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510(k) Data Aggregation
(148 days)
The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood.
The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast or metastatic colorectal cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast or metastatic colorectal cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring breast and colorectal cancer. Evaluation of CTC at any time during the course of disease allows assessment of patient prognosis and is predictive of progression free survival and overall survival.
The CellSearch" Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nanoparticles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and enumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.
The reagent/sample mixture is dispensed by the CellTracks® AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks® Analyzer II or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45 -.
Here's a breakdown of the acceptance criteria and the study details for the CellSearch™ Circulating Tumor Cell Kit, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document describes several performance characteristics without explicitly stating "acceptance criteria" for each. However, the study results clearly demonstrate the device's performance in these areas.
| Performance Characteristic | Acceptance Criteria (Implicit) | Reported Device Performance |
|---|---|---|
| Recovery | High percentage of spiked tumor cells recovered. | 93% recovery on average over the tested CTC range (0-1300 cells). Specifically: - 1300 expected: 1215 mean observed (91-95% range) - 325 expected: 308 mean observed (82-101% range) - 81 expected: 85 mean observed (80-136% range) - 20 expected: 22 mean observed (95-140% range) - 5 expected: 7 mean observed (120-200% range) Linear regression: Y=0.93x + 3.87, R=0.999. |
| Linearity/Reportable Range | Detection of CTCs should be linear over the reportable range. | Linear detection over the reportable range of 0 to 1238 tumor cells. After factoring out percent recovery, regression of observed vs. expected tumor cells yielded a slope of 1.007, an intercept of 3.0, and an R² = 0.990 (R = 0.995). |
| Limit of Detection (LoD) | Ability to detect a low number of CTCs. | 1 CTC per 7.5 mL can be detected by the CellTracks® Analyzer II. The 7% loss in recovery does not reduce this LoD. |
| System Reproducibility (Control) | Consistent results for control samples. | Low Control (N=99): Mean cell count 48, Total Precision Standard Deviation (% CV) 18%. High Control (N=99): Mean cell count 969, Total Precision Standard Deviation (% CV) 5%. |
| System Reproducibility (Patient Samples - MBC) | Consistent results for duplicate patient samples for MBC. | MBC (N=163 duplicate samples): Regression equation Y=0.98x + 0.67, R=0.99. |
| System Reproducibility (Patient Samples - MCRC) | Consistent results for duplicate patient samples for MCRC. | MCRC (N=1627 duplicate samples): Regression equation Y=0.98x + 0.18, R²=0.96. |
| PFS Prediction (MCRC) | Ability to differentiate patient groups with significantly different Progression Free Survival based on CTC levels. | Baseline CTC: Median PFS significantly longer in <3 CTC group (7.9 months) vs. ≥3 CTC group (4.5 months) (p=0.0002). Follow-up CTC (e.g., 1-2 weeks): Median PFS significantly longer in <3 CTC group (7.3 months) vs. ≥3 CTC group (3.8 months) (p<0.0001). This trend continues for all follow-up time points. Reduction/Increase in CTC: Group with <3 CTC at all time points had median PFS of 8.1 months; Group with ≥3 CTC at all time points had median PFS of 2.2 months (p<0.0001 for comparison). |
| OS Prediction (MCRC) | Ability to differentiate patient groups with significantly different Overall Survival based on CTC levels. | Baseline CTC: Median OS significantly longer in <3 CTC group (18.5 months) vs. ≥3 CTC group (9.4 months) (p<0.0001). Follow-up CTC (e.g., 1-2 weeks): Median OS significantly longer in <3 CTC group (15.7 months) vs. ≥3 CTC group (6.1 months) (p<0.0001). This trend continues for all follow-up time points. Reduction/Increase in CTC: Group with <3 CTC at all time points had longest median OS; Group with ≥3 CTC at all time points had shortest median OS (significant differences between groups). |
| Correlation with Imaging (MCRC) | CTC assessments should show a relationship with radiological assessments and overall survival. | Patient-wise comparison (CTC vs. Imaging or Death): - Positive % Agreement: 20% (12-30% CI) - Negative % Agreement: 95% (92-98% CI) - Overall Agreement: 79% (74-83% CI) - Odds Ratio: 5.2 (2.4-11.2) Observation-wise comparison (CTC vs. Imaging or Death): - Positive % Agreement: 21% (15-27% CI) - Negative % Agreement: 95% (93-96% CI) - Overall Agreement: 78% (75-81% CI) - Odds Ratio: 4.7 (2.8-7.7) CTC as adjunct to imaging: Multivariate Cox regression shows CTC (adjusted HR: 7.9) is a stronger predictor of OS than imaging (adjusted HR: 3.1) at 6-12 weeks. |
2. Sample Size Used for the Test Set and Data Provenance
The primary clinical study supporting the expanded indication for use involved Metastatic Colorectal Cancer (MCRC) patients.
