dx; the Applied Biosystems 7500 Fast Dx, or the Cepheid SmartCycler II, to detect the toxin gene sequences associated with toxin-producing C. difficile strains. The assay is intended to be performed directly on CDAD-suspected stool specimens, and is indicated for use as an aid in the diagnosis of CDAD. |
| Specimen Type | Liquid or soft stool | Unformed (liquid or soft) stool |
| Characteristic | Device | Predicate |
| Assay Targets | Toxin A gene ( tcdA )Toxin B gene ( tcdB and tcdBv ) | Toxin A gene ( tcdA )Toxin B gene ( tcdB ) |
| Amplification and Detection Technology | Real-time PCR DNAamplification | Real-time PCR DNAamplification |
| Differences | ||
| Assay Controls | Positive Control, Negative Control and Internal Control included in the kit. | Process Control included in the kit.Positive and Negative Controls not included in kit; separate control kit available for sale. |
| Nucleic Acid Extraction and Assay Setup | Assay uses the QIAsymphony SP/AS for automated sample preparation and assay setup. | Assay uses proprietary sample preparation buffer and manual assay setup. |
| Amplification and Detection Instrument System | Assay uses the Rotor-Gene Q MDx. | Assay can be performed using either the:• Life Technologies QuantStudio Dx• Applied Biosystems 7500 Fast Dx• Cepheid SmartCycler II |
{3}------------------------------------------------
The differences between the artus C. difficile QS-RGQ MDx Kit and Quidel Molecular Direct C. difficile assays are primarily centered around the control strategy and instrumentation. These differences do not affect substantial equivalency of the artus C. difficile QS-RGQ MDx Kit and the Quidel Molecular Direct C. difficile Assay. Both assays detect toxigenic C. difficile, and the assays have comparable intended uses. The differences noted above do not change the intended use and do not raise questions of safety and effectiveness.
{4}------------------------------------------------
Performance Characteristics - Non-Clinical Studies
Analytical Sensitivity (Limit of detection)
The limit of detection (LoD) was assessed for the artus C. difficile QS-RGQ MDx Kit using 3 toxigenic Clostridium difficile strains: NAP-1/BI/027 strain, toxinotype III A+B+ (ATCC® BAA-1870); 1470 strain, toxinotype VIII A-B+(ATCC 43598); and VPI 10463 strain, toxinotype 0 A+B+ (ATCC 43255). The LoD is defined as the toxigenic C. difficile bacterial titer (CFU/mL) detected with a probability of 95% or greater and was determined by probit analysis. The results, representative of the analytical sensitivity of the artus C. difficile QS-RGQ MDx Kit, are summarized in Table 2.
Table 2: Limit of Detection
| Strain | LoD (95%CI) |
|---|---|
| C. difficile NAP1ATCC BAA-1870, strain:4118 | 7.9 CFU/mL (6.1-15.0) |
| C. difficile 1470ATCC 43598, strain:1470 | 11.2 CFU/mL (8.7-16.8) |
| C. difficile 10463ATCC 43255, strain:10463 | 2.8 CFU/mL (2.1-4.2) |
Analytical Reactivity
The analytical reactivity of the artus C. difficile QS-RGQ MDx Kit was assessed to determine whether the kit could detect a broad range of toxigenic C. difficile strains representing temporal and geographical diversity. A total of 27 strains and characterized clinical isolates were diluted in TE buffer to 2-3x LOD of the reference strain and tested with the artus C. difficile QS-RGQ MDx Kit. C. difficile target was detected in all strains tested Table 3.
