(148 days)
CellSearch™ Circulating Tumor Cell Kit, K062013
Not Found
No
The device description mentions automated image scanning and display, but the final classification of cells is explicitly stated to be performed by the user based on morphological features and phenotype. There is no mention of automated classification or analysis using AI/ML algorithms.
No
The device is used for enumerating circulating tumor cells to aid in monitoring cancer and assessing prognosis, not for treating a disease or condition.
Yes
The device is described as "an aid in the monitoring of patients with metastatic breast or metastatic colorectal cancer" and provides "assessment of patient prognosis and is predictive of progression free survival and overall survival," which are diagnostic purposes.
No
The device description clearly outlines physical components like reagents, nanoparticles, cartridges, and specialized hardware systems (CellTracks® AutoPrep® System, MagNest® device, CellTracks® Analyzer II or CellSpotter® Analyzer) that are integral to the device's function. While software is used for image analysis and display, it is part of a larger system that includes significant hardware and chemical components.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states that the kit is "intended for the enumeration of circulating tumor cells (CTC)... in whole blood." This is a test performed on a biological sample (whole blood) outside of the body to provide information about a patient's health status.
- Device Description: The description details reagents and a system used to process and analyze a blood sample to identify and count specific cells (CTC). This is characteristic of an in vitro diagnostic device.
- Clinical Study: The inclusion of a clinical study evaluating the performance of the test in patients with metastatic breast or colorectal cancer further supports its classification as an IVD, as IVDs are used to aid in clinical decision-making.
- Predicate Device: The mention of a predicate device (K062013; CellSearch™ Circulating Tumor Cell Kit) indicates that this device is being compared to a previously cleared IVD.
The device performs a test on a biological sample (blood) to provide information about the presence and number of circulating tumor cells, which is used as an aid in monitoring patients with metastatic breast or colorectal cancer. This aligns directly with the definition and purpose of an In Vitro Diagnostic device.
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 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.
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
Yes
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
Non-clinical data:
- Recovery: Blood samples from a single healthy donor were pooled and spiked with cultured breast cancer cells (SK-RR-3) at concentrations of approximately 1300, 325, 81, 20, and 5 cells. An unspiked sample 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.
- Sample size: 30 samples (6 aliquots per donor, 5 donors).
- Key results: Linear regression analysis yielded Y=0.93x + 3.87 with R=0.999 (R=0.999). Average recovery was 93%.
- Linearity/Reportable Range: This involved re-analyzing the recovery data as a dilution series.
- 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). Detection of CTC was linear over the reportable range of 0 to 1238 tumor cells.
- Limits of Detection:
- Key results: 1 CTC per 7.5 mL can be detected by the CellTracks® Analyzer II. The 93% recovery factor does not reduce the limit of detection of 1 CTC.
Reproducibility:
- System Reproducibility with CellSearch™ Circulating Tumor Cell Control: Three separate control samples were processed daily for over 30 days.
- Sample size: 99 high control samples, 99 low control samples.
- 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%.
- System Reproducibility with Patient Samples:
- Metastatic Breast Cancer (MBC): 163 duplicate blood samples collected from 47 MBC patients at multiple sites.
- Key results: Regression equation Y=0.98x + 0.67, R=0.99.
- Metastatic Colorectal Cancer (MCRC): 1,627 duplicate blood samples collected from 430 MCRC patients at multiple sites.
- Key results: Regression equation Y=0.98x + 0.18, R2=0.96.
- Metastatic Breast Cancer (MBC): 163 duplicate blood samples collected from 47 MBC patients at multiple sites.
Clinical Data (MCRC Patients):
- Study Type: Multi-center prospective, clinical trial.
- Sample size: 430 MCRC patients with measurable disease starting a new line of therapy. 413 patients had a baseline CTC result available for PFS/OS analysis.
- PFS Analysis using Baseline CTC Results:
- Sample size: 413 MCRC patients.
- Key results: Median PFS was significantly longer in the Favorable group (3 vs. 3 CTC at 1st Follow-Up after Initiation of Therapy (N=320):
- Key results: Median OS for
§ 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.
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Image /page/0/Picture/1 description: The image shows the word "VERIDEX" in all caps. The letters are stylized with a geometric, sans-serif font. Below the word "VERIDEX" is the text "LLC" in a smaller font size.
33 Technology Drive Warren, NJ 07059
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 K071729
| 807.92 (a)(1): | Name: | Veridex, LLC | |
|---|---|---|---|
| Address: | 33 Technology Drive | ||
| PO Box 4920 | |||
| Warren, NJ 07059 | NOV 20 2007 | ||
| Phone: | (908) 791-2438 | ||
| FAX: | (908) 791-2381 | ||
| 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, K062013
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.
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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 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.
