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510(k) Data Aggregation
(90 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, colorectal or prostate* cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast, colorectal or prostate cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring metastatic breast, colorectal and prostate 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.
*Metastatic prostate cancer patients in this study were defined as having two consecutive increases in the serum marker PSA above a reference level, despite standard hormonal management. These patients are commonly described as having androgen-independent, hormone-resistant, or castration-resistant prostate cancer.
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 an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Device: CellSearch™ Circulating Tumor Cell Kit (expanded indications for use in Metastatic Prostate Cancer)
1. Table of Acceptance Criteria and Reported Device Performance:
| Acceptance Criteria Category | Specific Metric (as applicable) | Predetermined Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|---|
| Recovery | Regression analysis (slope, R-squared) | Slope = 1.0 (ideal) | Y = 0.93x + 3.87, R=0.999 (0.999) Average recovery: 93% |
| Linearity / Reportable Range | Regression analysis (slope, R-squared) | Slope ≈ 1.0 (after factoring out recovery loss) | Slope = 1.007, Intercept = 3.0, R² = 0.990 (R = 0.995) Range: 0 to 1238 tumor cells |
| Limits of Detection | Minimum detectable CTC count | 1 CTC per 7.5 mL | 1 CTC per 7.5 mL |
| System Reproducibility (Control) | % CV (low control) | Not explicitly stated, but generally <20% is acceptable for clinical assays | 18% |
| System Reproducibility (Control) | % CV (high control) | Not explicitly stated, but generally <10% is acceptable for clinical assays | 5% |
| System Reproducibility (Patient Samples MBC) | Regression analysis (slope, R) | Slope ≈ 1.0, R ≈ 1.0 | Y = 0.98x + 0.67, R=0.99 |
| System Reproducibility (Patient Samples MCRC) | Regression analysis (slope, R-squared) | Slope ≈ 1.0, R-squared ≈ 1.0 | Y = 0.98x + 0.18, R²=0.96 |
| Clinical Efficacy (PFS - Baseline CTC) | Log-rank p-value for <5 vs ≥5 CTC | p < 0.05 | p = 0.0008 |
| Clinical Efficacy (PFS - Follow-up CTC) | Log-rank p-value for <5 vs ≥5 CTC | p < 0.05 | <0.0001 for all follow-up time points |
| Clinical Efficacy (OS - Baseline CTC) | Log-rank p-value for <5 vs ≥5 CTC | p < 0.05 | p < 0.0001 |
| Clinical Efficacy (OS - Follow-up CTC) | Log-rank p-value for <5 vs ≥5 CTC | p < 0.05 | <0.0001 for all follow-up time points |
| Clinical Efficacy (PFS - CTC Reduction) | Survival difference between groups | Significantly longer PFS for CTC reduction groups | Median PFS for Group 2 significantly longer than Group 3; Group 4 shortest, Group 1 longest. |
| Clinical Efficacy (OS - CTC Reduction) | Survival difference between groups | Significantly longer OS for CTC reduction groups | Group 4 shortest median OS; Group 1 longest. Group 2 similar to Group 1; Group 3 shorter than Group 1, not significantly different from Group 4. |
| Multivariate Cox Regression (PFS AUC) | Hazard Ratio (HR) and p-value for CTC | HR > 1 and p < 0.05 | HR > 1 and p < 0.05 at most time points |
| Multivariate Cox Regression (OS AUC) | Hazard Ratio (HR) and p-value for CTC | HR > 1 and p < 0.05 | HR > 1 and p < 0.05 at most time points |
| Concordance with PSA (Overall Agreement) | % Agreement with 30% PSA reduction | Implied to be clinically acceptable for combined assessment | Ranging from 59% to 77% (patient-wise); 66% (observation-wise) |
Notes on Acceptance Criteria: The document does not explicitly state numerical acceptance criteria for most performance metrics. Instead, it presents the results of studies and statistical analyses, implying that the observed performance (e.g., strong linearity, good reproducibility, and statistically significant associations with clinical outcomes) met the internal and regulatory expectations for device approval. For clinical effectiveness, the key acceptance criterion is the demonstration of statistically significant associations between CTC counts and clinical outcomes (PFS and OS), and that CTC provides prognostic information, even in cases of discordance with PSA.
2. Sample Sizes Used for the Test Set and Data Provenance:
- Recovery: 30 samples (5 different spike levels x 5 donors + unspiked control, processed once). Data provenance: Blood samples from a single healthy donor pooled and spiked with cultured breast cancer cells (SK-BR-3), repeated for four additional donors. Not explicitly stated if prospective or retrospective, but likely prospective lab study.
- Linearity/Reportable Range: Same data as Recovery study (30 samples).
- Limits of Detection: Not a separate sample set, derived from Recovery data and system specifications.
- System Reproducibility (Control): N=99 for both low and high controls. Not explicitly stated if prospective or retrospective or country of origin, but implies controlled laboratory conditions over 30 days.