{5}------------------------------------------------
| Name | Strain | Toxinotype | Origin |
|---|---|---|---|
| ATCC 17857 | 870 | O | unknown |
| ATCC 17858 | 1253 | N/A | unknown |
| ATCC 43594 | W1194 | N/A | Human feces; Belgium |
| ATCC 43596 | 545 | N/A | Human feces; Belgium |
| ATCC 43599 | 2022 | N/A | Human feces; Belgium |
| ATCC 43600 | 2149 | N/A | Human feces; Belgium |
| ATCC 51695 | BDMS18AN | N/A | Becton DickinsonMicrobiology Systems,Johns Hopkins Univ.Hosp. Lab |
| ATCC 700792 | 14797-2 | N/A | Human feces;Michigan, USA |
| ATCC 9689 | 90556-M6S | O | unknown |
| ATCC BAA-1382 | 630 | X | Switzerland |
| ATCC BAA-1805 | N/A | III | unknown |
| ATCC BAA-1871 | 4111 | O | Human; New Jersey,USA |
| ATCC BAA-1872 | 4206 | O | Human; Maine, USA |
| ATCC BAA-1873 | 5283 | O | Human; New York,USA |
| ATCC BAA-1874 | 4205 | O | Human; Oregon, USA |
| ATCC BAA-1875 | 5325 | V | Human; Georgia, USA |
| ATCC BAA-2155 | LBM0801058 | N/A | Human; New Mexico,USA |
| ATCC BAA-2156 | LBM0801040 | N/A | Human; CambridgeUK |
| CCUG 20309 | 8864 | X | Birmingham, UK |
| Illinois VAHospital isolate278 | N/A | II | Illinois, USA |
| Illinois VAHospital isolate464 | N/A | IV | Illinois, USA |
| Illinois VAHospital isolate | N/A | VIII | Illinois, USA |
| Name | Strain | Toxinotype | Origin |
| 4092 | |||
| Illinois VAHospital isolate5572 | N/A | VIII | Illinois, USA |
| Illinois VAHospital isolate3430 | N/A | IX | Illinois, USA |
| Illinois VAHospital isolate1753 | N/A | XII | Illinois, USA |
| Illinois VAHospital isolate5090 | N/A | XXI | Illinois, USA |
| Illinois VAHospital isolate3130 | N/A | XXII | Illinois, USA |
Table 3: Strains Tested in Analytical Reactivity
{6}------------------------------------------------
Cross-Reactivity and Microbial Interference
A panel of microorganisms that may be present in patient specimens was tested to determine whether these microorganisms interfered with the detection of tcdA or tedB targets or were cross-reactive with the artus C. difficile QS-RGQ MDx Kit. Organisms were tested at a target concentration of approximately 1 x 10° CFU/ml for bacteria and fungi or ≥1 x 105 units/ml for viruses separately in the presence of 2-3x LOD of each of three C. difficile strains: NAP-1/BI/027 strain, and VPI 10463 strain. None of the potential interfering organisms cross-reacted or interfered with the detection of any of the 3 C. difficile strains by the artus C. difficile QS-RGQ MDx Kit (Table 4). Crossreactivity for Clostridium botulinum was analyzed in silico and predicted no cross reactivity or microbial interference for the artus C. difficile QS-RGQ MDx Kit.
| Table 4: Organisms Tested in Cross Reactivity and Microbial Interference | |||
|---|---|---|---|
| -------------------------------------------------------------------------- | -- | -- | -- |
| Organism Tested | Source ID |
|---|---|
| Abiotrophia defectiva | ATCC 49176 |
| Acinetobacter baumannii | ATCC 19606 |
| Aeromonas hydrophila | ATCC 7966 |
| Alcaligenes faecalis subsp. faecalis | ATCC 15554 |
| Bacillus cereus | ATCC 13472 |
| Bacteroides fragilis | ZMC 0601533 |
| Organism Tested | Source ID |
| Campylobacter coli | ATCC 43479 |
| Campylobacter coli | ATCC 33559 |
| Campylobacter jejuni subsp. jejuni | ATCC 33292 |
| Candida albicans | ATCC 10231 |