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 indications 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-RR-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 Turnor 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 aspanst the results of the expected cell count. The results are summarized in Table 1.
| Table 1. Percent Detection Estimates. | ||
|---|---|---|
| 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% |
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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 yielded 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 tumor 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 1 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% |
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.
Figure 1. Reproducibility of CTC Counts in Duplicate MBC Samples (n=163) with Average of 3 CTC at Baseline (N=413).
PFS Using Follow-up CTC Results
For Kaplan-Meier analysis, patients were segmented into two groups based upon their CTC count at each of the various follow-up blood draws. Both patient groups at each of the different follow-up blood draw times after initiation of therapy for PFS are illustrated in Figure 4. PFS times were calculated from the time of each blood draw, and any patient showing evidence of progression prior to a particular blood draw was excluded from the analysis of that and all subsequent follow-up blood draws. Figure 4 illustrates the ability of CTC in MCRC patients
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with 3 CTC.
Figure 4: PFS of MCRC Patients with 3 CTC at different times of Follow-Up
Image /page/8/Figure/5 description: This image is a graph that shows the probability of progression-free survival over time. The x-axis represents time from blood draw in months, ranging from 0 to 30. The y-axis represents the probability of progression-free survival, ranging from 0% to 100%. There are multiple lines on the graph, representing different groups of patients based on CTC levels at different time intervals, such as 1-2 weeks, 3-5 weeks, 6-12 weeks, and 13-20 weeks, with sample sizes indicated for each group.
Table 5 summarizes the results of the PFS analysis using the CTC levels and a threshold of >3 CTC/7.5mL at each of the different blood draw time points.
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| 1 | 2 | 3 | 4 | 5 | 6 |
|---|---|---|---|---|---|
| Sampling Time | |||||
| After Tx Initiation | N | ≥3 | |||
| CTC | Median PFS in Months (95% CI) | ||||
| 3 CTC at different time points |
As illustrated in Figure 4 and Table 5, MCRC patients with elevated CTC (≥3 CTC/7.5mL whole blood) at any of the time points had a much higher likelihood of rapid progression than did those with CTC ranged from 6.3 to 7.9 months and were substantially longer than the median PFS times for those patients with ≥3 CTC, which ranged from 1.2 to 4.5 months (column 5).
Reduction or Increase in CTC Predicts Improved or Decreased PFS
Elapsed PFS times were calculated from the baseline blood draw. For Kaplan-Meier analysis (Figure 5), MCRC patients were segmented into four groups based upon their CTC counts at baseline, 1-2 weeks, 3-5 weeks, 6-12 weeks, and 13-20 weeks:
- Group 1 (green curve), 303 (70%) patients with 3 CTC at all time points (Group 4) had the shortest median PFS, which was significantly different compared to the median PFS of Group 3, Group 2 and Group 1. The difference in the median PFS between those patients who showed a CTC reduction after the initiation of therapy (Group 2) was significantly longer compared to those patients who showed a CTC increase (Group 3).
1.3 Overall Survival (OS) Analysis of MCRC Patients
OS Analysis Using Baseline CTC Results
Death occurred in 202 (47%) of the 430 MCRC patients, with a mean follow-up time for the 228 (53%) patients still alive of 12.6 ± 6.5 months (median = 11.0, range = 0.8 - 30.0). At the time of these analyses, 124 (41%) of 305 patients from Favorable group {3 CTC at baseline) had died.
For Kaplan-Meier analysis, patients were segmented into two groups based upon their CTC count at baseline:
- . The Favorable group (N=305), represented in green, consisted of patients with 3 CTC. .
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Median OS was significantly longer in the Favorable group compared to the Unfavorable group (18.5 vs. 9.4 months, respectively). These results are illustrated in Figure 6.
Image /page/11/Figure/2 description: This image is a survival plot that shows the probability of survival over time, measured in months from a baseline blood draw. There are two survival curves, one for patients with less than 3 CTC and one for patients with greater than or equal to 3 CTC. The median overall survival for patients with less than 3 CTC is 18.5 months, while the median overall survival for patients with greater than or equal to 3 CTC is 9.4 months. The Cox Hazard Ratio is 2.5, and the p-value is less than 0.0001.
Figure 6: OS of MCRC Patients with 3 CTC at Baseline (N=413).
OS Using Follow-up CTC Results
The Kaplan-Meier analyses of both MCRC patient groups at each of the different follow-up blood draw times after initiation of therapy are illustrated in Figure 7. This figure illustrates the ability of CTC in patients with > CTC 1-2 weeks, 3-5 weeks, 6-12 weeks and 13-20 weeks after the initiation of therapy to predict time to death in 421 patients with metastatic colorectal cancer. 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 3 CTC.
