(30 days)
The UroVysion Bladder Cancer Recurrence Kit (UroVysion Kit) is designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from subjects with transitional cell carcinoma of the bladder. Results from the UroVysion Kit are intended for use as a noninvasive method for monitoring for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with bladder cancer.
The UroVysion Kit is based upon fluorescence in situ hybridization (FISH) DNA probe technology. The UroVysion probes are fluorescently labeled nucleic acid probes for use in in situ hybridization assays on urine specimens fixed on slides. The UroVysion Kit consists of a 4-color, four-probe mixture of DNA probe sequences homologous to specific regions on chromosomes 3, 7, 9, and 17. The UroVysion probe mixture consists of Chromosome Enumeration Probe (CEP®) 3 SpectrumRed™, CEP 7 SpectrumGreen™, CEP 17 SpectrumAqua™ and Locus Specific Identifier (LSI®) 9p21 SpectrumGold™.
Here's an analysis of the acceptance criteria and the study that proves the UroVysion Bladder Cancer Recurrence Kit meets those criteria, 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, based on the "Substantial Equivalence vs. BTAstat Test" section, the key performance metric for substantial equivalence appears to be that the 95% Confidence Intervals (CIs) for UroVysion's agreement percentages (positive, negative, and overall) are greater than the BTAstat test's scores minus 15%.
For other aspects, the "acceptance criteria" are implied by the reported performance deemed satisfactory for marketing authorization.
| Criteria Category | Acceptance Criteria (Implied/Derived) | Reported Device Performance |
|---|---|---|
| Hybridization Efficiency | ≥ 87% (for clinical practice simulation) | 87% (clinical study) |
| Analytical Specificity | No cross-hybridization to other chromosome loci | 100% (No cross-hybridization observed in 42 metaphase spreads) |
| Interference | No interference from tested substances/microbes/therapeutic agents | No interference detected from any tested substance |
| Preservative Equivalence | Acceptable microbial inhibition; average percent variation of signals per nucleus 95% accurate) | Mean signal numbers vary within a narrow range; 95% of observations on specimen 2 correctly classified as 9p21 loss; 1 false positive out of 16 normal specimen evaluations |
| Specificity (Non-cancer pts) | Overall specificity considered high (e.g., >90%) | Overall Specificity: 93.0% (332/357), Unique Patients: 94.5% (260/275) |
| Positive Agreement vs. SOCO | 95% CI > BTAstat score - 15% | 95% CI for UroVysion positive agreement (58.1%-81.8%) > BTAstat positive agreement (50.0%) - 15% (35.0%) |
| Negative Agreement vs. SOCO | 95% CI > BTAstat score - 15% | 95% CI for UroVysion negative agreement (56.3%-74.4%) > BTAstat negative agreement (69.3%) - 15% (54.3%) |
| Overall Agreement vs. SOCO | 95% CI > BTAstat score - 15% | 95% CI for UroVysion overall agreement (60.2%-74.5%) > BTAstat overall agreement (62.5%) - 15% (47.5%) |
| Longitudinal Study (Recurrence) | Statistically significant difference in recurrence rate between FISH+/cysto:histo- and FISH-/cysto:histo- groups | Significant difference (p=0.014) observed: 41.7% recurrence in FISH+/cysto:histo- vs. 19.1% in FISH-/cysto:histo- |
| Automated System Equivalence | Equivalent results with manual vs. semi-automated methods | All tested compounds and preservatives performed within 2 standard deviations of controls, supporting equivalence |
2. Sample Size Used for the Test Set and Data Provenance
- Specificity Study (Non-cancer patients):
- Sample Size: 315 patient visits initially, resulting in 309 usable office visits and ultimately 275 unique patients yielding informative results. The data points used for specificity calculation totaled 357 (some patients had multiple conditions).
- Data Provenance: Multi-center, prospective study. Patients were "healthy volunteers and urology patients without prior history or clinical evidence of bladder cancer." (implicitly from the US, given FDA submission context).