| Citrobacter freundii | ATCC 8090 |
| Clostridium bifermentans | ATCC 638 |
| Clostridium butyricum | ATCC 19398 |
| Clostridium haemolyticum | ATCC 9650 |
| Clostridium novyi | ATCC 19402 |
| Clostridium orbiscindens | ATCC 49531 |
| Clostridium perfringens | ATCC 13124 |
| Clostridium scindens | ATCC 35704 |
| Clostridium septicum | ATCC 12464 |
| Clostridium sordellii | ATCC 9714 |
| Clostridium difficile (non-toxigenic) | ATCC 43593 |
| Clostridium difficile (non-toxigenic) | ATCC 43601 |
| Clostridium sporogenes | ATCC 15579 |
| Edwardsiella tarda | ATCC 15947 |
| Enterobacter aerogenes | ATCC 13048 |
| Enterobacter cloacae | ATCC 13047 |
| Enterococcus faecalis (vanB) | ATCC 51299 |
| Escherichia coli | ATCC 23511 |
| Escherichia coli 0157:H7 | ATCC 700927 |
| Helicobacter pylori DNA | ATCC 43504D-5 |
| Klebsiella oxytoca | ATCC 33496 |
| Lactobacillus acidophilus | ATCC 4356 |
| Listeria monocytogenes | ZMC 0801534 |
| Peptostreptococcus anaerobius | ATCC 27337 |
| Plesiomonas shigelloides | ATCC 14029 |
| Porphyromonas asaccharolytica | ATCC 25260 |
| Prevotella melaninogenica | ATCC 25845 |
| Proteus mirabilis | ATCC 25933 |
| Providencia alcalifaciens | ATCC 9886 |
| Pseudomonas aeruginosa | ATCC 35554 |
| Salmonella choleraesuis (Typhimurium) | ATCC 14028 |
| Salmonella enterica subsp. arizonae | ATCC 13314 |
| Salmonella enterica subsp. enterica | ATCC 7001 |
| Serratia liquefaciens | ATCC 27592 |
| Serratia marcescens | ATCC 13880 |
| Shigella boydii | ATCC 9207 |
| Shigella dysenteriae | ATCC 11835 |
| Organism Tested | Source ID |
| Shigella sonnei | ATCC 29930 |
| Staphylococcus aureus | ATCC 43300 |
| Staphylococcus epidermidis | ATCC 14990 |
| Streptococcus agalactiae | ATCC 27541 |
| Vibrio parahaemolyticus | ATCC 17802 |
| Adenovirus | ZMC 0810110 CF |
| Rotavirus | ZMC 0810041 CF |
| Norovirus | ZMC 0810086 CF |
| Enterovirus | ZMC 0810047 CF |
| Echovirus | ZMC 0810023 CF |
| Coxsackie virus | ZMC 0810075 CF |
| Cytomegalovirus | ZMC 0810003 CF |
| Human Genomic DNA | Promega G3041 |
{7}------------------------------------------------
{8}------------------------------------------------
510(k) Submission K 133936 Amendment Page 9 of 15
Precision
The precision of the artus C. difficile QS-RGQ Kit was assessed using a 7-member panel consisting of 2 C. difficile strains: NAP-1/BI/027 strain, toxinotype III A+B+ (ATCC BAA-1870) and 1470 strain, toxinotype VIII A-B+(ATCC 43598). Panel members were initially diluted in TE buffer then tested in Buffer ATL containing negative stool matrix with a single strain present (NAP-1/B1/027 or 1470) at 3 concentrations; positive (approximately 2-3x LoD), low positive (1x LoD), and high negative (<1x LoD). A seventh panel member (negative) was prepared using TE buffer only and also tested in Buffer ATL containing negative stool matrix. The data obtained were used to determine the mean Cr, standard deviation (SD) and the coefficient of variation (%CV) for each target and the internal control.
For the within laboratory repeatability study, the seven-member panel was tested in replicates of three, once a day for a total of twelve days (for a total of 262 data points for the 12 runs). The testing was conducted by two operators using one instrument (QS/AS RGQ MDx) and one reagent kit lot (Table 5).
