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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.

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.

Here's a breakdown of the acceptance criteria and the study details for the CellSearch™ Epithelial Cell Kit and CellSpotter™ Analyzer, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the performance goals demonstrated in the clinical and analytical studies, particularly concerning the predictive power of the CTC count cutoff for patient outcomes. The primary clinical acceptance is based on the device's ability to identify patients with decreased Progression-Free Survival (PFS) and Overall Survival (OS) using a defined cutoff.

2. Sample Sizes Used for the Test Set and Data Provenance

• Analytical Test Sets (Precision, Linearity, Recovery, Specificity):

  • Spiked Specimens (SKBr-3 cells): 80 samples for low spike and 80 for high spike in precision studies (over 20 days, using blood from 20 different normal donors). 25 samples for linearity (serial dilutions of SKBr-3 cells spanning 4 to 1022 cells). 25 samples for recovery (serial dilutions of SKBr-3 cells spanning 4 to 1142 cells).
  • Patient Specimens (Reproducibility): 163 duplicate samples from 47 patients.
  • Control Subjects (Normal Background): 145 healthy volunteers, 101 women with non-malignant breast disease, 99 women with other non-malignant diseases (Total N=345).
  • Data Provenance: The document does not explicitly state the country of origin. The clinical trial involving metastatic breast cancer patients was a "multi-center prospective, longitudinal clinical trial," implying multiple sites within a country or countries (likely the US, given FDA submission). The analytical studies involve healthy donors and patient samples, also without explicit geographic origin. The clinical trial data is prospective.

• Clinical Test Set:

  • Metastatic Breast Cancer Patients: N=177 patients for the main clinical trial.
  • Training Set (for CTC Cutoff determination): 90 patients (subset of the 177).
  • PFS using Baseline CTC: N=177 (Split into <5 CTC group N=90, ≥5 CTC group N=87)
  • PFS using 1st Follow-up CTC: N=154 (177 - 23 non-evaluable). Split into <5 CTC group N=111, ≥5 CTC group N=43.
  • Predictive Value of CTC on PFS (3 groups): N=163. Negative (N=81), Decrease to <5 (N=33), Positive (N=49).
  • OS using Baseline CTC: N=177 (Split into <5 CTC group N=90, ≥5 CTC group N=87)
  • OS using 1st Follow-up CTC: N=163 (177 - 14 deaths/lost to follow-up, based on text: "56 patients died of the 163 patients who were evaluable at the first follow-up"; implies 177-14=163 eval at FU - this number seems to fluctuate slightly with PFS for FU analyses). Split into <5 CTC group N=114, ≥5 CTC group N=49.
  • Predictive Value of CTC on OS (3 groups): N=163. Negative (N=81), Decrease to <5 (N=33), Positive (N=49).
  • Data Provenance: Multi-center prospective, longitudinal clinical trial.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not mention experts being used to establish a ground truth for individual CTC counts in the test set.

• Ground Truth for Clinical Performance: The ground truth for the clinical studies (PFS and OS) was established by clinical outcomes data (disease progression determined by CT scans and/or clinical signs/symptoms, and patient death). The determination of CTC counts by the CellSearch™ system itself (which involves an operator to classify cells) serves as the "device output" that is then correlated with these clinical outcomes.
• CTC Final Classification: The CellSpotter Analyzer presents images to a user "for final cell classification." "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." This indicates human involvement in the final count, but not "experts" establishing a "ground truth" independent of the device's output and operator.

4. Adjudication Method for the Test Set

Not applicable in the usual sense of expert adjudication of device output. The device itself involves a human operator to perform the final classification of potential CTCs identified by the analyzer. This is inherent to the "semi-automated" nature of the device. There's no mention of multiple operators adjudicating discrepant counts or external expert review of the operator's classifications.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

No, a multi-reader multi-case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not done. This device is a semi-automated system where the "human reader" (operator) is an integral part of its final output (classifying the identified events as CTCs). The study focuses on the system's ability to count CTCs and correlate those counts with clinical outcomes of metastatic breast cancer patients.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done

No, a standalone algorithm-only performance study was not done. The device description explicitly states it is a "semi-automated" system. The CellSpotter™ Analyzer "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-. A check mark placed by the operator... classifies the event as a Circulating Tumor Cell (CTC)." This clearly indicates a human-in-the-loop process for obtaining the final CTC count.

7. The Type of Ground Truth Used

• Analytical Performance:
  • For precision, linearity, and recovery, the ground truth was spiked cells of a known concentration (SKBr-3 cell line).
  • For analytical specificity, the ground truth was controlled exposure to known interfering substances or physiological conditions.
  • For normal background, the ground truth was blood samples from presumptively healthy/non-malignant individuals.
• Clinical Performance:
  • For the determination of the clinical cutoff (5 CTCs) and the clinical utility studies (PFS and OS), the ground truth was clinical outcomes data: disease progression (diagnosed by CT scans and/or clinical signs and symptoms) and overall survival (time to death).

8. The Sample Size for the Training Set

• CTC Cutoff Determination Training Set: 90 patients. This was a subset of the 177 patients from the multi-center prospective clinical trial.

9. How the Ground Truth for the Training Set Was Established

The "ground truth" for the training set (in the context of determining the optimal CTC cutoff) was established by correlating the device's CTC counts with clinical progression-free survival (PFS) outcomes.

• The training set of 90 patients (who were not diagnosed with disease progression before or at first follow-up) was used.
• PFS was calculated from the date of the 1st follow-up.
• The system analyzed various CTC cutoffs (from 1 to 82, and up to 10,000) for their ability to differentiate median PFS for positive and negative patient groups.
• The optimal cutoff (5 CTCs) was determined based on three criteria:
  1. Above normal background levels.
  2. PFS of positive patients reached an initial plateau.
  3. Highest Cox hazard's ratio at or adjacent to the plateau.
• This process involved statistical analysis of the relationship between CTC counts obtained by the semi-automated device (with human operator classification) and the observed clinical PFS data. The FDA statistician, Harry Bushar, Ph. D., reviewed and agreed with the chosen optimal cutoff.

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