(19 days)
None.
Not Found
No
The device description details image analysis based on predefined criteria (EpCAM+, CK+, DAPI+, CD45-) and user classification, not AI/ML algorithms. The performance studies focus on analytical and clinical outcomes based on a fixed cutoff value, not on the performance of an AI/ML model.
No
The device is an in vitro diagnostic device used to enumerate circulating tumor cells, which is a diagnostic function, not a therapeutic one.
Yes
The "Device Description" explicitly states, "The CellSearch Assay is a semi-automated in vitro diagnostic device." Additionally, the "Intended Use" describes its purpose as enumerating circulating tumor cells associated with patient prognosis, which is a diagnostic function.
No
The device description clearly states it is a "semi-automated in vitro diagnostic device" that includes a "CellSpotter™ Analyzer" which is a hardware component used for data acquisition and analysis. While software is involved in image analysis and counting, it is part of a larger system that includes physical reagents and hardware.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states it's for the "enumeration of circulating tumor cells (CTC) of epithelial origin... in whole blood." This is a diagnostic purpose performed on a biological sample (blood) outside of the body.
- Device Description: The description clearly states, "The CellSearch Assay is a semi-automated in vitro diagnostic device." This is a direct declaration of its classification.
- Process: The process involves collecting a blood sample, adding reagents, and analyzing the sample to identify and count specific cells. This is the core function of an in vitro diagnostic test.
N/A
Intended Use / Indications for Use
The CellSearch™ Epithelial 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™ Epithelial Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer.
Product codes (comma separated list FDA assigned to the subject device)
NQI
Device Description
The CellSearch™ Epithelial Cell Kit analyzed on the CellSpotter™ Analyzer is called the CellSearch Assay. The CellSearch Assay is a semi-automated in vitro diagnostic device.
Epithelial cells are immunomagnetically labeled by targeting the Epithelial Cell Adhesion Molecule (EpCAM) antigen. Anti-EpCAM monoclonal antibodies conjugated to ferrofluid particles are colloidal and, when mixed with a sample containing the target epithelial cells, bind to the EpCAM antigen associated with the epithelial cells. After immunomagnetic selection of epithelial cells from 7.5 mL of blood, fluorescent reagents are added at this time to discriminate between the immunomagnetically selected cells. Anti-Cytokeratin - Phycoerythrin (CK-PE) stains the intracellular cytoskeleton cytokeratin proteins expressed in cells of epithelial origin, anti-CD45-Allophycocyan (CD45-APC) stains leukocytes and DAPI stains DNA present in the cell nucleus. A strong magnetic field is applied to the processed reagent/sample mixture that causes the labeled target cells to move to the cartridge surface. The cartridge is then placed on the CellSpotter™ Analyzer for data acquisition and analysis. The CellSpotter™ Analyzer acquires images of PE, APC and DAPI fluorescence staining of the entire viewing surface.
After data acquisition is completed, the images are analyzed for any event where cytokeratin-PE and DAPI are within a specified space in the CellSpotter™ Cartridge, i.e. indicating the possible presence of a cell with a nucleus that expresses cytokeratin. Images from each fluorescent color as well as a composite image of the cytokeratin staining (green) and the nuclear staining (purple) are presented to the user in a gallery for final cell classification. A cell is classified as a tumor cell when it its EpCAM+ (i.e., it is captured), CK+, DAPI+ and CD45-. A check mark placed by the operator next to the composite images classifies the event as a Circulating Tumor Cell (CTC) and the software tallies all the checked boxes to obtain the CTC count.
The CellSearch™ Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nano-particles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the Epithelial Cell Adhesion Molecule (EpCAM) antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and enumeration of CTC. Anti-CK-PE is specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI stains the cell nucleus, and anti-CD45-APC is specific for leukocytes.
The reagent/sample mixture is dispensed by the CellPrep™ Semi-Automated Cell Preparation System into a CellSpotter™ Cartridge that is inserted into a MagNest™ fixture, a device of two magnets held together by steel. The strong magnetic field of the MagNest™ fixture causes the magnetically-labeled epithelial cells to move to the surface of the cartridge. The CellSpotter™ Analyzer automatically scans the entire surface of the CellSpotter™ Cartridge, acquires images and displays any event to the user where CK-PE and DAPI are co-located. Images are presented to the user in a gallery format for final classification of the magnetically captured cells. An event is classified as a tumor cell when its morphological features are consistent with that of a cell and it exhibits the correct phenotype, i.e., EpCAM+, CK+, DAPI+ and CD45-.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Fluorescence microscopy
Anatomical Site
Whole blood / peripheral blood
Indicated Patient Age Range
Not Found
Intended User / Care Setting
For prescription use only.