{9}------------------------------------------------
| PanelMember | Internal Control | tcdA | tcdB | ||||||
|---|---|---|---|---|---|---|---|---|---|
| MEAN | STDEV | %CV | MEAN | STDEV | %CV | MEAN | STDEV | %CV | |
| NAP1 Positive | 29.78 | 0.49 | 1.64% | 30.84 | 0.47 | 1.52% | 33.58 | 0.64 | 1.91% |
| NAP1 LowPositive | 30.07 | 0.55 | 1.82% | 32.19 | 0.99 | 3.08% | 34.92 | 0.68 | 1.94% |
| NAP1 HighNegative | 29.99 | 0.72 | 2.41% | 34.21 | 0.91 | 2.66% | 36.18 | 0.23 | 0.64% |
| 1470 Positive | 29.85 | 0.52 | 1.73% | 30.95 | 0.55 | 1.78% | 33.72 | 0.45 | 1.33% |
| 1470 LowPositive | 29.89 | 0.41 | 1.39% | 32.14 | 0.65 | 2.03% | 35.13 | 0.63 | 1.80% |
| 1470 HighNegative | 29.92 | 0.53 | 1.76% | 34.14 | 0.66 | 1.92% | 36.39 | 0.03 | 0.07% |
| Negative | 30.00 | 0.44 | 1.46% | N/A | N/A | N/A | N/A | N/A | N/A |
Table 5: Within Laboratory Repeatability Study Results
To measure site-to-site reproducibility, the 7-member panel was run by 2 users at each of 3 sites (IMDx and 2 external sites). Each of the 2 users performed 5 runs on alternating testing days. Panel members were tested in replicates of 3 that were randomized and blinded to the user. A single QlAsymphony RGQ instrument system and one lot of the artus C. difficile QS-RGQ Kit were used at each site to conduct the study (Table 6).
| Internal Control | tcdA | tcdB | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Strain | PanelMember | Site | MeanCt | SD | % CV | MeanCt | SD | %CV | MeanCt | SD | %CV |
| NAP-1/B1/027 | Positive | 1 | 30.61 | 0.42 | 1.38 | 31.85 | 0.73 | 2.3 | 34.32 | 0.69 | 2.02 |
| 2 | 30.58 | 0.51 | 1.65 | 32.16 | 0.8 | 2.5 | 34.43 | 0.71 | 2.05 | ||
| 3 | 30.55 | 0.32 | 1.05 | 31.97 | 0.85 | 2.65 | 34.87 | 0.78 | 2.25 | ||
| overall | 30.58 | 0.42 | 1.37 | 32.00 | 0.80 | 2.49 | 34.53 | 0.76 | 2.19 | ||
| LowPositive | 1 | 30.63 | 0.4 | 1.3 | 33.38 | 0.71 | 2.14 | 35.58 | 0.55 | 1.55 | |
| 2 | 30.73 | 0.6 | 1.94 | 33.27 | 0.81 | 2.45 | 35.01 | 0.53 | 1.52 | ||
| 3 | 30.86 | 0.62 | 2 | 33.07 | 0.84 | 2.53 | 35.45 | 0.69 | 1.96 | ||
| overall | 30.74 | 0.55 | 1.78 | 33.24 | 0.79 | 2.38 | 35.36 | 0.62 | 1.76 | ||
| HighNegative | 1 | 30.71 | 0.35 | 1.15 | 34.21 | 0.54 | 1.58 | 35.88 | N/A | N/A | |
| 2 | 30.59 | 0.33 | 1.09 | 34.21 | 0.29 | 0.86 | 35.92 | N/A | N/A | ||
| 3 | 30.64 | 0.47 | 1.53 | 34.17 | 0.57 | 1.68 | N/A | N/A | N/A | ||
| overall | 30.65 | 0.39 | 1.27 | 34.19 | 0.45 | 1.32 | 35.91 | 0.16 | 0.43 |
Table 6: Site-to-Site Reproducibility Study Results
{10}------------------------------------------------
QIAGEN artus® C. difficile QS-RGQ MDx Kit Attachment 1, Revised 510(k) Summary
510(k) Submission K 133936 Amendment Page 11 of 15