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Image /page/12/Figure/1 description: This image is a survival plot that shows the probability of survival over time in months from a blood draw. There are two groups of patients, one with less than 3 CTC and one with greater than 3 CTC. The survival curves are stratified by the time it took to clear CTCs, with the groups being 1-2 weeks, 3-5 weeks, 6-12 weeks, and 13-20 weeks. The sample sizes for each group are also provided.
Figure 7: OS of MCRC Patients with 3 CTC at different times of Follow-Up.
Table 6 summarizes the results of the OS analysis using the CTC levels and a threshold of ≥3 CTC/7.5mL at each of the different blood draw time points.
| Table 6: Overall Survival (OS) for MCRC patients with 3 CTC, which ranged from 3.3 to 9.4 months.
Reduction or Increase in CTC Predicts Improved or Decreased OS
Elapsed OS times were calculated from the baseline blood draw. For Kaplan-Meier analysis (Figure 8), MCRC patients were segmented into four groups based on their CTC counts at baseline, 1-2 weeks, 3-5 weeks, 6-12 weeks, and 13-20 weeks:
- Group 1 (green curve), 303 (70%) patients with 3 CTC:
- Group 2 (blue curve), 74 (17%) patients with >3 CTC prior to the initiation of therapy but . who had decreased to 3 CTC at baseline and 3 CTC at the last draw, and group 4 having >3 CTC at all draws. The median overall survival (OS) in months is also provided for each group, along with the p-values for curve comparisons.
Figure 8: A Reduction in CTC Below 3 After the Initiation of Therapy Predicts Longer OS whereas an Increase in CTC Count to 3 or above Predicts Shorter OS in MCRC Patients
Figure 8 shows that MCRC patients who exceed the threshold of 3 CTC at any point after the initiation of therapy had a much higher likelihood of dying sooner. Patients with >3 CTC at all time points (Group 4) had the shortest median OS, which was significantly different compared to the median OS of Group 2, Group 2 and Group 1. Patients with 3 or 3 or 3 | 3 | 3 | 3 | 3 | 3 CTC) groups using CTC results at two different time points and the first follow-up imaging study. Using results from the first followup imaging studies performed 9.1 + 2.9 weeks (median = 8.6 weeks) after initiation of therapy (i.e. the baseline blood draw), the median survival of the 307 (76%) patients determined by imaging to have NPD was 19.1 months (95% CI = 17.0 to 23.1) (Figure 9, Table 9). For the 95 (24%) patients determined by imaging to have PD, the median survival was 5.8 months (95% CI= 4.4 to 7.7).
A total of 320 MCRC patients had imaging studies performed before and after initiation of therapy or they died prior to a follow-up imaging study being performed and they had CTC assessed 3-5 weeks after initiation of therapy (average = 3.8 + 0.7 weeks from the time of the baseline blood draw, median = 4.0 weeks). The median survival of 282 (88%) patients with Favorable CTC results (3 CTC 38 (12%) 80% Cox Hazard Ratio = 4.1 70% chi-square = 34.85 robability of Surv (p-value 3 CTC at 1st Follow-Up after Initiation of Therapy (N=320)
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Image /page/21/Figure/1 description: The image is a title for a figure. The title is "Figure 11: Correlation of Radiological and CTC Assessment with OS: OS of MCRC Patients with 3 CTC / 7.5 mL.
Because the prognostic value of the CTC results at an earlier time-point were equivalent to that of the CTC results at the time of imaging (Figure 10 & Figure 11), a patient-wise comparison using results from only the 1st follow-up imaging study, performed approximately 9 weeks after the initiation of therapy, and the CTC results obtained approximately 4 weeks after initiation of therapy was constructed. A total of 320 (80%) of the 402 patients had CTC results 3-5 weeks after the initiation of therapy. The result of this "patient-wise" comparison between CTC at an earlier time point and imaging (or death) is shown in Table 12.
| Table 12: MCRC Patient-Wise Comparison of CTC and Imaging | on of the comments of the comments of the comments of the comments of the contribution of the contribution of the contribution of the contribution of the contribution of the | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| -- | -- | -- | -- | -- | ----------------------------------------------------------- | -- | -- | -- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
| Response at 1st Follow-Up
Imaging Study | CTC 3-5 Weeks
After Initiation of Therapy | | Total |
|--------------------------------------------|----------------------------------------------|-------------------|-------|
| | X
(Part 21 CFR 801 Subpart D) | AND/OR
maria in chan
Division Sign-Off | Over-the-Counter Use
(21 CFR 801 Subpart C) |
| ---------------------------------------------------------- | ----------------------------------------------------- | --------------------------------------------------------- |
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Office of In Vitro Diagnostic
Device Evaluation and Safety
| 510(k) | K071729
Page 4 of 33 |
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CONFIDENTIAL