(90 days)
Not Found
No
The device description details image acquisition and presentation for user classification, but there is no mention of automated image analysis or classification using AI/ML algorithms. The "Mentions AI, DNN, or ML" section is explicitly marked as "Not Found".
No.
Explanation: The device is intended for the enumeration of circulating tumor cells (CTC) to aid in monitoring patients with metastatic cancer by providing prognostic information, not for treating or preventing disease.
Yes.
The device is intended for the enumeration of circulating tumor cells (CTC) and is used as an aid in monitoring patients with metastatic breast, colorectal or prostate cancer, which directly supports diagnosis, monitoring, and prognosis.
No
The device description explicitly mentions physical components like a "ferrofluid-based capture reagent and immunofluorescent reagents," "nanoparticles with a magnetic core," a "cartridge," and a "MagNest® cell presentation device." It also relies on hardware systems like the "CellTracks® AutoPrep® System," "CellTracks Analyzer II," or "CellSpotter® Analyzer" for processing and image acquisition. While software is involved in image analysis and presentation, the device is fundamentally a system that includes hardware and reagents.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states that the kit is for the "enumeration of circulating tumor cells (CTC) of epithelial origin... in whole blood." This involves testing a sample taken from the human body (whole blood) to obtain information about a patient's health status (presence and number of CTCs).
- Device Description: The description details reagents and a system used to process and analyze a biological sample (blood) to identify and count specific cells (CTCs). This is a core function of an IVD.
- Clinical Data: The provided clinical data demonstrates how the results obtained from this device are used to aid in the monitoring and assessment of prognosis for patients with metastatic cancers. This information is used to make clinical decisions about patient care.
The definition of an In Vitro Diagnostic (IVD) is a medical device that is used to perform tests on samples such as blood, urine, or tissue, taken from the human body to detect diseases, conditions, or infections. The CellSearch™ Circulating Tumor Cell Kit clearly fits this definition.
N/A
Intended Use / Indications for Use
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.
Product codes
NQI
Device Description
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 -.
Mentions image processing
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.
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Peripheral blood
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies
Recovery
Study Type: Non-clinical data, recovery study
Sample Size: Blood samples from 5 healthy donors. Each donor's pooled blood was divided into six 7.5 mL aliquots, with five spiked with cultured breast cancer cells (SK-BR-3) at approximately 1300, 325, 81, 20, and 5 cells, and one unspiked aliquot as a zero point.
Key Results: The regression equation for these 30 samples was Y=0.93x + 3.87 with an R=0.999. The average recovery was 93%.
Linearity / Reportable Range
Study Type: Non-clinical data, linearity study (re-analysis of recovery data)
Key Results: 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). The detection of CTC was linear over the reportable range of 0 to 1238 tumor cells.
Limits of Detection
Study Type: Non-clinical data
Key Results: One CTC per 7.5 mL can be detected by the CellTracks® Analyzer II, resulting in a limit of detection of 1 CTC in a cartridge.
Reproducibility: System Reproducibility with CellSearch™ Circulating Tumor Cell Control
Study Type: Non-clinical data, reproducibility study
Sample Size: Three separate CellSearch™ Circulating Tumor Cell Control samples processed each day for over 30 days. N=99 for both low and high controls.
Key Results:
- Low control: Mean cell count 48, Total Precision Standard Deviation (ST) % CV 18%.
- High control: Mean cell count 969, Total Precision Standard Deviation (ST) % CV 5%.
Reproducibility: System Reproducibility with Patient Samples (Metastatic Breast Cancer)
Study Type: Non-clinical data, reproducibility study
Sample Size: 163 duplicate blood samples from 47 metastatic breast cancer patients.
Key Results: The regression equation was Y=0.98x + 0.67, R=0.99.
Reproducibility: System Reproducibility with Patient Samples (Metastatic Colorectal Cancer)
Study Type: Non-clinical data, reproducibility study
Sample Size: 1,627 duplicate blood samples from 430 MCRC patients.
