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The Parsortix® PC1 system is an in vitro diagnostic device intended to enrich circulating tumor cells (CTCs) from peripheral blood collected in K>EDTA tubes from patients diagnosed with metastatic breast cancer. The system employs a microfluidic chamber (a Parsortix cell separation cassette) to capture cells of a certain size and deformability from the population of cells present in blood. The cells retained in the cassette are harvested by the Parsortix PC1 system for use in subsequent downstream assays. The end user is responsible for the validation of any downstream assay. The standalone device, as indicated, does not identify, enumerate or characterize CTCs and cannot be used to make any diagnostic/prognostic claims for CTCs, including monitoring indications or as an aid in any disease management and/or treatment decisions.

The Parsortix® PC1 system is a bench top laboratory instrument consisting of five main subsystem components:

• . Parsortix PC1 instrument incorporating a computer, keypad and display, pneumatic and hydraulic components including reservoir bottles and tubes, a separation cassette mounting clamp and other electronics to control the instrument hardware and behavior.
• Parsortix PC1 Software consisting of a Windows 7 Embedded operating system together . with dedicated Parsortix PC1 proprietary Windows application software (Software).
• A set of embedded and encrypted Protocol Files (Protocols) that are sequences of simple . instructions, interpreted by the Software and used to control the instrument fluidic and hydraulic components and circuits. The Protocols supplied embedded within the Software enable the four core instrument processes: Clean, Prime, Separate, and Harvest.
• Parsortix PC1 MBC-01 Metastatic Breast Cancer Kit which contains Separation Cassettes . (n = 10, 50 or 100), Cleaning Cassettes [(n = 1, 5, or 10), one Cleaning Cassette for every multiple of 10 x separation cassette], Encrypted Instrument protocol file distributed on a USB memory stick as required to perform the proposed intended use, Cassette labels and one package insert (per kit) containing instructions for use and expected performance data for the Parsortix PC1 instrument, when used in conjunction with the MBC-001 Metastatic Breast Cancer Kit.
• Parsortix PC1 ICT-01 Instrument Control Test Kit which contains Control tubes . containing a known, aliquoted cell suspension which is used to periodically confirm acceptable performance of the system, Separation Cassettes Polystyrene 12mL 16x100 mm tubes (n = 10 or 25) and one package insert (per kit) containing instructions for use for the ICT-001 Instrument Control Test Kit.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

The provided document details various analytical performance studies demonstrating the device's capabilities. While explicit "acceptance criteria" are not presented in a single, clear list with pass/fail thresholds, the studies' objectives and reported results implicitly define what was considered acceptable performance for the device's de novo classification. The performance data is summarized below based on these implicit criteria.

Table of Implicit Acceptance Criteria and Reported Device Performance

Study Information

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

The document details numerous analytical validation studies and two clinical studies. Given the nature of a CTC enrichment device, "test set" and "training set" aren't explicitly delineated for algorithm development as they would be for an AI model. Instead, performance is validated through various analytical and clinical studies.

Analytical Test Sets (Spiked Samples):

• Cell Recovery Studies:
  • High-level SKBR3 (125-1000 cells): 12 healthy donors (blood collected from 2 donors on each of 6 testing days).
  • Low-level SKBR3, MCF7, Hs578T (2-100 cells): 10 healthy female donors for each cell line tested (8x 10mL tubes from each donor).
• Detection Limit: Minimum of 60 7.5mL healthy donor blood samples for each cell line (SKBR3, Hs 578T, MCF7) and each spike level tested. Additionally, 63 different healthy donors for limit of blank assessment.
• Blood Volume Study: Not explicitly stated, but implies multiple healthy donor blood samples across 5mL, 7.5mL, and 10mL volumes for assessment.
• Blood Stability: Healthy donors whose blood was spiked with SKBR3 cells (samples were stored at RT or 4°C for various durations).
• Cell Carryover: Healthy donors (blood samples spiked with SKBR3, Hs578T, MCF7 cells). Subsequent PBS samples processed to check carryover.
• Cleaning Reagent Carryover: Not applicable (tested with deionized water).
• Cassette Lot Study: 328 runs in total, using healthy donor blood spiked with fixed SKBR3 cells in PBS using the Parsortix Control Tube (PCT-001).
• Interfering Substances: Healthy donors for spiked blood samples.
• Reproducibility & Repeatability:
  • 10-day precision: 600 measurements (fixed SKBR3 in PBS).
  • 20-day reproducibility (multi-site): 800 data points (fixed SKBR3 in PBS).
  • 20-day single site precision (live SKBR3 in blood): 400 measurements (from 2 healthy donors each day).
  • 20-day single site precision (fixed SKBR3 in blood): 400 measurements.
  • 5-day single site precision (live SKBR3, MCF7, Hs578T in blood): 900 measurements (from healthy women, 100 measurements per cell line/spike level).

Clinical Test Sets:

• Study #1 (ANG-008):
  • Spiked SKBR3 (primary eval): 76 healthy volunteer (HV) subjects and 74 metastatic breast cancer (MBC) patients.
  • Patient-derived CTCs (secondary eval): 72 HV subjects and 75 MBC patients.
• Study #2 (ANG-002):
  • Approximately 200 MBC patients and 200 HV subjects (actual evaluable: 202 MBC patients and 192 HVs for cytological evaluation).