Description of the training set, sample size, data source, and annotation protocol
The training set used to determine the optimal CTC cutoff consisted of 90 patients (from a total of 102 patients initially). The PFS time for each patient was calculated from the date of the 1st follow-up.
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Analytical Performance:
- Precision/Reproducibility:
- System Reproducibility with Spiked Specimens: Blood from a single healthy donor was pooled and 7.5 mL samples were spiked with SKBr-3 cells. Low cell spikes (~58 cells/7.5mL) and high cell spikes (~319 cells/7.5mL) were prepared and run in duplicate twice each day for 20 days, using blood from 20 different normal donors. Three operators, two CellPrep™ Systems, and two CellSpotter™ Analyzers were used.
- Low spike: N=80, Mean CTC Count per 7.5mL = 47, Total Precision Standard Deviation (ST) % CV = 15.8%.
- High spike: N=80, Mean CTC Count per 7.5mL = 258, Total Precision Standard Deviation (ST) % CV = 9.4%.
- System Reproducibility with Patient Specimens: 163 duplicate samples from 47 patients were processed on multiple systems at different sites. The regression equation for the comparison was y=0.98x + 0.67, r^2=0.9978.
- For duplicates with average CTC 80 weeks (>18 months).
- Median OS for ≥5 CTC: 43.3 weeks (~10.1 months).
- Log-rank p80 weeks (>18 months).
- Median OS for ≥5 CTC: 30.0 weeks (~7.0 months).
- Log-rank p80 weeks (18 months).
- Patients with ≥5 CTC at baseline that decreased to 5 CTC = 0, Min = 0, Max = 1.
- For duplicates with average CTC 80 weeks (>18 months).
- Non-malignant breast disease (N=101): Mean # CTC = 0.2, SD = 1.2, Patients with > 5 CTC = 1, Min = 0, Max = 12.
- Non-malignant other disease (N=99): Mean # CTC = 0.1, SD = 0.4, Patients with > 5 CTC = 0, Min = 0, Max = 3.
- System Reproducibility with Spiked Specimens: Blood from a single healthy donor was pooled and 7.5 mL samples were spiked with SKBr-3 cells. Low cell spikes (~58 cells/7.5mL) and high cell spikes (~319 cells/7.5mL) were prepared and run in duplicate twice each day for 20 days, using blood from 20 different normal donors. Three operators, two CellPrep™ Systems, and two CellSpotter™ Analyzers were used.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Not Found (Clinical sensitivity and specificity not done; Kaplan-Meier analysis used instead).
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
None.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
A. 510(k) Number:
-
B. Analyte:
EpCam, Cytokeratins 8, 18 and/or 19, and CD45 -
C. Type of Test:
Semi-automated Immunomagnetic and immunofluorescent
D. Applicant:
Veridex, LLC, A Johnson and Johnson Company
E. Proprietary and Established Names:
Cell Search Epithelial Cell Kit and CellSpotter Analyzer
F. Regulatory Information:
-
- Regulation section: 21 CFR 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system
- Classification: 2. Class II
-
- Product Code:
NQI System, immunomagnetic, circulating cancer cell, enumeration
-
- Panel:
Pathology 88
- Panel:
G. Intended Use:
The CellSearch™ Epithelial 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.
-
- Indication(s) for use:
The presence of CTC in the peripheral blood, as detected by the CellSearch™ Epithelial Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer.
- Indication(s) for use:
-
- Special condition for use statement(s): For prescription use only.
-
- Special instrument Requirements:
The CellPrep™ Semi-Automated Cell Preparation System and the CellSpotter™ Analyzer. The CellSpotter™ Analyzer is a semi-automated fluorescence microscope intended to enumerate fluorescently labeled cells that are immunomagnetically selected and distributed over a viewing surface
H. Device Description:
The CellSearch™ Epithelial Cell Kit analyzed on the CellSpotter™ Analyzer is called the CellSearch Assay. The CellSearch Assay is a semi-automated in vitro diagnostic device.
