(73 days)
The ProGastro™ Cd Assay is a Real Time PCR in vitro diagnostic test for the qualitative detection of toxigenic Clostridium difficile nucleic acids isolated and purified from liquid or soft stool specimens obtained from symptomatic patients. This test targets the Clostridium difficile toxin B gene (tcdB) and is intended for use to aid in the diagnosis of toxigenic Clostridium difficile infections.
The ProGastro Cd Assay detects toxigenic Clostridium difficile and an Internal Control by a process of nucleic acid extraction from patient specimens followed by PCR amplification and detection. Following collection of a soft or liquid stool sample from a symptomatic patient, a portion of the sample is diluted in Stool Transport and Recovery (S.T.A.R.) Buffer and the solids separated via centrifugation (Stool Clarification). The Internal Control is added to the sample prior to extraction to monitor for PCR inhibitors that may be present. The nucleic acids from the sample are extracted and purified using the bioMérieux NucliSENS easyMAG automated extractor. Nucleic acids are added to the C. diff Mix for subsequent PCR amplification and detection using the Cepheid SmartCycler II.
The C. diff Mix contains oligonucleotide primers and probes that target the tcdB gene of toxigenic strains of C. diff. The probes are dual-labeled with a reporter dye attached to the 5'-end and a quencher dye attached to the 3'-end (see table below). During PCR amplification the primers and probes anneal to the template (if present) followed by primer extension and template amplification. The 5'-3' exonuclease activity of the Taq polymerase cleaves the probe thus separating the reporter dye from the quencher and generating an increase in fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification product present. The SmartCycler II instrument and software monitors the process, interprets the data, and presents a report upon completion.
Here’s a breakdown of the acceptance criteria and the study proving the ProGastro Cd Assay meets them, based on the provided document:
1. Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria for Sensitivity and Specificity in a table format. However, the reported performance against the reference method (Tissue Culture Cytotoxin Assay - CTA) implies an expectation of high diagnostic accuracy. For reproducibility, a high percentage of agreement with expected results across sites and operators is an implicit criterion.
Based on the provided data, we can infer the following:
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Clinical Study | ||
| Sensitivity | High sensitivity (e.g., >80-90%) compared to CTA | 91.7% (95% CI: 83.0% - 96.1%) |
| Specificity | High specificity (e.g., >90%) compared to CTA | 94.7% (95% CI: 92.8% - 96.1%) |
| Reproducibility | ||
| Overall Agreement | High overall agreement with expected results (e.g., >95%) | 99.0% (95% CI: 97.1% - 99.7%) for primary reproducibility study |
| Agreement for Intermediate Samples | Expected to be in a specific range (e.g., 5-95% positive) due to low concentration | 42.2% (95% CI: 32.5% - 52.5%) for intermediate concentration |
2. Sample Size and Data Provenance
- Sample Size for Test Set: A total of 771 raw stool samples were tested in the clinical performance study.
- Data Provenance: The study was a prospective study conducted at 3 U.S. clinical laboratories from July through October 2008. The samples were "leftover raw stool specimens that were collected for routine Clostridium difficile testing from patients over two years of age by each site." This indicates real-world clinical samples from a U.S. patient population.
3. Number of Experts and Qualifications for Ground Truth
The document does not specify the number of experts used or their qualifications for establishing the initial ground truth (Tissue Culture Cytotoxin Assay - CTA). CTA is a laboratory-based method, and its interpretation would typically be performed by trained laboratory personnel.
4. Adjudication Method for the Test Set
A discrepant analysis was performed for samples where the ProGastro Cd Assay and CTA results disagreed. This involved a predetermined algorithm including:
- A molecular (PCR) test targeting a different region of the tcdB gene.
- Bidirectional genetic sequencing.
- Enzyme Immunoassay (EIA).
- Culture followed by PCR and bidirectional sequencing.
This constitutes a form of adjudication where additional, more definitive tests are used to resolve disagreements between the device and the primary reference method.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was done. This study evaluates an in vitro diagnostic (IVD) test, where the "reader" is essentially the instrument and the assay, not a human interpreter of an image or signal. Therefore, assessing how human readers improve with AI vs. without AI assistance is not applicable here.