| Internal Control | tcdA | tcdB | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Strain | PanelMember | Site | Mean Ct | SD | Mean Ct | SD | % CV | Mean Ct | SD | %CV | Mean Ct | SD | %CV |
| 1470 | Positive | 1 | 30.67 | 0.49 | 30.67 | 0.49 | 1.58 | 32.22 | 0.86 | 2.67 | 34.74 | 0.61 | 1.76 |
| 2 | 30.69 | 0.41 | 30.69 | 0.41 | 1.32 | 31.74 | 0.95 | 2.99 | 34.66 | 0.74 | 2.14 | ||
| 3 | 30.86 | 0.33 | 30.86 | 0.33 | 1.06 | 31.81 | 0.78 | 2.45 | 34.95 | 0.7 | 2.01 | ||
| overall | 30.74 | 0.42 | 30.74 | 0.42 | 1.35 | 31.92 | 0.88 | 2.77 | 34.78 | 0.69 | 1.99 | ||
| 1470 | Low Positive | 1 | 30.74 | 0.42 | 30.74 | 0.42 | 1.37 | 33.17 | 0.94 | 2.83 | 35.61 | 0.49 | 1.38 |
| 2 | 30.51 | 0.42 | 30.51 | 0.42 | 1.38 | 33.06 | 0.89 | 2.7 | 35.62 | 0.6 | 1.7 | ||
| 3 | 30.7 | 0.33 | 30.7 | 0.33 | 1.08 | 33.41 | 1.08 | 3.22 | 35.77 | 0.46 | 1.29 | ||
| overall | 30.65 | 0.4 | 30.65 | 0.4 | 1.31 | 33.2 | 0.96 | 2.9 | 35.65 | 0.53 | 1.48 | ||
| High Negative | 1 | 30.76 | 0.46 | 30.76 | 0.46 | 1.5 | 34.64 | 0.14 | 0.4 | 36.41 | N/A | N/A | |
| 2 | 30.55 | 0.45 | 30.55 | 0.45 | 1.46 | 34.15 | 0.28 | 0.83 | 35.82 | N/A | N/A | ||
| 3 | 30.44 | 0.42 | 30.44 | 0.42 | 1.38 | 34.63 | 0.27 | 0.77 | N/A | N/A | N/A | ||
| overall | 30.58 | 0.46 | 30.58 | 0.46 | 1.49 | 34.49 | 0.31 | 0.91 | 36.12 | 0.42 | 1.16 | ||
| Negative | 1 | 30.68 | 0.37 | 30.68 | 0.37 | 1.2 | N/A | N/A | N/A | N/A | N/A | N/A | |
| 2 | 30.66 | 0.47 | 30.66 | 0.47 | 1.55 | N/A | N/A | N/A | N/A | N/A | N/A | ||
| 3 | 30.67 | 0.42 | 30.67 | 0.42 | 1.37 | 33.58 | N/A | N/A | N/A | N/A | N/A | ||
| overall | 30.67 | 0.42 | 30.67 | 0.42 | 1.36 | 33.58 | N/A | N/A | N/A | N/A | N/A |
Target Carryover Study
Absence of carryover between samples for the entire workflow was proven by performing 5 runs with alternating high positive (formulated at a concentration which exceeded that of organisms found in 95% of specimens from diseased patients in the intended use population) and negative samples were detected correctly, generating a carryover rate of 0.0%.
Interfering Substances
A panel of 23 substances that may be present in patient specimens (Table 7) was tested to determine whether these substances interfered with the performance of the artus C. difficile QS-RGQ MDx Kit. Three toxigenic C. difficile strains: NAP-1/BI/027 strain, 1470 strain, and VPI 10463 strain, were diluted to approximately 2-3x LoD and spiked with each potentially inhibitory substance. None of the substances showed an inhibitory effect on the detection of C, difficile by the artus C. difficile QS-RGQ MDx Kit.
{11}------------------------------------------------
.