Epithelial cells are immunomagnetically labeled by targeting the Epithelial Cell Adhesion Molecule (EpCAM) antigen. Anti-EpCAM monoclonal antibodies
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conjugated to ferrofluid particles are colloidal and, when mixed with a sample containing the target epithelial cells, bind to the EpCAM antigen associated with the epithelial cells. After immunomagnetic selection of epithelial cells from 7.5 mL of blood, fluorescent reagents are added at this time to discriminate between the immunomagnetically selected cells. Anti-Cytokeratin - Phycoerythrin (CK-PE) stains the intracellular cytoskeleton cytokeratin proteins expressed in cells of epithelial origin, anti-CD45-Allophycocyan (CD45-APC) stains leukocytes and DAPI stains DNA present in the cell nucleus. A strong magnetic field is applied to the processed reagent/sample mixture that causes the labeled target cells to move to the cartridge surface. The cartridge is then placed on the CellSpotter™ Analyzer for data acquisition and analysis. The CellSpotter™ Analyzer acquires images of PE, APC and DAPI fluorescence staining of the entire viewing surface.
After data acquisition is completed, the images are analyzed for any event where cytokeratin-PE and DAPI are within a specified space in the CellSpotter™ Cartridge, i.e. indicating the possible presence of a cell with a nucleus that expresses cytokeratin. Images from each fluorescent color as well as a composite image of the cytokeratin staining (green) and the nuclear staining (purple) are presented to the user in a gallery for final cell classification. A cell is classified as a tumor cell when it its EpCAM+ (i.e., it is captured), CK+, DAPI+ and CD45-. A check mark placed by the operator next to the composite images classifies the event as a Circulating Tumor Cell (CTC) and the software tallies all the checked boxes to obtain the CTC count.
Substantial Equivalence Information: I.
-
- Predicate device name(s): None.
-
- Predicate K number(s): None.
-
- Comparison with predicate:
| DEVICE | PREDICATE |
|---|---|
| A. Similarities | |
| Not Applicable | Not Applicable |
| B. Differences | |
| Not Applicable | Not Applicable |
J. Standard/Guidance Document Referenced (if applicable):
-
- NCCLS Approved Guideline EP5A, "Evaluation of Precision Performance of Clinical Chemistry Devices".
-
- NCCLS Approved Guideline C28-A2, "How to Define and Determine Reference Intervals in the Clinical Laboratory".
K. Test Principle:
The CellSearch™ Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nano-particles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the Epithelial Cell Adhesion Molecule (EpCAM) antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for
2
identification and enumeration of CTC. Anti-CK-PE is specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI stains the cell nucleus, and anti-CD45-APC is specific for leukocytes.
The reagent/sample mixture is dispensed by the CellPrep™ Semi-Automated Cell Preparation System into a CellSpotter™ Cartridge that is inserted into a MagNest™ fixture, a device of two magnets held together by steel. The strong magnetic field of the MagNest™ fixture causes the magnetically-labeled epithelial cells to move to the surface of the cartridge. The CellSpotter™ Analyzer automatically scans the entire surface of the CellSpotter™ Cartridge, acquires images and displays any event to the user where CK-PE and DAPI are co-located. Images are presented to the user in a gallery format for final classification of the magnetically captured cells. An event is classified as a tumor cell when its morphological features are consistent with that of a cell and it exhibits the correct phenotype, i.e., EpCAM+, CK+, DAPI+ and CD45-.
L. Performance Characteristics (if/when applicable):
-
- Analytical performance:
- a. Precision/Reproducibility:
- System Reproducibility with Spiked Specimens i. Each day, blood from a single healthy donor was pooled and 7.5 mL samples were spiked with SKBr-3 cells. Low cell spikes (~58 cells/7.5mL) and high cell spikes (~319 cells/7.5mL) were prepared on CellPrep™ instruments and run in duplicate twice each day. This process was repeated each day for a period of 20 days as per NCCLS guideline EP5-A using blood from a total of twenty different normal donors. Over the course of the study, three operators, two different CellPrep™ Systems and two different CellSpotter™ Analyzers were used to generate the cell count data. Summary statistics for cell counts of the spiked samples are presented in Table 1.
Table 1. Summary of Precision Analyses
| Low | High | |
|---|---|---|
| N | 80 | 80 |
| Mean CTC Count per 7.5mL | 47 | 258 |
| Total Precision Standard | ||
| Deviation (ST) % CV | 15.8% | 9.4% |
ii. System Reproducibility with Patient Specimens A total of 163 duplicate samples were collected from 47 patients over the course of the clinical study. These samples were processed separately on multiple systems at different sites (including different CellPrepTM instruments) to determine the reproducibility of CTC measurements. The regression equation for the comparison of these 163 duplicate samples was y=0.98x + 0.67, r2=0.9978. Table 2 shows the summary of the data for
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replicates where the average of the two CTC results was 5.