6. Standalone (Algorithm-Only) Performance
The entire clinical performance study report (Sensitivity, Specificity) evaluates the standalone performance of the ProGastro Cd Assay. The assay is an in vitro diagnostic test for the qualitative detection of C. difficile nucleic acids, which runs entirely on the Cepheid SmartCycler II instrument and software for amplification, detection, and data interpretation. There is no human-in-the-loop component for the result generation itself.
7. Type of Ground Truth Used
The primary reference method used to establish ground truth for the clinical performance study was the Tissue Culture Cytotoxin Assay (CTA). For discrepant analysis, additional molecular tests (PCR, sequencing), EIA, and culture were used to refine the ground truth. This combines a gold standard (CTA) with a more comprehensive "adjudicated" gold standard for discordant results.
8. Sample Size for the Training Set
The document does not provide information about a specific training set or its sample size. This is typical for 510(k) submissions for diagnostic assays, where the focus is on the performance of the finalized device rather than the development process involving training data for algorithms. The "assay" itself, like most IVDs, is developed and validated, but does not typically undergo a 'training' phase with a specific dataset in the same way a machine learning algorithm would.
9. How Ground Truth for the Training Set Was Established
As no specific training set information is provided, the method for establishing its ground truth is also not described.
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Prodesse, Inc. ProGastro Cd Assay 510(k) Submission
K0906239
Page 1 of 4
Date: April 14, 2009
Attachment D 510(k) SUMMARY
CONTACT
Kristine Schraufnagel Prodesse, Inc. W229 N1870 Westwood Dr. Waukesha, WI 53186
APR 1 6 2009
NAME OF DEVICE
| Trade Name: |
|---|
| Regulation Number: |
| Classification Name: |
ProGastro Cd Assay 21 CFR 866.2660 reagents, Clostridium difficile toxin
PREDICATE DEVICE
K923463 - TechLab C. difficile toxin/Antitoxin Kit K081920 - BD Geneohm CDiff Assay
INTENDED USE
The ProGastro™ Cd Assay is a Real Time PCR in vitro diagnostic test for the qualitative detection of toxigenic Clostridium difficile nucleic acids isolated and purified from liquid or soft stool specimens obtained from symptomatic patients. This test targets the Clostridium difficile toxin B gene (tcdB) and is intended for use to aid in the diagnosis of toxigenic Clostridium difficile infections.
PRODUCT DESCRIPTION
The ProGastro Cd Assay detects toxigenic Clostridium difficile and an Internal Control by a process of nucleic acid extraction from patient specimens followed by PCR amplification and detection. Following collection of a soft or liquid stool sample from a symptomatic patient, a portion of the sample is diluted in Stool Transport and Recovery (S.T.A.R.) Buffer and the solids separated via centrifugation (Stool Clarification). The Internal Control is added to the sample prior to extraction to monitor for PCR inhibitors that may be present. The nucleic acids from the sample are extracted and purified using the bioMérieux NucliSENS easyMAG automated extractor. Nucleic acids are added to the C. diff Mix for subsequent PCR amplification and detection using the Cepheid SmartCycler II.
The C. diff Mix contains oligonucleotide primers and probes that target the tcdB gene of toxigenic strains of C. diff. The probes are dual-labeled with a reporter dye attached to the 5'-end and a quencher dye attached to the 3'-end (see table below). During PCR amplification the primers and probes anneal to the template (if present) followed by primer extension and template amplification. The 5'-3' exonuclease activity of the Taq polymerase cleaves the probe thus separating the reporter dye from the quencher and generating an increase in fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification product present. The SmartCycler II instrument and software monitors the process, interprets the data, and presents a report upon completion.