Key Results: The regression equation was Y=0.98x + 0.18, R2=0.96. An independent study at Memorial Sloan-Kettering Cancer Center on metastatic prostate cancer patients showed no systematic site-to-site or tube-to-tube variation in CTC counts across a range of 0 to 1192 CTC per tube.
Metastatic Prostate Cancer (MPC) Patients - Clinical Trial
Study Type: Multi-center prospective, clinical trial
Sample Size: 231 metastatic prostate cancer patients with evidence of PSA progression despite standard hormonal therapy were enrolled. 219 evaluable patients for baseline analysis.
Key Metrics & Results:
- PFS Using Baseline CTC Results:
- Median PFS: 5.8 months for =5 CTC (N=125).
- Log-rank p-value: 0.0008.
- PFS Using Follow-up CTC Results (2-5, 6-8, 9-12, 13-20 Weeks):
- MPC patients with >=5 CTC/7.5mL whole blood had a much higher likelihood of rapid progression.
- Median PFS for =5 CTC ranged from 1.2 to 4.2 months.
- Log-rank p-values: All 5 CTC at all time points) had the shortest median PFS.
- CTC reduction (Group 2) significantly longer PFS compared to CTC increase (Group 3).
- OS Analysis Using Baseline CTC Results:
- Median OS: 21.7 months for =5 CTC (N=125).
- Log-rank p-value: =5 CTC at any time point had a much higher likelihood of dying sooner.
- Median OS for =5 CTC ranged from 6.7 to 11.5 months.
- Log-rank p-values: All =5 CTC at any point after initiation of therapy had a much higher likelihood of dying sooner.
- Patients with =5 vs. =5): HR=2.91, p=5): HR=3.75, p=0.001 for OS risk.
- Concordances between CTC and PSA Changes:
- 2-5 Weeks (Patient-Wise):
- Positive % Agreement: 49% (CI 41-58%)
- Negative % Agreement: 82% (CI 70-91%)
- Overall Agreement: 59% (CI 52-66%)
- Odds Ratio: 4.4 (CI 2.1-9.2)
- 13-20 Weeks (Patient-Wise):
- Positive % Agreement: 60% (CI 46-72%)
- Negative % Agreement: 89% (CI 80-95%)
- Overall Agreement: 77% (CI 69-84%)
- Odds Ratio: 11.8 (CI 4.9-28.3)
- Observation-Wise (all time points combined):
- Positive % Agreement: 51% (CI 46-56%)
- Negative % Agreement: 86% (CI 81-89%)
- Overall Agreement: 66% (CI 62-70%)
- Odds Ratio: 6.1 (CI 4.1-9.1)
- Overall concordance between CTC and PSA changes ranged from 59% to 77% (for >=30% PSA reduction) and 52% to 75% (for >=50% PSA reduction), indicating 25% to 40% discordance.
- 2-5 Weeks (Patient-Wise):
- CTC Levels and PSA Reduction Combined to Predict OS:
- Patients with >=5 CTC at any point had a much higher likelihood of dying sooner, irrespective of PSA changes.
- Favorable CTC at any time point were more accurate than PSA evaluation for predicting survival.
- In cases of discordance, CTC provided more accurate assessment of prognosis.
Key Metrics
Recovery: average 93% (linear regression R=0.999).
Linearity: slope 1.007, R2=0.990.
Limit of Detection: 1 CTC in a cartridge (per 7.5 mL).
System Reproducibility (Control): Low control: 18% CV; High control: 5% CV.
System Reproducibility (MBC Patients): Y=0.98x + 0.67, R=0.99.
System Reproducibility (MCRC Patients): Y=0.98x + 0.18, R2=0.96.
PFS (Baseline): 5.8 months (=5 CTC). p=0.0008.
