(118 days)
REMEL's Xpect™ Clostridium difficile Toxin A/B is a rapid in vitro immunochromatographic test for the direct, qualitative detection of Clostridium difficile Toxin A and/or B in human fecal specimens from patients suspected of having Clostridium difficile-associated disease (CDAD). The test is intended for use as an aid in diagnosis of CDAD. The test can also be used for confirmation of toxigenic Clostridium difficile from Brain Heart Infusion (BHI) broth culture.
The Xpect™ Clostridium difficile Toxin A/B test is a qualitative immunochromatographic assay that detects C. difficile Toxin A and Toxin B in stool specimens or cultures of toxigenic C. difficile. In performing the test, a specimen is first diluted with Specimen Diluent to help solubilize the toxins. A portion of the diluted sample is then mixed with a volume of Conjugate 1 containing antibodies to Toxin A and Toxin B coupled to colored microparticles, plus a volume of Conjugate 2 containing biotinylated antibodies to Toxin A and Toxin B. A volume of this mixture is transferred to a test device having immobilized streptavidin as a test line and goat antiimmunoqlobulin antibody a as a control line. Immunocomplexes of toxin and conjugated antibodies form a visible band as they flow across the test line. Excess colored particle conjugates form a visible band at the control line to document that the test is functioning properly.
Here is a summary of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are not explicitly stated as distinct numerical targets in the provided text. However, they can be inferred from the reported performance results and the comparison to the predicate device and other commercially available assays. The primary implied acceptance criteria revolve around achieving competitive or superior sensitivity, specificity, and agreement compared to established methods for diagnosing C. difficile-associated disease (CDAD).
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (Xpect™ C. difficile Toxin A/B) |
|---|---|---|
| Clinical Accuracy | ||
| Sensitivity | Comparable to or better than predicate/other methods (e.g., CTA) | 86.3% (95% CI = 79.8-91.3%) |
| Specificity | Comparable to or better than predicate/other methods (e.g., CTA) | 96.2% (95% CI = 94.5-97.5%) |
| Positive Predictive Value | Not explicitly defined, but good | 84.1% (95% CI = 77.4-89.4%) |
| Negative Predictive Value | Not explicitly defined, but good | 96.8% (95% CI = 95.2=98.0%) |
| % Correlation (Agreement) | Comparable to or better than predicate/other methods (e.g., CTA) | 94.4% (95% CI = 92.5-95.8%) |
| BHI Broth Culture Performance | High agreement with expected values of known strains | 94.7% (54/57) agreement with expected values |
| Analytical Sensitivity | Detection of Toxins A and B at low concentrations | Toxin A: ≥ 6.25 ng/ml; Toxin B: ≥ 40.0 ng/ml |
| Cross-Reactivity | No cross-reactivity with common microorganisms | No cross-reactivity observed with 54 microorganisms |
| Interfering Substances | No interference from common substances found in fecal specimens | No interference observed from 10 tested substances |
| Reproducibility | High consistency of results across sites and samples | 98.6% (71/72) of samples produced expected result |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size (Clinical Accuracy): A total of 815 specimens were tested.
- Data Provenance: The study was conducted at four geographically diverse regions of the United States, suggesting a prospective collection or at least a multi-site prospective analysis of collected samples. The text does not explicitly state if the samples were collected retrospectively or prospectively, but the term "evaluated at" suggests prospective evaluation over a period of time.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The ground truth for the clinical accuracy study was established using the cytotoxin assay (CTA). This is a laboratory-based assay and does not involve human experts in the same way, for example, a radiologist reads images. Therefore, the concept of "number of experts" and "qualifications of experts" does not directly apply to the primary ground truth method used here. The CTA is considered a gold standard for C. difficile toxin detection.
For discordant results, further investigation involved "toxigenic culture and microwell enzyme immunoassay." Again, these are laboratory methods, not expert human review.
4. Adjudication Method for the Test Set
There was a form of adjudication for discordant results.
- "Discordant results were further investigated by toxigenic culture and microwell enzyme immunoassay that detects both Toxin A and B."