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| ProGastro Cd Assay 510(k) Submission |
|---|
| Analyte | Gene Targeted | ProbeFluorophore | AbsorbancePeak | EmissionPeak | InstrumentChannel |
|---|---|---|---|---|---|
| Clostridium difficile | tcdB, Toxin B | FAM | 495 nm | 520 nm | FAM |
| Internal Control | NA | Quasar 670 | 647 nm | 667 nm | Cy5 |
SUBSTANTIAL EQUIVALENCE Clinical Performance
Performance characteristics of the ProGastro Cd Assay were established during a prospective study at 3 U.S. clinical laboratories from July through October 2008. Samples used for this study were leftover raw stool specimens that were collected for routine Clostridium difficile testing from patients over two years of age by each site. The reference method was tissue culture cytotoxin assay (CTA). Demographic details for this patient population are summarized in the following table:
| Age | Number of Subjects(Percentage of Total) |
|---|---|
| 2 - 5 years | 60 (7.8 %) |
| 6 - 21 years | 163 (21.1%) |
| 22 - 59 years | 292 (37.9%) |
| ≥ 60 years | 256 (33.2%) |
A total of 771 raw stool samples were tested with the ProGastro Cd Assay and by CTA. None of the 771 samples were inhibited when tested with the ProGastro Cd Assay.
| CTA | |||||
|---|---|---|---|---|---|
| Positive | Negative | Total | Comments | ||
| ProGastroCd Assay | Positive | 66 | 37a | 103 | Sensitivity 91.7%(83.0% - 96.1%) 95% CI |
| Negative | 6b | 662 | 668 | Specificity 94.7%(92.8% - 96.1%) 95% CI | |
| Total | 72 | 699 | 771 |
Discrepant analysis for samples where ProGastro Cd Assay and CTA results were in disagreement was performed using a predetermined algorithm including a molecular (PCR) test (which targeted a different region of the tcdB gene than that of the ProGastro Cd Assay) followed by bidirectional genetic sequencing, enzyme immunoassay (EIA), and culture followed by PCR and bidirectional sequencing.
" 34 samples positive by discrepant analysis. Of these 33 were positive by sequencing, and one (1) was positive by culture followed by sequencing.
6 Four (4) samples positive by discrepant analysis. Of these, one (1) was positive by seguencing, one (1) was positive by EIA, and two (2) were positive by culture followed by sequencing.
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Reproducibility
The reproducibility of the ProGastro Cd Assay was evaluated at 3 laboratory sites. Reproducibility was assessed using a panel of 6 simulated samples that included medium positive, low positive (near the assay limit of detection) and "high negative" samples. Panels and controls were tested at each site by 2 operators for 5 days (6 samples and 4 controls X 2 operators X 5 days X 3 sites = 300). The overall percent agreement with the expected result for the ProGastro Cd Assay was 99.0%.
| Site 1 | Site 2 | Site 3 | Total | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PanelMember ID | Agreementwithexpectedresult | AVE CT | %CV | Agreementwithexpectedresult | AVE CT | %CV | Agreementwithexpectedresult | AVE CT | %CV | Agreementwith expectedresult (%) | 95%ConfidenceInterval | OverallAverage CTValue | Overall%CV |
| High Negatives1 | 19/20 | 35.2 | 1.52 | 20/20 | 35.3 | 1.05 | 20/20 | 35.5 | 1.30 | 59/60(98.3%) | 91.1% -99.7% | 35.3 | 1.35 |
| LowPositives | 19/20 | 36.2 | 1.04 | 20/20 | 36.2 | 1.30 | 20/20 | 36.3 | 0.75 | 59/60(98.3%) | 91.1% -99.7% | 36.2 | 1.05 |
| MediumPositives | 19/20 | 34.1 | 0.99 | 20/20 | 33.8 | 0.89 | 20/20 | 33.9 | 1.07 | 59/60(98.3%) | 91.1% -99.7% | 33.9 | 1.04 |
| PositiveControl | 10/10 | 36.7 | 3.45 | 10/10 | 34.6 | 1.03 | 10/10 | 34.1 | 1.22 | 30/30(100%) | 88.7% -100% | 35.1 | 3.88 |
| PositiveMatrix Control | 10/10 | 26.8 | 1.26 | 10/10 | 26.5 | 0.43 | 10/10 | 26.4 | 0.76 | 30/30(100%) | 88.7% -100% | 26.6 | 1.05 |
| NegativeControl1 | 10/10 | 35.0 | 0.98 | 10/10 | 35.0 | 1.44 | 10/10 | 35.4 | 1.46 | 30/30(100%) | 88.7% -100% | 35.1 | 1.38 |
| NegativeMatrix Control1 | 10/10 | 35.1 | 1.06 | 10/10 | 35.2 | 1.03 | 10/10 | 35.6 | 2.62 | 30/30(100%) | 88.7% -100% | 35.3 | 1.80 |
| TotalAgreementAll | 97/100 (97%) | 100/100 (100%) | 100/100 (100%) | 297/300(99.0%) | 97.1% -99.7% |
