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510(k) Data Aggregation
(912 days)
Nucleix Ltd.
Bladder EpiCheck Kit is intended for the qualitative detection of DNA methylation patterns of 15 loci in human DNA that are associated with transitional cell carcinoma of the bladder. The test is performed on voided urine samples and run on the ABI® 7500 Fast Dx Real-Time PCR system.
Bladder EpiCheck Kit is indicated for use as a non-invasive method to monitor for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with Non-Muscle Invasive Bladder Cancer.
The Bladder EpiCheck Test is a real-time PCR-based in vitro diagnostic assay intended for the qualitative detection of DNA methylation patterns associated with transitional cell carcinoma of the bladder to monitor for tumor recurrence (in conjunction with cystoscopy) in patients previously diagnosed with non-muscle invasive bladder cancer (NMIBC).
The assay consists of a panel of 15 novel DNA methylation (covalent addition of methyl (CH3) groups to the C5 position of the pyrimidine ring of cytosines, typically in a CpG dinucleotide) biomarkers that were found to distinguish between patients with bladder cancer and patients without bladder cancer. The Bladder EpiCheck Test differentiates between methylated and non-methylated DNA, creating a unique platform for methylation profiling of urine specimens towards the detection of bladder cancer recurrence in patients previously diagnosed with the disease. The test is comprised of reagents for end-to-end (sample-to-answer) processing of urine samples (reagents for DNA extraction, DNA digestion, PCR amplification, and analysis software), and is performed using the Applied Biosystems® 7500 Fast Dx Real-Time PCR system.
A voided urine specimen is centrifuged, and the cells (both normal and cancerous if present) are separated from the urine supernatant. DNA is then extracted from the cell pellet using the Bladder EpiCheck Extraction kit (P/N NX899090-01C). The extracted DNA is digested using a methylation-sensitive restriction enzyme mix. which cleaves DNA at specific recognition sequences if they are unmethylated. Methylated DNA is protected from enzymatic digestion and therefore remains intact.
Here's a breakdown of the acceptance criteria and study details for the Bladder EpiCheck Kit, based on the provided FDA 510(k) summary:
Device: Bladder EpiCheck Kit
Intended Use: Qualitative detection of DNA methylation patterns of 15 loci in human DNA associated with transitional cell carcinoma of the bladder, used as a non-invasive method to monitor for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with Non-Muscle Invasive Bladder Cancer.
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in a dedicated table format. However, performance metrics are reported. Based on the "Method Comparison" section (9.2 Clinical), the de facto acceptance criteria appear to be tied to non-inferiority against the predicate device (UroVysion Bladder Cancer Kit) and sufficient performance against a Gold Standard.
| Performance Metric | Implicit Acceptance Criteria (Inferred from comparison to Predicate / Gold Standard) | Reported Device Performance (Bladder EpiCheck) |
|---|---|---|
| Against Gold Standard (Clinical Performance) | ||
| Accuracy | Must be clinically acceptable | 78.8% ([74.8%; 82.4%]) |
| Sensitivity | Must be clinically acceptable | 66.7% ([58.4%; 74.0%]) |
| Specificity | Must be clinically acceptable | 84.2% ([79.8%; 87.9%]) |
| Positive Predictive Value (PPV) | Must be clinically acceptable | 65.3% ([57.1%; 72.6%]) |
| Negative Predictive Value (NPV) | Must be clinically acceptable | 85.1% ([80.7%; 88.6%]) |
| Against Predicate Device (Comparative Effectiveness) | ||
| Sensitivity Difference | Non-inferior (e.g., within a predefined margin) | +4.82% (Bladder EpiCheck higher than UroVysion) ([ -5.7%; 15.3%]) |
| Specificity Difference | Non-inferior (e.g., within a predefined margin) | -2.97% (Bladder EpiCheck lower than UroVysion) ([ -7.8%; 1.9%]) |
| Analytical Performance (Examples) | ||
| Interlaboratory Reproducibility (Overall Agreement, Lab to Lab with contrived samples) | High agreement (e.g., >95%) | 99.3% ([98.28%; 99.72%]) |
| Interlaboratory Reproducibility (Overall Agreement, Lab to Lab with clinical samples) | High agreement (e.g., >95%) | 96.5% ([94.0%; 98.0%]) |
| Operator-to-Operator/Day-to-Day Reproducibility (Overall Agreement) | High agreement (e.g., >95%) | 99% ([96.4%; 99.7%]) (for Operator 1) and 99% ([94.6%; 99.8%]) (for Operator 2) |
| Lot-to-Lot/Instrument-to-Instrument Reproducibility (Overall Agreement) | High agreement (e.g., >95%) | 100.0% ([99.09%; 100.0%]) |
| Functional Limit of Detection (fLoD) | Clinically relevant lower limit | 0.186 ng/well (2.23 ng/sample) |
| Tumor Limit of Detection (tLoD) | Clinically relevant lower limit | 7.5% tumor DNA fraction (~0.17 ng tumor DNA) |
| Methylation Limit of Detection (mLoD) | Clinically relevant lower limit | 0.348% for BE-1, 0.06681% for BE-2 |
| Digestion Restriction Efficiency | >99% | >99.9% for all 15 biomarkers |
| Robustness (Contrived samples) | High agreement (e.g., >95%) | 98.5% ([96.77%; 99.31%]) |
| Robustness (Clinical samples) | High agreement (e.g., >95%) | 99.3% ([96.9%; 99.8%]) |
| Lack of Interference | No significant interference at clinical levels | No evidence of interference caused by substances tested at clinically relevant physiological ranges. |
| In-use & Real-time Stability (Overall Agreement) | No significant performance change | 100% agreement (for kit performance up to 486 days based on descriptions) |
| Freeze-Thaw Stability (Overall Agreement) | No significant performance change | No significant performance changes and low variability in EpiScore value between the 3 timepoints |
| Shipping Stability (Overall, Positive, Negative Agreement) | 100% | 100% |
| Sample Stability (Fresh Urine) | Clinically acceptable duration | 99.01% ([95.68%; 99.78%]) for 5 days |
| Sample Stability (Pelleted Urine) | Clinically acceptable duration | 100.0% ([97.08%; 100.0%]) for 19 days at -20°C |
| Sample Stability (Extracted DNA) | Clinically acceptable duration | 98.25% ([94.84%; 99.42%]) for 30 days at -20°C |
| DNA Extraction Efficiency (Overall, Positive, Negative Agreement) | 100% | 100% |
2. Sample Size and Data Provenance for Test Set (Clinical Performance Study)
- Sample Size:
- Against Gold Standard: 583 subjects (
total voided urine specimens collected from 583 subjects). Valid Bladder EpiCheck and GS results were obtained from 449 subjects. - Against Predicate Device (Matched Cases): Valid Bladder EpiCheck, UroVysion, and GS results were obtained from 352 samples.