- This suggests that when the Xpect™ test result and the CTA result did not agree, additional, more definitive laboratory tests (toxigenic culture and a different EIA) were used to ascertain the true status of the sample. This acts as an "adjudication" in a laboratory context, where a more definitive test is used to resolve discrepancies between the index test and the primary reference standard.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
This is not applicable to this device. The Xpect™ Clostridium difficile Toxin A/B test is an in-vitro diagnostic (IVD) assay, not an AI-powered image analysis or diagnostic support tool for human readers. It directly detects bacterial toxins in a specimen. Therefore, there are no "human readers" in the context of interpreting the device's output, nor is there any AI assistance involved.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
This is not applicable to this device. As an IVD assay, the Xpect™ test inherently operates in a "standalone" fashion in terms of its direct detection mechanism (immunochromatography). It produces a visible line without requiring human interpretation other than observing the presence or absence of the line. The performance data presented (sensitivity, specificity) reflects this standalone performance.
7. The Type of Ground Truth Used
The primary ground truth for the clinical accuracy study was the Cytotoxin Assay (CTA). For discordant results, Toxigenic Culture and Microwell Enzyme Immunoassay (EIA) were used as further confirmatory ground truth methods.
8. The Sample Size for the Training Set
The document does not explicitly mention a distinct "training set" for the clinical accuracy study in the traditional sense of machine learning. For traditional IVD assays, optimization and initial validation (which could be considered analogous to training/development) would occur internally during product development, prior to the formal clinical performance study described. The clinical performance study (n=815) serves as the primary validation of the device's performance against the established ground truth.
9. How the Ground Truth for the Training Set Was Established
As no specific "training set" is identified, this question is not directly applicable. However, the ground truth for any internal development or optimization would likely have been established using the same (or similar) gold standard methods as the clinical validation, i.e., Cytotoxin Assay and/or Toxigenic Culture.
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NOV 1 5 2004
510(k) SUMMARY
| Contact Information: | Mary Ann Silvius |
|---|---|
| Director, Business & Product Development | |
| Remel Inc. | |
| 12076 Santa Fe Drive | |
| Lenexa, KS 66215 | |
| Phone: (913) 895-4054 | |
| Fax: (913) 895-4054 | |
| email: msilvius@remel.com |
July 16, 2004 Date Prepared:
Xpect™ Clostridium difficile Toxin A/B Device Trade Name:
BD ColorPAC™ Toxin A Predicate Device:
21 CFR 866.2660; Microorganism differentiation and Device Classification: identification device: reagents, Clostridium difficile toxin.
REMEL's Xpect™ Clostridium difficile Toxin A/B is a rapid Intended Use: in vitro immunochromatographic test for the direct, qualitative detection of Clostridium difficile Toxin A and/or B in human fecal specimens from patients suspected of having Clostridium difficile-associated disease (CDAD). The test is intended for use as an aid in diagnosis of CDAD. The test can also be used for confirmation of toxigenic Clostridium difficile from Brain Heart Infusion (BHI) broth culture.
The Xpect™ Clostridium difficile Toxin A/B test is a Device Description: qualitative immunochromatographic assay that detects C. difficile Toxin A and Toxin B in stool specimens or cultures of toxigenic C. difficile. In performing the test, a specimen is first diluted with Specimen Diluent to help solubilize the toxins. A portion of the diluted sample is then mixed with a volume of Conjugate 1 containing antibodies to Toxin A and Toxin B coupled to colored microparticles, plus a volume of Conjugate 2 containing biotinylated antibodies to Toxin A and Toxin B. A volume of this mixture is transferred to a test device having immobilized streptavidin as a test line and goat antiimmunoqlobulin antibody a as ત્વ control line. Immunocomplexes of toxin and conjugated antibodies form a visible band as they flow across the test line. Excess colored particle conjugates form a visible band at the control line to document that the test is functioning properly.