1 Average Ct value is calculated for the Internal Control (IC).
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Prodesse, Inc. ProGastro Cd Assay 510(k) Submission
An additional reproducibility study was performed to assess samples that were at an intermediate concentration, below the assay's LoD but above the "high negatives" tested during the original reproducibility study. The percent positive for the intermediate member across all sites was 42.2%. This result was expected as the intermediate concentration should be positive in the range of 5 - 95% as the samples were lower concentration than the LoD concentration (≥ 95% positive) and higher than the "high negative" concentration (< 5% positive).
| Site 1 | Site 2 | Site 3 | Total | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PanelMember ID | Agreementwithexpectedresult | AVE CT | %CV | Agreementwithexpectedresult | AVE CT | %CV | Agreementwithexpectedresult | AVE CT | %CV | Agreementwith expectedresult (%) | 95%ConfidenceInterval | OverallAverage CTValue | Overall%CV |
| Intermediate | 13/30* | 40.4 | 2.10 | 12/30* | 40.5 | 3.50 | 13/30* | 40.5 | 2.07 | 38/90*(42.2%) | 32.5% -52.5% | 40.5 | 2.55 |
| PositiveControl | 10/10 | 35.2 | 0.88 | 10/10 | 34.4 | 0.37 | 10/10 | 35.1 | 2.64 | 30/30(100%) | 88.7% -100% | 34.9 | 1.88 |
| PositiveMatrix Control | 10/10 | 26.5 | 0.78 | 10/10 | 26.5 | 0.86 | 10/10 | 26.3 | 1.12 | 30/30(100%) | 88.7% -100% | 26.4 | 1.00 |
| NegativeControl | 10/10 | 34.9 | 1.30 | 10/10 | 35.1 | 1.33 | 10/10 | 35.0 | 1.26 | 30/30(100%) | 88.7% -100% | 35.0 | 1.28 |
| NegativeMatrix Control | 10/10 | 35.4 | 1.29 | 10/10 | 35.1 | 1.72 | 10/10 | 35.6 | 1.43 | 30/30(100%) | 88.7% -100% | 35.4 | 1.55 |
- Number positive
Average Ct value is calculated for the Internal Control (IC).
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/4/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. 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 image of an eagle.
Public Health Service
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
APR 1 6 2009
Kristine Schraufnagel Ouality Assurance Officer Prodesse, Inc. W229 N1870 Westwood Dr. Waukesha, WI 53186
Re: K090239
Trade/Device Name: ProGastroTM Cd Assay Regulation Number: 866.2660 Microorganism differentiation and identification device Regulation Name: Regulatory Class: Class I LLH Product Code: January 30, 2009 Dated: Received: February 2, 2009
Dear Ms. Schraufnagel:
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
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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 attayim
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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Prodesse, Inc. ProGastro Cd Assay 510(k) Submission
Attachment C Indication for Use
510(k) Number (if known): K090239
Device Name: ProGastro Cd Assay
Indication For Use:
The ProGastro™ Cd Assay is a Real Time PCR in vitro diagnostic test for the qualitative detection of toxigenic Clostridium difficile nucleic acids isolated and purified from liquid or soft stool specimens obtained from symptomatic patients. This test targets the Clostridium difficile toxin B gene (tcdB) and is intended for use to aid in the diagnosis of toxigenic Clostridium difficile infections.
Prescription Use __ X (21 CFR Part 801 Subpart D) And/Or
Over the Counter Use _ (21 CFR Part 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Luddi le Paolo
ision Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K0906239
Division Sign-Off
Office of In Vitro Diagno Device Evaluation and Safely
公司网站
Page 1 of 1
§ 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.