- Specificity in Urology Patients without Bladder Cancer: 147 subjects.
- Clinical Specificity - Cross Reactivity with Other Cancers: 147 urine samples.
- Against Gold Standard: 583 subjects (
- Data Provenance:
- Country of Origin: U.S. and Canada (from 11 academic and urology specialty medical centers).
- Retrospective or Prospective: The main clinical study (Method Comparison) was a multi-center, prospective, IRB-approved longitudinal study. The specificity study in urology patients without bladder cancer was also multi-center, prospective. The cross-reactivity study utilized banked remnant de-identified urine samples, which would generally be considered retrospective.
3. Number of Experts and their Qualifications for Establishing Ground Truth for the Test Set
The document does not specify the number of experts or their qualifications for establishing the ground truth. It states that positive cases were confirmed by "cystoscopy and pathology." This implies that the ground truth was established by clinical diagnoses and pathological examination of tissue, presumably performed by trained urologists and pathologists, which are standard practices. No "experts" are explicitly described as reviewing cases for the purpose of establishing a "ground truth" consensus for the study, beyond the routine clinical workflow.
4. Adjudication Method for the Test Set
The adjudication method is implicitly described for the Gold Standard (GS) definition:
- "a subject was considered 'positive' if the interpretation for either cytology or the combined cystoscopy/pathology results were positive"
- "and a subject was considered 'negative' if both cytology and the combined cystoscopy/pathology results were negative."
This indicates a hierarchical or "any positive result makes it positive" adjudication for the ground truth definition. There is no explicit mention of an adjudication panel (e.g., 2+1, 3+1) for cases of disagreement between cytology and pathology results, or for disagreements among multiple readers of the ground truth modalities.
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 a molecular diagnostic test (in-vitro diagnostic) and not an imaging AI device that assists human readers. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply in this context. The comparison was between the Bladder EpiCheck test result and clinical ground truth (cytology/pathology), and between Bladder EpiCheck test results and the predicate device's test results.
6. Standalone (Algorithm Only Without Human-in-the-Loop) Performance Study
Yes, the device's performance, as reported in the "Method Comparison" section, is a standalone (algorithm only without human-in-the-loop) performance. The Bladder EpiCheck Kit provides a qualitative result (positive/negative) based on its algorithm (EpiScore), and this result is compared directly to the established Gold Standard.
7. Type of Ground Truth Used
The primary ground truth used for the clinical performance study consisted of:
- Combined Cystoscopy/Pathology data: This is the gold standard for definitive diagnosis of bladder cancer recurrence.
- Clinical Cytology: Urine cytology was also part of the Gold Standard definition.
Therefore, the ground truth is a combination of pathology (histopathological examination of biopsy/resection specimens) and outcomes data (clinical diagnosis via cystoscopy, supplemented by cytology).
8. Sample Size for the Training Set
The document refers to "Clinical Cutoff (Training and Feasibility Data)" in section 9.1.
- Total for software algorithm development: 178 samples.
- First set (for cut-off definition): 109 samples (40 control, 69 UCC positive).
- Second set (for cut-off validation): 67 samples (51 control, 16 UCC positive).
It's important to note that this "training" refers to the development and validation of the EpiScore algorithm's cutoff, not necessarily a machine learning training set in the AI sense.
9. How the Ground Truth for the Training Set Was Established
For the "training" set (used for algorithm development and cutoff definition, section 9.1), the ground truth was established by:
- "urine samples collected from control patients with a history of bladder cancer and bladder cancer positive patients confirmed by cystoscopy and pathology."
- "Urothelial Cell Carcinoma (UCC) positive patients confirmed by pathology."
Similar to the test set, the ground truth for algorithm development was based on definitive clinical diagnosis and pathological confirmation.
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