- Sample Size (Test Set/Clinical Study): 430 MCRC patients with measurable disease.
- PFS Analysis: 413 patients for baseline, decreasing for follow-up time points (e.g., 356 for 1-2 weeks, 180 for 13-20 weeks).
- OS Analysis: 413 patients for baseline, decreasing for follow-up time points (e.g., 357 for 1-2 weeks, 193 for 13-20 weeks).
- CTC/Imaging Correlation: 366 MCRC patients for "patient-wise" comparison; 815 observations for "observation-wise" comparison.
- Data Provenance:
- The study was a multi-center prospective, clinical trial.
- The document does not explicitly state the country of origin, but the context of an FDA 510(k) submission for a US market device implies that the data likely includes US sites.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The term "ground truth" here refers to the clinical outcomes and radiological assessments used to validate the predictive power of CTC counts.
- Number of Experts: Not explicitly stated as a specific number of individual experts for "ground truth" establishment, but rather implied through standard clinical practice.
- Qualifications of Experts:
- Treating Oncologists: Determined the method of imaging and treatment for each patient.
- Certified Radiologist: Performed image interpretation at the participating site using RECIST uni-dimensional criteria.
- Clinical Data: Survival data (PFS and OS) are objective clinical endpoints collected as standard of care.
4. Adjudication Method for the Test Set
The document does not describe an explicit adjudication method (e.g., 2+1, 3+1) for establishing the "ground truth" from experts for the MCRC clinical study.
- Imaging Interpretation: Performed by a single "certified radiologist at the participating site using RECIST uni-dimensional criteria." This suggests individual expert reads rather than a consensus or adjudication panel for each image.
- Clinical Outcomes (PFS/OS): These are objective endpoints based on clinical assessments (CT scans, clinical signs/symptoms for progression; death for overall survival) monitored over time.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a multi-reader multi-case (MRMC) comparative effectiveness study comparing human readers with AI assistance versus without AI assistance was not reported in this summary.
The device is an enumerating system for circulating tumor cells, intended to provide a quantitative biomarker, not to assist human readers in interpreting medical images like a CAD system would. The clinical study evaluated the prognostic value of the CTC count itself, as determined by the system.
6. Standalone Performance Study
Yes, a standalone performance study was done. The CellSearch™ Circulating Tumor Cell Kit is designed to enumerate CTCs automatically (with user image verification). The studies on recovery, linearity, limits of detection, and reproducibility directly assess the standalone performance of the algorithm and system in generating CTC counts.
- The system uses CellTracks® AutoPrep® System for capture and fluorescent labeling, and CellTracks® Analyzer II or CellSpotter® Analyzer to scan, acquire images, and display events.
- "Images are presented to the user in a gallery format for final classification." This implies a human-in-the-loop for final classification of events as tumor cells if the automated system generates "events" for review, but the core enumeration process is largely automated and its performance characteristics (recovery, linearity, LOD) are measured on the system's output. The clinical outcome studies then evaluate the prognostic value of these counted CTCs.
7. Type of Ground Truth Used for the Test Set
The ground truth for the clinical effectiveness study in MCRC patients comprised:
- Clinical Outcomes/Survival Data:
- Progression Free Survival (PFS): Measured from baseline blood draw to diagnosis of progression by CT scans and/or clinical signs and symptoms.
- Overall Survival (OS): Measured from baseline blood draw to the time of death.
- Radiological Assessment: Disease status (Complete Response, Partial Response, Stable Disease, Progressive Disease) determined by a certified radiologist using RECIST uni-dimensional criteria.
8. Sample Size for the Training Set
The document does not provide information on a specific "training set" sample size for the algorithm within the device.
As this is a 510(k) submission for an expanded indication for an existing device (K062013), the underlying algorithm was likely developed prior to this submission. The summary focuses on the validation of the device's performance for the new indication and its analytical characteristics. If the algorithm uses machine learning components, its training set details are not included in this summary. The current document describes the validation (test) set for the expanded clinical indication.
9. How the Ground Truth for the Training Set Was Established
Since no "training set" is explicitly mentioned or detailed for the algorithm's development in this document, the method for establishing its ground truth is not provided. The reported studies primarily focus on the analytical performance and clinical utility of the already developed device.
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