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Device Comparison:
| Characteristic | ColorPAC™ Toxin A | Xpect™ C. difficile Toxin A/B |
|---|---|---|
| Intended Use | ColorPAC™ Toxin A is a rapidchromatographic assay for the qualitativedetection of Clostridium difficile Toxin A(enterotoxin) in stool specimens frompatients suspected of having C. difficile-associated disease. The test can also beused for confirmation of suspect coloniesof toxigenic C. difficile from agar plates orBHI Broth. This assay is intended for useas an aid in the diagnosis of C. difficile-associated disease. | REMEL's Xpect™ Clostridium difficile A/Btest kit is a rapid in vitroimmunochromatographic test for thedirect, qualitative detection of Clostridiumdifficile Toxin A and/or B in human fecalspecimens from patients suspected ofhaving Clostridium difficile-associateddisease (CDAD). The test is intended foruse as an aid in diagnosis of CDAD. Thetest can also be used for confirmation oftoxigenic Clostridium difficile from BrainHeart Infusion (BHI) broth culture. |
| Detection | Qualitative; Toxin A only detected. | Qualitative; Toxin A and Toxin B detected. |
| Technology | Chromatographic membrane assay | Immunochromatographic membraneassay |
| Specimen Type | Fecal specimens, colonies, BHI Broth | Fecal specimens, BHI Broth |
Summary of Performance Data:
Clinical Accuracy:
The performance of the Xpect™ Clostridium difficile Toxin A/B was evaluated at four geographically diverse regions of the United States. A total of eight hundred fifteen specimens were tested with the Xpect™ Clostridium difficile Toxin A/B test and compared to results obtained from the cytotoxin assay (CTA).
| CTA Results | ||
|---|---|---|
| Overall | + | - |
| XpectTMResults | 132 | 25 |
| 21 | 637 | |
| TOTAL | 153 | 662 |
Sensitivity: 86.3% (95% CI = 79.8-91.3%) Specificity: 96.2% (95% Cl = 94.5-97.5%) Positive Predictive Value: 84.1% (95% C1 = 77.4-89.4%) Negative Predictive Value: 96.8% (95% Cl = 95.2=98.0%) % Correlation: 94.4% (95% Cl = 92.5-95.8%)
Note : CI = Confidence Interval
Discordant results were further investigated by toxigenic culture and microwell enzyme immunoassay that detects both Toxin A and B. Four of 25 specimens that were cytotoxin negative and Xpect™ Clostridium difficile Toxin A/B positive on initial testing were positive by toxigenic culture and enzyme immunoassay. Ten of 21 (47.6%) specimens that were CTA positive and Xpect™ Clostridium difficile Toxin A/B negative on initial testing were negative by toxigenic culture and microwell enzyme immunoassay.
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Performance Compared to Commercially Available Devices:
The Xpect™ C. difficile Toxin A/B test was also compared to two commercially available rroducts. Each of the four clinical trial sites tested a chromatographic membrane assay that detects Toxin A only (Predicate Device), the Xpect™ C. difficile Toxin A/B test, and indi Golocie Toxil TTA) for each sample. In addition, one clinical trial site tested a microwell enzyme immunoassay for the detection of both Toxin A and B for each sample. The results presented below are calculated using CTA as the reference.
| n = 815 | n = 267 | |||
|---|---|---|---|---|
| Xpect™C. difficile Toxin A/B | PredicateDevice | Xpect™C. difficile Toxin A/B | EIA | |
| Sensitivity | 86.3% | 62.7% | 91.0% | 80.6% |
| Specificity | 96.2% | 98.8% | 98.0% | 97.5% |
| Agreement | 94.4% | 92.0% | 96.3% | 93.3% |
BHI Broth Culture Performance:
An in-house study was conducted using twenty-one known reference strains and thirty-six suspect Clostridium difficile isolates from stool specimens. BHI broth cultures were tested with the Xpect™ Clostridium difficile Toxin A/B test following 72hours incubation. Under these conditions, the BHI broth culture of Clostridium sordellii ATCC® 9714 produced a positive reaction. There was 94.7% (54/57) agreement with expected values.
Analytical Sensitivity:
The analytical sensitivity was evaluated using purified C. difficile Toxin A and Toxin B. Xpect™ C. difficile Toxin A/B assay detects Toxin A at levels of ≥ 6.25 ng/ml (0.12 ng/test device) and Toxin B at levels of ≥ 40.0 ng/ml (0.76 ng/test device).