| Type | Substance | Potential Interferent | ConcentrationTested* |
|---|---|---|---|
| Anti-fungal | Miconazolenitrate cream | Miconazole nitrate | 2% w/v |
| Cream/Suppositories | Preparation H | Hydrocortizone | 2% w/v |
| Cream/Suppositories | Zinc oxide | Zinc oxide | 40% w/v |
| Cream/Suppositories | Vaseline | Petroleum jelly | 100% |
| Anti-hemorrhoidcreams | Hemorrhoid gel | Phenylephrinehydrochloride | 2% w/v |
| Condoms | Condoms | Nonoxynol-9 | 7% |
| MoistTowelettes | Moist Towelettes | BenzalkoniumChloride | 0.12% w/v |
| Antacids | Gaviscon | Aluminum hydroxide,Magnesium carbonate | 0.1 mg/mL |
| Antacids | Tums | Ca carbonate | 0.5 mg/mL |
| Antacids | Tagamet | Cimetidine | 0.5 mg/mL |
| Antacids | Prilosec (delayedrelease) | Omeprazolemagnesium | 0.5 mg/mL |
| Enemas | Mineral Oil | Mineral Oil | 2% v/v |
| Anti-DiarrhealMedication | Imodium | Loperamide HCl | 0.00667 mg/mL |
| Anti-DiarrhealMedication | Pepto Bismol | Bismuth Subsalicylate | 0.87 mg/mL |
| Laxative | ExLax | Sennosides | 0.1 mg/mL |
| Antibiotics | Vancomycin HCl | Vancomycin | 12.5 mg/mL |
| Antibiotics | Metronidazole | Metronidazole | 14 mg/mL |
| Anti-inflammatory | Naproxen Sodium(Aleve) | Naproxen Sodium | 14 mg/mL |
| Blood | Whole blood | Glucose, hormones,enzymes, iron, etc., | 5% v/v |
| FecalComponents | Mucus | Mucin | 3 mg/mL |
| FecalComponents | Palmitic acid | Palmitic acid | 2 mg/mL |
| FecalComponents | Stearic acid | Stearic acid | 4 mg/mL |
| MRI ContrastAgents | Barium sulfate | Barium sulfate | 5 mg/mL |
Table 7: Potentially Interfering Substances Tested
- Represents physiologically relevant concentrations of substances
{12}------------------------------------------------
Performance Characteristics - Clinical Studies
The performance of the artus C. difficile QS-RGQ MDx Kit was evaluated at 3 external testing sites using C. difficile patient samples from 5 geographically diverse locations within the United States in 2013. The artus C. difficile QS-RGQ MDx Kit was compared to direct and/or enriched culture. The tables below present the data from these studies.
Assay vs. Direct and Enriched Culture Comparison
A total of 759 liquid or soft stool specimens were collected from patients suspected of having Clostridium difficile-associated disease. Ten (10) specimens were missing artus and culture results and were withdrawn from the study. Of the 749 specimens with artus results reported. sixteen (16) specimens reported an invalid result (2.14%) with the artus C. difficile QS-RGQ MDx Kit. Of these samples, 8 returned valid results upon retesting (all negative) and 8 reported a final invalid result for the artus C. difficile QS-RGQ MDx Kit (1.07%). The remaining 741 specimens with valid artus results were included in the final data set and analyzed for product performance.
Assav vs. Enriched Culture Comparison
A total of 741 specimens were tested by both the artus C. difficile QS-RGQ MDx Kit and enriched toxigenic culture. The overall assessment of sensitivity and specificity versus enriched toxigenic culture is shown in Table 8.
{13}------------------------------------------------
Table 8: Clinical Performance of artus C. difficile QS-RGQ MDx Kit vs. Enriched Toxigenic Culture
| Combined Sites – Combined Ages | ||||
|---|---|---|---|---|
| Enriched Toxigenic Culture | ||||
| Positive | Negative | Total | ||
| artus C. difficileQS-RGQ MDxKit | Positive | 114 | 17* | 131 |
| Negative | 13** | 597 | 610 | |
| Total | 127 | 614 | 741 | |
| 95% CI | ||||
| Sensitivity | 90% | 83% - 94% | ||
| Specificity | 97% | 96% - 98% | ||
| Positive Predictive Value | 87% | 80% - 92% | ||
| Negative Predictive Value | 98% | 96% - 99% | ||
| Prevalence | 17% | 15%-20% |
*17 discordant specimens (arus C. difficile QS-RGQ MDx Positive, Enriched Toxigenic Culture Negative) reported were analyzed by alternative PCR followed by bi-directional sequencing and the result was that 12 out of 17 were positive for toxigenic C. difficile, agreeing with the artus C. difficile QS-RGQ MDx result.
** 12 discordant specimens (artus C. difficile QS-RGO MDx Negative. Enriched Toxigenic Culture Positive) reported were analyzed by alternative PCR followed by bi-directional sequencing and the result was that 10 out of 12 were negative for toxigenic C. difficile, agreeing with the artus C. difficile QS-RGQ MDx result. The remaining I discordant specimen was unavailable for testing.