Table 2. Reproducibility of CTC Counts in Duplicate Samples (n=163) with an Average of 5 CTC per 7.5 mL of blood
| | CTC 1, patients with 1 CTC (red line) had a PSF time of 3.4 months.
The median PFS reached an initial plateau in the positive patient group at a PSF of 1.4 months for a cutoff of 5 or more CTC (criterion 2 above). This 5 CTC cutoff is well above the normal CTC background of 0 to 2 CTC (criterion 1 above). The third criterion used to define the cutoff was the Cox hazard's ratio; at 5 CTC the Cox hazard's ratio was 2.41, at 4 CTC it was 2.36 and at 6 CTC it also was 2.34. Thus, the 5 CTC cutoff provided the highest Cox hazard's ratio at or adjacent to the plateau defined by the median PFS. Based on the criteria outlined above, a cutoff of 5 or more CTC was chosen, and is indicated by a vellow line in Figure 1.
The cutoff of 5 CTC was determined using only results from the 1st follow-up and PFS as the outcome. Additional analyses have shown that the cutoff for OS at the 1st blood draw, as well as for PFS and OS at baseline, may differ from 5 CTC. For purposes of uniformity and simplicity in the interpretation of test results (by the clinician), a CTC cutoff of 5 was used for all analyses.
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Image /page/6/Figure/1 description: This figure shows three different plots. The first plot shows the Cox Hazard's Ratio, the second plot shows the median PFS for patients with less than CTC# at the 1st follow-up blood draw, and the third plot shows the median PFS for patients with greater than or equal to CTC# at the 1st follow-up blood draw. The x-axis shows the 1st follow-up blood draw CTC cutoff, and the y-axis shows the median PFS in months and the Cox Hazard's Ratio.
Figure 1. Determination of CTC Cutoff Using Median PFS in Training Set (n=90)
Figure 2 shows the median PFS for the positive patients (red line) and the percentage of positive patients (black line) for the Training Set at the cutoffs where either of these values changed. At the 5 CTC cutoff, 30% of patients are within the positive group and have a median PFS of 1.4 months.
Figure 2
Image /page/6/Figure/5 description: The image shows two line graphs that compare the percentage of patients with a circulating tumor cell (CTC) number at the first follow-up blood draw and the median progression-free survival (PFS) for patients with a CTC number at the first follow-up blood draw. The x-axis represents the CTC cutoff number, while the left y-axis represents the percentage of patients, and the right y-axis represents the median PFS in months. As the CTC cutoff number increases, both the percentage of patients and the median PFS generally decrease. For example, at a CTC cutoff of 1, approximately 54% of patients have a CTC number at the first follow-up blood draw, with a median PFS of 3.4 months.
The cutoff chosen also corresponded well with expected values determined with populations of healthy volunteers, persons with non-malignant breast disease, and persons with non-malignant other
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disease. (See Table 3). Single point CTC analyses were performed on control groups of 145 healthy volunteers, 101 women with non-malignant breast disease, and 99 women with other non-malignant diseases.
Epithelial cells are not expected to be in the peripheral blood. Of the 345 total samples from healthy volunteers and women with nonmalignant disease, only one subject had more than 5 CTC/7.5 mL. The results are presented in Table 3.
Table 3. Control Subjects
| Category | N | Mean
CTC | SD | # Patients
with > 5 CTC | Min.* | Max.* |
|---------------------------------|-----|---------------|-----|----------------------------|-------|-------|
| Healthy | 145 | 0.1 | 0.2 | 0 | 0 | 1 |
| Non-malignant
breast disease | 101 | 0.2 | 1.2 | 1 | 0 | 12 |
| Non-malignant
other disease | 99 | 0.1 | 0.4 | 0 | 0 | 3 |
- NCCLS Guideline C28-A2
Based on the above data and analyses, the optimal CTC cutoff was determined to be at 5 CTC per 7.5 mL of blood. The FDA statistician, Harry Bushar, Ph. D., checked all of the statistical claims and agreed that the cutoff chosen by the sponsor was optimal.