Cross-Reactivity:
Fifty-four microorganisms were evaluated with the Xpect™ C. difficile Toxin A/B test. No cross-reactivity was observed. Bacteria and yeast isolates were tested at 10° colony-forming units per ml concentration. Viral isolates were tested at concentrations of 104 to 105 TCID50 (tissue culture infectious dose) per ml concentration. The following organisms were tested in the Xpect™ C. difficile Toxin A/B test.
| Aeromonas hydrophila | Proteus mirabilis |
|---|---|
| Bacillus cereus | Proteus vulgaris |
| Bacillus subtilis | Pseudomonas aeruginosa |
| Bacteroides fragilis | Salmonella Typhimurium |
| Campylobacter coli | Serratia liquefaciens |
| Campylobacter fetus subsp. fetus | Shigella boydii |
| Campylobacter jejuni subsp. jejuni | Shigella dysenteriae |
| Campylobacter lari | Shigella flexneri |
| Candida albicans | Shigella sonnei |
| Clostridium botulinum (toxin 20 µg/ml) | Staphylococcus aureus |
| Clostridium beijerinickii | (Cowan) |
| Clostridium difficile (non-toxigenic) | Staphylococcus epidermidis |
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Clostridium haemolyticum Clostridium histolyticum Clostridium innocuum Clostridium novvi Clostridium perfringens Clostridium septicum Clostridium sordellii Clostridium sporogenes Clostridium subterminale Clostridium tetani Enterobacter aerogenes Enterobacter cloacae Enterococcus faecalis Enterococcus faecium Escherichia coli Klebsiella pneumoniae Peptostreptococcus anaerobius Porphyromonas asaccharolytica
Vibrio cholerae Vibrio parahaemolvticus Yersinia enterocolitica Giardia intestinalis Entamoeba histolytica Adenovirus type 2 Adenovirus tvpe 40 Adenovirus type 41 Coxsackievirus B4 Cytomegalovirus Echovirus (type 22) Enterovirus (type 69) Rotavirus
Interfering Substances:
The following substances were tested with the Xpect™ C. difficile Toxin A/B test and no interference was observed in the assay for any substance tested at the indicated levels: blood, mucous, fecal fat, Pepto-Bismol® (10%V/v), Imodium® AD (10%v/v), Kaopectate® (10%v/v), Castoria® (10%v/v), vancomycin (12.5 mg/ml), metronidazole (12.5 mg/ml), and barium sulfate (12.5 mg/ml).
Reproducibility:
Reproducibility testing was conducted at three sites, including one in-house site, on four separate days with six blinded samples. The samples consisted of known positive and negative stool specimens. The samples produced the expected result with the Xpect™ C. difficile Toxin A/B test 98.6% (71/72) of the time.
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Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized image of an eagle with three curved lines representing its wings.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Nov 1 5 2004
Ms. Mary Ann Silvius Director. Business and Product Development Remel Inc. 12076 Santa Fe Drive Lenexa, KS 66215
Re: K041951 Trade/Device Name: Xpect TM Clostridium difficile Toxin A/B Regulation Number: 21 CFR 866.2660 Regulation Name: Microorganism Differentiation and Identification Device Regulatory Class: Class I Product Code: LLH Dated: October 19, 2004 Received: October 22, 2004
Dear Ms. Silvius:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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Page 2
This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). 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) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Sincerely yours,
Salartys
Sally A. Hoivat. 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
510(k) Number (if known):_____________________________________________________________________________________________________________________________________________________
Device Name: Xpect™ Clostridium difficile Toxin A/B
Indications For Use: REMEL's Xpect™ Clostridium difficile Toxin A/B is a rapid in vitro immunochromatographic test for the direct, qualitative detection of Clostridium difficile Toxin A and/or B in human fecal specimens from patients suspected of having Clostridium difficileassociated disease (CDAD). The test is intended for use as an aid in diagnosis of CDAD. The test can also be used for confirmation of toxigenic Clostridium difficile from Brain Heart Infusion (BHI) broth culture.
Prescription Use (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (Part 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)
Freddie A. Coode
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Salety
Page 1 of 1
510(k) K041951
§ 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.