OS (Baseline): 21.7 months (=5 CTC). p=5 CTC). p=30%): 17.2 months (>=30% red.) vs. 15.2 months (=5 CTC). p=30%): 22.8 months (>=30% red.) vs. 11.5 months (=5 CTC). p=30%): 18.5 months (>=30% red.) vs. 10.2 months (=5 CTC). p=30%): 17.7 months (>=30% red.) vs. 8.7 months (
§ 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system.
(a)
Identification. An immunomagnetic circulating cancer cell selection and enumeration system is a device that consists of biological probes, fluorochromes, and other reagents; preservation and preparation devices; and a semiautomated analytical instrument to select and count circulating cancer cells in a prepared sample of whole blood. This device is intended for adjunctive use in monitoring or predicting cancer disease progression, response to therapy, and for the detection of recurrent disease.(b)
Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Immunomagnetic Circulating Cancer Cell Selection and Enumeration System.” See § 866.1(e) for availability of this guidance document.
0
CellSearch™ Circulating Tumor Cell Kit Premarket Notification- Expanded Indications for Use-Metastatic Prostate Cancer
Image /page/0/Picture/1 description: The image shows a sequence of handwritten alphanumeric characters. The sequence starts with the letter 'K', followed by the number '0', then the number '7'. The sequence continues with three '3's and ends with the number '8'. The characters are written in a bold, slightly uneven style.
FEB 26 2003
SECTION 3
510(K) SUMMARY
1
Veridex. LLC CellSearch™ Circulating Tumor Cell Kit Premarket Notification- Expanded Indications for Use-Metastatic Prostate Cancer
VEΓIDEX
LLC
1001 US Highway 202 Raritan, NJ 08869
510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is
| 807.92 (a)(1): Name: | Veridex, LLC |
|---|---|
| Address: | 1001 US Highway 202 |
| Raritan, NJ 08869 | |
| Phone: | (908) 541-5843 |
| FAX: | (908) 575-3010 |
| Contact: | Debra J. Rasmussen |
| Worldwide Executive Director Regulatory Affairs |
807.92 (a)(2): Device Name - trade name and common name, and classification
| Trade name: | CellSearch™ Circulating Tumor Cell Kit |
|---|---|
| Common name: | CellSearch™ Circulating Tumor Cell Kit |
| Classification: | Immunomagnetic Circulating Cancer Cell Selection and |
| Enumeration System, Class II, 21 CFR 866.6020, Product | |
| Code NQI, Immunology Devices- 82 |
807.92 (a)(3): Identification of the legally marketed predicate device
CellSearch™ Circulating Tumor Cell Kit, K071729
807.92 (a)(4): Device Description
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.
2
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 -.
807.92 (a)(5): Intended use
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
807.92 (a)(6): Technological Similarities and Differences to Predicate
There have been no material changes to the CellSearch " Circulating Tumor Cell Kit; this 510(k) is being submitted for an expanded indication for use.
807.92 (b)(1): Brief Description of Non-clinical data
Recovery
Blood samples from a single healthy donor were pooled and five of six 7.5 mL aliquots were spiked with approximately 1300, 325, 81, 20, and 5 cultured breast cancer cells (SK-BR-3). The sixth tube was unspiked pooled blood and served as a zero point. These samples were processed on the CellTracks® AutoPrep® System with the CellSearch™ Circulating Tumor Cell Kit and CTC counts were determined on the CellTracks® Analyzer II. The experiment was repeated for four additional donors. The observed cell counts were plotted against the results of the expected cell count. The results are summarized in Table 1.
3
| Expected Tumor Cell
Count | Mean Observed
Tumor Cell Count | Range of Percent Recovery |
|------------------------------|-----------------------------------|---------------------------|
| 1300 | 1215 | 91 to 95% |
| 325 | 308 | 82 to 101% |
| 81 | 85 | 80 to 136% |
| 20 | 22 | 95 to 140% |
| 5 | 7 | 120 to 200% |
Table 1: Percent Detection Estimates.