- System Reproducibility (MBC Patient Samples): 163 duplicate blood samples from 47 metastatic breast cancer patients. Data provenance: Not explicitly stated country of origin, appears to be retrospective analysis of samples collected during a clinical study.
- System Reproducibility (MCRC Patient Samples): 1,627 duplicate blood samples from 430 MCRC patients. Data provenance: Not explicitly stated country of origin, appears to be retrospective analysis of samples collected during a clinical study.
- Clinical Study (Metastatic Prostate Cancer Patients):
- Test set for clinical efficacy: 231 metastatic prostate cancer patients enrolled.
- PFS/OS analyses:
- Baseline: 219 patients
- 2-5 Weeks: 199 patients (PFS), 203 patients (OS)
- 6-8 Weeks: 141 patients (PFS), 163 patients (OS)
- 9-12 Weeks: 134 patients (PFS), 149 patients (OS)
- 13-20 Weeks: 116 patients (PFS), 143 patients (OS)
- Concordance with PSA: 197, 159, 146, and 138 patients at 2-5, 6-8, 9-12, and 13-20 weeks respectively had paired CTC and PSA data.
- Data Provenance: Multi-center prospective clinical trial. Country of origin not specified, but typically such trials would involve multiple sites in the US and/or Europe.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:
The document does not mention the use of experts to establish a "ground truth" for the test set in the traditional sense of image adjudication or pathological review for the clinical study.
- For the technical performance studies (Recovery, Linearity, LOD, Reproducibility), the "ground truth" for cell counts was effectively established by the engineered spiking of known numbers of cells (Recovery, Linearity) or by established analytical methods for the control materials. The CellTracks Analyzer II or CellSpotter Analyzer automatically scans and displays events, with a user performing final classification based on EpCAM+, CK+, DAPI+, CD45- phenotype and morphological features. While this involves human review, the expertise and number of individuals are not specified as a "ground truth" panel.
- For the clinical study (Metastatic Prostate Cancer), the "ground truth" for clinical outcomes (Progression-Free Survival and Overall Survival) was established through:
- Disease Progression: Determined by the clinical sites using PSA, imaging, and/or clinical signs and symptoms. This implies a standard clinical assessment by the patient's treating physicians and/or study investigators, not a centralized expert panel for ground truth labeling of images.
- Overall Survival: Determined from the date of death or date of last contact (for those still alive) from the study follow-up. This is an objective outcome.
Essentially, the device itself generates the "CTC count," and the study evaluates how these counts correlate with established clinical endpoints, rather than evaluating the accuracy of the CTC count against a separate "expert ground truth" for each specific scan.
4. Adjudication Method for the Test Set:
- Clinical Outcomes (PFS/OS): As noted above, disease progression was determined by the clinical sites using a combination of PSA, imaging, and clinical signs/symptoms. It is not described as a formal "adjudication panel" in the sense of multiple independent reviewers resolving discrepancies. Survival is an objective endpoint.
- CTC Enumeration: The CellTracks Analyzer II or CellSpotter Analyzer displays images of potential CTC events to a user for "final classification." The document does not detail an adjudication method (e.g., 2+1, 3+1) for these user classifications of CTCs, implying a single user's classification is considered the final count.
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. The study focused on the prognostic value of the device's output (CTC counts) as a standalone marker, not on how the device assists human readers in making a diagnosis or prognosis. The device enumerates CTCs, and a human user reviews the images for final classification, but the study design does not involve comparing human readers with and without AI assistance on a case set.
6. If a Standalone Study Was Done (Algorithm only without human-in-the-loop performance):
The device is described as having a human-in-the-loop component where 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." Therefore, the reported performance throughout the document (e.g., clinical efficacy) represents the performance of the system including the final human classification, not a purely standalone algorithm.
7. The Type of Ground Truth Used:
- For Technical Performance (Recovery, Linearity): Known spike concentrations of cultured cancer cells.
- For Clinical Efficacy (PFS, OS):
- Progression-Free Survival (PFS): Clinical determination of disease progression (based on PSA, imaging, and clinical signs/symptoms) or death.
- Overall Survival (OS): Date of death or last contact.
These are real-world clinical outcomes and are considered the definitive "ground truth" for prognostic value.
8. The Sample Size for the Training Set:
The document does not explicitly describe a separate "training set" in the context of developing the CellSearch™ Circulating Tumor Cell Kit. The studies described are primarily performance validation and clinical validation studies. The CellSearch system and its CTC enumeration method likely underwent internal development and optimization using various samples, but a formally documented "training set" for an AI/algorithm component is not presented. It refers to a "long run method of NCCLS guideline EP5-A2" for reproducibility with control samples, which implies standardized internal quality control, not an AI training set.
9. How the Ground Truth for the Training Set Was Established:
Since a formal "training set" for an AI/algorithm in the sense of machine learning is not described, the method for establishing its ground truth is also not detailed. The "ground truth" for the technical aspects of the device's operation (e.g., successful capture and identification of cells) would have been established through microscopy, immunostaining controls, and other laboratory techniques during the device's design and analytical validation.
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