(265 days)
The cobas® Cdiff Test on the cobas® 4800 system is an automated, qualitative in vitro diagnostic test, that utilizes realtime polymerase chain reaction (PCR), for the direct detection of the toxin B (tcdB) gene of toxigenic Clostridium difficile (C. difficile) in unformed (liquid or soft) stool specimens obtained from patients suspected of having C. difficile infection (CDI). The cobas® Cdiff Test is intended for use as an aid in the diagnosis of CDI in humans in conjunction with clinical and epidemiological risk factors.
The Roche Molecular Systems (RMS) cobas® Cdiff Test utilizes real-time polymerase chain reaction (PCR) for the detection of Clostridium difficile (C. difficile) DNA from unformed (liquid or soft) stool specimens to aid in the diagnosis of Clostridium difficile infections in humans. The cobas Cdiff Test contains two major processes: (1) automated sample preparation to extract nucleic acids from the unformed stool specimens; (2) PCR amplification of target DNA sequences using C. difficile specific primers, and real-time detection of cleaved fluorescentlabeled C. difficile specific oligonucleotide detection probes. An Internal Control (IC), containing unrelated randomized DNA sequence, is added to all samples prior to automated sample preparation and is amplified and detected simultaneously with each sample to monitor the entire process. The cobas® Cdiff Test utilizes six reagent kits and is used with the cobas® 4800 System, which includes the cobas x 480 Instrument for sample preparation and the cobas z 480 Analyzer for amplification and detection, controlled by the cobas® 4800 System Software.
Here's a summary of the acceptance criteria and study details for the cobas® Cdiff Test, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state quantitative acceptance criteria in a dedicated section. However, performance targets are implicitly demonstrated and met by the reported study results. The clinical performance section compares the cobas® Cdiff Test to a "combined direct and enrichment culture" which serves as the reference standard. The reported performance metrics are:
| Performance Metric | Acceptance Criteria (Implied by Study Results) | Reported Device Performance (95% CI) |
|---|---|---|
| Sensitivity | High (e.g., >85-90%) | 92.9% (131/141; 87.4% to 96.1%) |
| Specificity | High (e.g., >95%) | 98.7% (534/541; 97.4% to 99.4%) |
| Positive Predictive Value (PPV) | High (e.g., >90%) | 94.9% (89.9% to 97.5%) |
| Negative Predictive Value (NPV) | High (e.g., >95%) | 98.2% (96.6% to 99.0%) |
| Analytical Sensitivity (LOD) | Low concentration for 95% positive rate | 225 CFU/swab (highest LOD among 7 strains) |
| Inclusivity | ≥ 95% positive rate at specified concentration | Achieved for 28 additional toxigenic strains |
| Analytical Specificity (Cross-reactivity) | No cross-reactivity with common organisms | 0% (expected negative results for 131 organisms) |
| Cross-Contamination | Very low rate | 0.24% (1/423 negative samples became positive) |
| Carry-over Contamination | 0% | 0.00% (0/282 negative samples became positive) |
| Reproducibility (Positive Agreement) | High at 1xLOD and 3xLOD | 100.0% |
| Reproducibility (Negative Agreement) | High for negative samples | 100.0% |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Clinical Performance (Test Set): 682 specimens were included in the statistical analysis for comparison with combined direct and enrichment culture. 683 subjects were initially collected from.
- Data Provenance: Prospective, multi-site investigation across five geographically diverse sites in the US. The samples were "leftover, de-identified, unformed stool samples from subjects suspected of having CDI."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not explicitly state the number or qualifications of experts used to establish the ground truth. However, the ground truth for the clinical study was based on toxigenic culture, which involved laboratory procedures conducted at a "single reference laboratory." This suggests trained laboratory personnel, but no specific professional qualifications (e.g., "radiologist with 10 years of experience") are provided.
4. Adjudication Method for the Test Set
The primary ground truth for the clinical performance was established by toxigenic culture (direct and enrichment culture followed by cytotoxicity testing). Discrepant analysis was performed on all samples with discordant results and a random subset of concordant results between the cobas® Cdiff Test and toxigenic culture using a second FDA-cleared nucleic acid amplification test (NAAT). This indicates an adjudication method involving a third, independent test to resolve discrepancies.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not reported. This study evaluates the impact of AI on human reader performance. The cobas® Cdiff Test is an automated diagnostic test that doesn't involve human interpretation of images or complex data in a way that an MRMC study would be applicable.
6. If a Standalone Study Was Done
Yes, a standalone study was done. The entire clinical performance evaluation directly assesses the performance of the cobas® Cdiff Test (the algorithm/device) against the established ground truth (toxigenic culture) without human intervention in the interpretation of the device's results.
7. The Type of Ground Truth Used
The ground truth used for the clinical performance evaluation was expert consensus informed by culture and cytotoxicity testing. Specifically, a specimen was considered positive for toxigenic C. difficile if C. difficile was recovered from stool by either direct or enriched toxigenic culture and if isolates recovered tested positive by cytotoxicity testing. Specimens were negative only if they tested negative by both direct, repeat direct, and enrichment culture. Additionally, a second FDA-cleared NAAT was used for discrepant analysis, further supporting the ground truth adjudication.
8. The Sample Size for the Training Set
The document does not provide information on the sample size for the training set. This K142422 submission focuses on the performance of a developed device, not on the details of its developmental training data.
9. How the Ground Truth for the Training Set Was Established
The document does not provide information on how the ground truth for the training set was established. The submission focuses on the clinical validation of the device, not its initial development or training process.
§ 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.