To determine the overall, or least squares fit, for the comparison of the observed and expected cell counts across all the data, linear regression analysis was performed. The regression equation for these 30 samples was Y=0.93x + 3.87 with an R=0.999 (R=0.999). The results of this study indicate that on average, over the tested CTC range, the recovery, as derived from regression analysis, is 93%.
Given the linear response of the tumor cell counts, one would expect the slope of the observed versus expected plot to be 1.0. However, the slope was 0.93. This is because the CellTracks® AutoPrep® System with CellSearch™ CTC Kit involves the capture and fluorescent labeling of cells followed by their detection and enumeration by the CellTracks® Analyzer II. The loss of cells could therefore be attributed to one of the following possibilities; 1) the recovery of only 93% of the tumor cells spiked into 7.5mL of blood by the CellTracks® AutoPrep® System, 2) the detection of only 93% of the tumor cells present in the sample chamber by the CellTracks® Analyzer II or 3) a combination of both of these sources of error.
Linearity / Reportable Range
Another way to examine the previous data is to analyze it as a dilution series to evaluate test linearity. We removed the confounding variable of percent recovery by using the observed value of the initial sample in the dilution series (i.e. the first tube) divided by the dilution factors to determine the expected values for the dilution series for each patient sample. Regression of all of these numbers of observed tumor cells versus the numbers of expected tumor cells vielded a slope of 1.007, an intercept of 3.0, and an R2 = 0.990 (R = 0.995). Therefore, once the percent recovery (cell loss) was factored out of the CTC values of each of the initial samples, the analysis of the data demonstrated that the detection of CTC was linear over the reportable range of 0 to 1238 turnor cells.
Limits of Detection
One CTC per 7.5 mL can be detected by the CellTracks® Analyzer II resulting in a limit of detection of 1 CTC in a cartridge. Linear regression shows that on average, 93% of CTC present in a 7.5 mL blood sample are recovered using the CellTracks® AutoPrep® System (see Recovery section). The loss of approximately 7% of the CTC in the sample is not sufficient to reduce the limit of detection of I CTC.
Reproducibility:
a. System Reproducibility with CellSearch™ Circulating Tumor Cell Control
Three separate CellSearch" Circulating Tumor Cell Control samples were prepared and processed each day for over 30 days, per the long run method of NCCLS guideline EP5-A2. Each single-use sample bottle contains a low and a high concentration of cells from a fixed cell line that have been pre-stained with two different fluorochromes. Summary statistics for the high and low control cells is presented below.
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| Low | High | |
|---|---|---|
| N | 99 | 99 |
| Mean cell count | 48 | 969 |
| Total Precision Standard Deviation (ST) % CV | 18% | 5% |
Table 2. Summary of Precision Analyses
b. System Reproducibility with Patient Samples
Metastatic Breast Cancer (MBC)
A total of 163 duplicate blood samples were collected from 47 metastatic breast cancer patients over the course of the clinical study. These samples were processed at multiple sites to determine the reproducibility of CTC measurements. The regression equation for the comparison of these 163 duplicate samples was Y=0.98x + 0.67, R=0.99. Figure 1 shows a scatter plot of the duplicate CTC results in blood from MBC patients plotted on a logarithmic scale, with the threshold of 5 CTC indicated by the dashed lines.
Image /page/4/Figure/6 description: This image is titled "Figure 1: Reproducibility of CTC Counts in Duplicate MBC Samples (n=163) with Average of 5 CTC at 2-5 weeks (n=77).
Figure 4: PFS of MPC Patients with 5 CTC 2-5 weeks (n=203), 6-8 weeks (n=163), 9-12 weeks (n=149) and 13-20 weeks (n=143) after the initiation of therapy to predict time to death. OS times were calculated from the time of each blood draw.
- The Favorable group, represented in olive green, blue, purple, and cyan, consisted of patients . with 5 CTC at different time points
As illustrated in Figure 7 and Table 6 in columns 4 & 5, MPC patients with ≥5 CTC at any of the time points had a much higher likelihood of dying sooner than did those with