2. Comparison studies:
- Method comparison with predicate device: a. Since the claimed predicate device was so different from the new device, no comparative studies were able to be performed.
- b. Matrix comparison: Since the only matrix claimed was blood, no matrix comparison studies were necessary nor performed.
-
- Clinical studies:
- Clinical sensitivity: a.
Not done. Kaplan-Meier analysis.
- b. Clinical specificity: Not done. Kaplan-Meier analysis
- Other clinical supportive data (when a and b are not applicable) C.
Summary of Clinical Trial Results
Metastatic Breast Cancer Patients
A multi-center prospective, longitudinal clinical trial was conducted to determine whether trends in the number of CTCs correlates with disease progression. Only patients with measurable disease and who were starting therapy were enrolled (N=177). Patients were included on an intent to treat basis.
Clinical Trial Results
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Baseline CTC count was determined prior to initiation of a new line of therapy. A first follow-up CTC count was determined after the initiation of therapy. For the baseline analyses. PFS was measured from the time of the baseline blood draw to the diagnosis of progression by CT scans and/or clinical signs and symptoms, and OS was measured from the time of baseline blood draw to the time of death. For the first follow-up analyses, PFS was measured from the time of 1st follow-up blood draw (mean 4.5 + 2.4 weeks following enrollment) to diagnosis of progression or death, and OS was measured from the time of 1st follow-up blood draw to the time of death.
Progression Free Survival (PFS) Analysis
PFS Using Baseline CTC Results
All 177 patients had a baseline CTC test performed. For Kaplan-Meier analysis, patients were segmented into two groups based upon their CTC count at baseline:
- Negative group (N=90), represented in green, was those patients with 5 CTC.
Median PFS was 30.3 weeks (~7.0 months) for the Negative group and 11.7 weeks (~2.7 months) for the Positive group. The difference in PFS between the two groups is highly significant (Log-rank p=0.0001, Cox Hazards Ratio=1.9547, chisquare=15.33, p = 0.0001). These results are illustrated in Figure 1
Image /page/8/Figure/8 description: This image is a Kaplan-Meier plot showing the probability of progression-free survival over time. There are two curves, one for patients with less than 5 CTCs at baseline and another for patients with 5 or more CTCs at baseline. The median progression-free survival time for patients with less than 5 CTCs at baseline is 30.3 weeks, while for patients with 5 or more CTCs at baseline, it is 11.7 weeks. The log-rank p-value is 0.0001, the Cox hazards ratio is 1.9547, and the chi-square value is 15.33.
Figure 1. PFS of Patients with 5 CTC at Baseline (N=177).
PFS Using 1st Follow-up CTC Results
Of the 177 patients, 23 were not evaluable at first follow-up. Of these 23 patients, ten patients died before a follow-up blood draw could be obtained, nine patients progressed prior to the 1st follow-up blood draw, and four were lost to follow-up. Additionally, the ten patients who died had high to extremely high CTC counts at baseline (CTC counts 9. 11, 15, 24, 111, 126, 301, 1143, 4648 and 23618). For Kaplan-Meier analysis, patients were segmented into two groups based upon their CTC count at 1st follow-up:
- Negative group (N=111), represented in green, was those patients with 5 CTC. .
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Median PFS was 26.4 weeks (~6.1 months) for the Negative group and 5.7 weeks (~1.3 months) for the Positive group. The difference in PFS between the two groups is highly significant (Log-rank p 5 CTC at 1st Follow-Up (N=154).
Predictive Value of CTC on PFS
For Kaplan-Meier analysis, patients were segmented into three groups based on their CTC counts at baseline and 1st follow-up:
- Negative group (N=81), represented in green, was those patients with 5 CTCs at 1st follow-up.
Elapsed PFS time was calculated from the baseline blood draw. Three groups were plotted in Figure 3. The Negative group (N=81, green line) had a median PFS of 30.3 weeks (~7.0 months) and the patients represented by the olive green line (N=33) had a median PFS of 32.9 weeks (~7.6 months). The Positive group (N=49, red line) had a median PFS of 8.9 weeks (~2.1 months). The difference in the PFS of the patients in the Negative and olive green groups compared to the PFS of the patients in the Positive group is highly significant (Log-rank p5 CTC at baseline) died. Median OS was greater than 80 weeks (>18 months) for the Negative group and 43.3 weeks (~10.1 months) for the Positive group. The OS difference between the two groups is highly significant (Log-rank p 5 CTC at Baseline (N=177).