Data Provenance:

• Country of Origin: Not explicitly stated for all studies, but ANGLE Europe Ltd. is the applicant, suggesting likely European origin (or at least studies conducted under their oversight). The 20-day 3-site reproducibility study was conducted across "three different sites," implying multiple locations.
• Retrospective/Prospective: The analytical and clinical studies described are prospective in nature, as they involve blood collection from healthy donors and patients specifically for the purpose of testing the device's performance.

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

The concept of "experts establishing ground truth" here applies primarily to the manual counting of cells and the cytological evaluation of clinical samples.

• Analytical Studies (Cell Recovery, Detection Limit, Reproducibility):
  • Cell counting (fluorescently labeled cells) was performed by one operator (e.g., in the initial cell recovery study) or by two independent readers (e.g., for cassette lot study, which was used to establish acceptance ranges).
  • No specific qualifications for these operators/readers are provided (e.g., "radiologist with 10 years of experience"). They are implied to be laboratory personnel trained in fluorescence microscopy and cell counting.
• Clinical Study #1 (ANG-008):
  • Fluorescent microscopy was used to determine the number of SKBR3 cells on slides.
  • IF staining was used to identify CTCs based on specific marker profiles (DAPI+, CD45-, EpCAM+/CK+).
  • A follow-up study involved re-staining IF slides with Wright-Giemsa and evaluation by "a pathologist" (singular). No specific qualifications are given for this pathologist.
• Clinical Study #2 (ANG-002):
  • For cytological evaluation, cells were assessed by "a qualified pathologist" (singular). No specific qualifications for this pathologist are given.
  • For molecular evaluations, standard techniques were used, implying trained laboratory personnel performed these, but not "experts" in the sense of independent adjudication.

4. Adjudication Method for the Test Set

• Analytical Studies: For some analytical studies, such as the Cassette Lot Study, where two independent readers determined the number of cells harvested, there is an implicit "adjudication" by comparison of their counts. However, the exact method for resolving discrepancies (e.g., average, third reader, consensus) is not explicitly stated. For other studies, it mentions "one operator counted," indicating no formal adjudication.
• Clinical Studies: For the primary clinical endpoints (detection of CTCs by IF or cytological evaluation), the text refers to assessment by "a pathologist" or "a qualified pathologist." This suggests that the final determination for cases was made by a single expert rather than through a multi-reader, adjudicated process (e.g., 2+1, 3+1). If multiple pathologists reviewed, it's not described as an adjudication process to reach a consensus.

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

No. A formal MRMC comparative effectiveness study comparing human readers with AI assistance vs. without AI assistance was not conducted or described. The Parsortix PC1 device is a physical enrichment system, not an AI diagnostic tool, and its evaluation focuses on its ability to isolate cells for subsequent human or machine analysis. The evaluation of its "effect" is on the quality and presence of isolated cells for downstream applications, not on improving human reader performance directly.

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

The Parsortix PC1 is a standalone device in the sense that it performs the cell enrichment process independently of direct real-time human intervention during the "Separate" phase. The studies described are essentially "algorithm only" (device only) in terms of its core function: enriching cells. Human intervention occurs before (loading samples) and after (harvesting cells, performing downstream analyses, and interpreting those analyses). The performance metrics (recovery rates, detection limits, precision) are entirely dependent on the device's physical and fluidic processes, not on a human-in-the-loop during the core enrichment.

7. The Type of Ground Truth Used

The ground truth for device performance was established in several ways:

• Analytical Studies:
  • Spiked Samples: The "ground truth" for cell recovery and detection limit studies was the known number of cultured tumor cells deliberately spiked into healthy donor blood. These cells were pre-labeled (fluorescently) for easier identification and counting post-processing.
  • Absence of Cells: For "limit of blank" and "cell carryover" studies, the ground truth was the known absence of spiked cells or tumor cells in donor blood/PBS samples.
• Clinical Studies:
  • Expert Consensus/Pathology: For patient samples, the "ground truth" for the presence of CTCs was established by expert (pathologist) evaluation of the harvested cells using morphological (Wright-Giemsa staining, cytology) and immunofluorescent (IF) criteria. For IF, CTCs were defined by a specific immunophenotype (DAPI+, CD45-, EpCAM+/CK+).
  • Molecular Data: The ability to perform subsequent molecular analyses (qPCR) on harvested cells also implicitly served as a "ground truth" for the utility of the enriched sample.

8. The Sample Size for the Training Set

As this device is a physical cell enrichment system and not an AI/ML algorithm, the concept of a "training set" for model development (as in deep learning) does not apply. All the studies described are essentially validation or performance characterization studies.

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

Since there is no "training set" in the context of an AI/ML algorithm for this device, this question is not directly applicable. If "training set" is taken to mean the data used for initial device development and internal optimization before formal validation, then the text does not provide details on how ground truth was established during those earlier stages. However, the ground truth for validation (as described in point 7) was established through known spiked cell counts and subsequent expert evaluation of harvested cells.

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