Assay vs. Direct Toxigenic Culture Comparison
There were a total of 699 specimens for which a direct toxigenic culture result was available. The overall assessment of sensitivity and specificity versus direct toxigenic culture is shown in Table 9.
{14}------------------------------------------------
Table 9: Clinical Performance of artus C. difficile QS-RGQ MDx Kit vs. Direct Toxigenic Culture
| Combined Sites - Combined Ages | ||||
|---|---|---|---|---|
| Direct Toxigenic Culture | ||||
| Positive | Negative | Total | ||
| artus C. difficileQS-RGQ MDxKit | Positive | 84 | 21* | 105 |
| Negative | 1** | 593 | 594 | |
| Total | 85 | 614 | 699 | |
| 95% CI | ||||
| Sensitivity | 99% | 94%-100% | ||
| Specificity | 97% | 95%-98% | ||
| Positive Predictive Value | 80% | 71%-87% | ||
| Negative Predictive Value | 100% | 99%-100% | ||
| Prevalence | 12% | 10%-15% |
*19 discordant specimens (artus C. difficile QS-RGQ MDx Positive. Direct Toxigenic Culture Negative) reported were analyzed by alternative PCR followed by bi-directional sequencing and the result was that 14 out of 19 were positive for toxigenic C. difficile, agrecing with the artus C. difficile QS-RGQ MDx result. The remaining 2 specimens were unavailable for testing.
** The I discordant specimen (artus C. difficile QS-RGQ MDx Negative, Direct Toxigenic Culture Positive) was unavailable for testing.
Conclusions
The artus® C. difficile QS-RGQ MDx Kit is substantially equivalent to the legally marketed Quidel Molecular Direct C. difficile Assay.
{15}------------------------------------------------
Image /page/15/Picture/0 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is an abstract symbol that resembles an eagle or bird-like figure with three stylized wing shapes.
DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G60 Silver Spring, MD 20993-0002
QIAGEN GMBH KIMBERLY MAPP, Ph.D MANAGER, REGULATORY AFFAIRS 1201 CLOPPER ROAD GAITHERSBURG MD 20878
April 4, 2014
Re: K133936
Trade/Device Name: artus C. difficile QS-RGQ MDx Kit Regulation Number: 21 CFR 866.3130 Regulation Name: Clostridium difficile toxin gene amplification assay Regulatory Class: II Product Code: OZN, OOI Dated: January 6, 2014 Received: January 6, 2014
Dear Dr. Mapp:
、
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
{16}------------------------------------------------
Page 2—Dr. Mapp
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact 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/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of 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/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
Uwe Scherf -S for
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
{17}------------------------------------------------
Indications for Use
510(k) Number (if known) K133936
Device Name artus® C. difficile QS-RGQ MDx Kit
Indications for Use (Describe)
The artus C. difficile QS-RGQ MDx Kit is an in vitro polymerase chain reaction (PCR) assay for use on the QIAsymphony RGQ MDx system for the qualitative detection of toxigenic Clostridium difficile toxin A and toxin B genes in human liquid or soft stool specients suspected of having Clostridium difficile associated disease. The test is intended to be used directly on patient samples.
The artus C. difficile QS-RGQ MDx Kit is intended to be used to aid in diagnosis of Clostridium difficile infection.
Type of Use (Select one or both, as applicable)
2 Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
Form Approved: OMB No. 0910-0120
Expiration Date: January 31, 2017
See PRA Statement below.
PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.
FOR FOR FDA USE ONLY
Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)
Ribhi Shawar -S 2014.04.01 07:31 22
This section applies only to requirements of the Paperwork Reduction Act of 1995.
*DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW."
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
§ 866.3130 Clostridium difficile toxin gene amplification assay.
(a)
Identification. AClostridium difficile toxin gene amplification assay is a device that consists of reagents for the amplification and detection of target sequences inClostridium difficile toxin genes in fecal specimens from patients suspected of havingClostridium difficile infection (CDI). The detection of clostridial toxin genes, in conjunction with other laboratory tests, aids in the clinical laboratory diagnosis of CDI caused byClostridium difficile. (b)
Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Toxin Gene Amplification Assays for the Detection ofClostridium difficile; Guideline for Industry and Food and Drug Administration Staff.” See § 866.1(e) for information on obtaining this document.