Image /page/10/Figure/6 description: This image is a survival plot showing the probability of survival over time. The x-axis represents time from baseline in weeks, and the y-axis represents the probability of survival. There are two curves on the plot, one for patients with less than 5 CTCs at baseline and one for patients with greater than or equal to 5 CTCs at baseline. The median survival time for patients with less than 5 CTCs at baseline is greater than 80 weeks, while the median survival time for patients with greater than or equal to 5 CTCs at baseline is 43.3 weeks.
OS Using 1st Follow-up CTC Results
For Kaplan-Meier analysis, patients were segmented into two groups based upon their CTC count 1st follow-up:
- Negative group (N=114), represented in green, was those patients with 5 CTC.
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Fifty-six patients died of the 163 patients who were evaluable at the first follow-up. Twenty-three (20%) from the Negative group died with a median OS greater than 80 weeks (>18 months). Thirty-three (67%) from the Positive group died, with a median OS of 30.0 weeks (~7.0 months). The difference in OS between the two groups is highly significant (Log-rank p5 CTC at 1st ● follow-up,
Figure 6 illustrates that a decrease to 80 weeks (18 months) and the patients represented by the olive green line (N=33) had a median OS of 62.6 weeks (~14.6 months). The Positive group (red line) had a median OS of 35.4 weeks (~8.2 months). This difference in the OS of the patients in the Negative and olive green groups compared to the OS of the patients in the Positive group is highly significant (Log-rank p 5 CTC | Min.* | Max.* |
|---------------------------------|-----|---------------|-----|----------------------------|-------|-------|
| Healthy | 145 | 0.1 | 0.2 | 0 | 0 | 1 |
| Non-malignant
breast disease | 101 | 0.2 | 1.2 | 1 | 0 | 12 |
| Non-malignant
other disease | 99 | 0.1 | 0.4 | 0 | 0 | 3 |
Table 3. Control Subiect
M. Instrument Name:
CellSpotter™ Analyzer
N. System Descriptions:
- Modes of Operation: 1.
- semi-automated
2. Software:
Operating System -Windows NT 4.0
- User Interface -
Primarily written in Visual Basic; Graphic User Interface (GUI)
- NCCLS Guideline C28-A23
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Communication -
No communication in or out of the system;
No LIMs or LIS System interface (no standards exist for this device) Data Management -
DB2 database from IBM is used for data management
FDA has reviewed applicant's Hazard Analysis and software development processes for this line of product types: Yes X
-
- Sample Identification: Sample information is manually entered by user from printout from CellPrep
-
- Specimen Sampling and Handling: Sample prepared on the CellPrep™ Analyzer and manually placed into instrument
-
- Assay Types: Cytochemistry image analysis
- Reaction Types: 6. Fluorescence microscopy
-
- Calibration: None
-
- Quality Control: The CellSearch™ Control Cell Kit is provided by the manufacturer to control the system.
O. Other Supportive Instrument Performance Characteristics Data Not Covered In The "L. Performance Characteristics" Section Of The SE Determination Decision Summary.
Recovery
Blood from a single healthy donor was pooled and five 7.5 mL samples were spiked with cells of a breast cancer cell line (SKBr-3). Serial dilutions were performed resulting in twenty-five samples with expected cell counts ranging from 4 to 1142 cells per 7.5 mL. These samples were processed on CellPrep™ instruments, analyzed over five consecutive days, and the results of the observed cell counts were plotted against the results of the expected cell counts. The mean recovery of cells ranged from 85 to 123%. However, because of the low cell numbers and the inherent variation in spiking low numbers of cells, recovery at the low end of the range was imprecise. A difference of only 2 cells in the lowest dilution represents a 50% difference. 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 25 samples was Y=0.85x +5.64, R =0.9973. Analysis of the regression data showed that the 95% confidence interval of the intercept of 5.64 was -4.421 to 15.69, which overlaps zero and therefore is not statistically different from zero. This study suggests that the average recovery of spiked cells using the CellPrep™ instrument and the CellSearch™ Kit is approximately 85%.
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P. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.
Q. Conclusion:
The petition for Evaluation of Automatic Class III Designation for this device is accepted. The device is classified as Class II under regulation 21 CFR 866.6020 with special controls. The special control guidance document "Immunomagnetic Circulating Cancer Cell Selection and Enumeration System" is available at WWW.fda.gov/cdrh/oivd/guidance/1531.pdf