- Performance vs. Standard of Care (Bladder cancer recurrence monitoring):
- Sample Size: 309 patient visits initially, resulting in 251 usable office visits and 176 unique patients with informative FISH results.
- Data Provenance: Multi-center, prospective, longitudinal study. Patients had a "history of bladder cancer." (implicitly from the US, given FDA submission context).
- Reproducibility: 4 specimens from bladder carcinoma cell lines.
- Interference/Preservative: Three voided urine pools from normal healthy volunteers, spiked with various substances.
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 of experts used to establish the ground truth or their specific qualifications (e.g., "radiologist with 10 years of experience").
- For the Performance vs. Standard of Care study, the comparative reference was "cystoscopy followed by histology." Histology is typically interpreted by pathologists. The document mentions "central pathologist" in the longitudinal study details (Page 18), but doesn't specify how many or their experience level.
4. Adjudication Method for the Test Set
The document does not explicitly detail an adjudication method (e.g., 2+1, 3+1) for the ground truth establishment.
- For the "Performance vs. Standard of Care" study:
- "The comparative reference used for all percent agreement calculations was cystoscopy with histology confirmation for positive or suspicious cystoscopies."
- "If a patient had a positive cystoscopy but histology was absent (e.g., the lesion was fulgurated), then the specimen was considered positive for bladder cancer."
- "If a test had a suspicious cystoscopy but histology was absent, then the case was omitted from analysis."
This indicates a defined hierarchy and decision rule for establishing the ground truth (cystoscopy + histology).
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study
A MRMC study was not explicitly done comparing human readers with and without AI assistance, because the device is a Fluorescence in situ hybridization (FISH) DNA probe technology, not an AI-assisted diagnostic tool.
However, the study did compare the UroVysion Kit's performance to two other human-interpreted methods:
- BTAstat test (lateral flow assay, antigen-specific antibodies, qualitative interpretation)
- Cytology (visual interpretation of cells)
The study demonstrated the superiority of the UroVysion Kit over BTAstat and cytology, particularly in agreement of positive results across various tumor stages and grades. For example:
- Overall Agreement of (+) Results:
- UroVysion: 71.0%
- BTAstat: 50.0%
- Cytology: 26.2%
- For patients treated with BCG:
- UroVysion: 92.3%
- BTAstat: 69.2%
- Cytology: 30.8%
The basis for substantial equivalence was to demonstrate that the UroVysion Kit's 95% CIs for agreement were greater than the BTAstat test's score minus 15%, which it met across positive, negative, and overall agreement categories. This showcases a significant effectiveness improvement compared to a legally marketed predicate directly by the device itself, rather than human readers improving with AI assistance.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
The UroVysion Kit is a FISH assay that involves human visual interpretation by an analyst to recognize fluorescent signals. Therefore, its performance is inherently human-in-the-loop, and a standalone (algorithm only) performance study, in the context of AI, is not applicable. The detection relies on DNA probes and fluorescence, with an analyst visually counting signals, rather than an automated algorithm making the final call.
7. Type of Ground Truth Used
- Specificity Study: Ground truth was "healthy volunteers and urology patients without prior history or clinical evidence of bladder cancer."
- Performance vs. Standard of Care Study: Ground truth for bladder cancer recurrence was established by cystoscopy followed by histology confirmation. If cystoscopy was positive but histology was absent (e.g., lesion fulgurated), it was considered positive. Suspicious cystoscopies without histology were omitted. This can be categorized as a form of clinical outcome/pathology-confirmed diagnosis.
- Reproducibility and Analytical Specificity: Used cultured human bladder carcinoma cell lines (positive target) and normal lymphoblast cell lines (negative target), and metaphase spreads for structural analysis.
8. Sample Size for the Training Set
The document describes premarket clinical studies and does not refer to a "training set" in the context of machine learning. The studies are for device validation.
9. How the Ground Truth for the Training Set Was Established
As there is no mention of a "training set" for an AI algorithm, this question is not applicable to the provided document. The studies describe validation of a diagnostic kit based on established biological principles (FISH technology).
§ 866.6010 Tumor-associated antigen immunological test system.
(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.