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Elecsys CYFRE 21-1:

Immunoassay for the in vitro quantitative determination of tragments of cytokeratin 19 in human serum and plasma (Li-Heparin. K2-EDTA and K3-EDTA). The assay is to be used as an aid in monitoring disease progression during the course of disease and treatment in lung cancer patients. Serial testing for patient CYFRA 21-1 assay values should be used in conjunction with other clinical methods used for monitoring lung cancer.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Elecsys CYFRA 21-1 CalSet:

CYFRA 21-1 is used for calibrating the quantitative Elecsys CYFRA 21-1 assay on the Elecsys and cobas e immunoassay analyzers.

Elecsys PreciControl Tumor Marker:

PreciControl Tumor Marker is used for quality control of Elecsys immunoassays on Elecsys and cobas e immunoassay analyzers.

(1) The Elecsys CYFRA 21-1 Immunoassay is a two-step sandwich immunoassay with streptavidin microparticles, a biotinylated monoclonal cytokeratin 19-specific antibody, and a monoclonal cytokeratin 19-specific antibody labeled with a ruthenium complex and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration master curve (5-pointcalibration) provided with the reagent bar code.

(2) The Elecsys CYFRA 21-1 CalSet is a lyophilized product consisting of Cytokeratin from cell culture of the cell line MCF-7 in two concentration ranges (approximately 0 ng/mL and 50 ng/mL) in a cytokeratin free human serum matrix with preservative. During manufacture, the analyte is spiked ito the matrix at the desired concentration levels.

(3) The Elecsys PreciControl Tumor Marker (CYFRA 21-1) is a lyophilized control serum in two concentration ranges (approximately 3.29 ng/mL and 27.2 ng/mL).

Note: The reagent, calibrator, and the quality control materials are all packaged separately.

The provided document describes the Elecsys CYFRA 21-1 Immunoassay, a device intended for quantitative determination of cytokeratin 19 fragments in human serum and plasma, used as an aid in monitoring disease progression and treatment for lung cancer patients.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA clearance for this in-vitro diagnostic device does not typically specify "acceptance criteria" in the same way a medical image analysis AI might have specific sensitivity/specificity thresholds. Instead, it demonstrates substantial equivalence to a predicate device by comparing various performance characteristics. The acceptance is implied by demonstrating performance that is comparable to or better than the predicate device across critical analytical and clinical metrics.

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

The document details numerous analytical validation studies. Here's a breakdown for key performance metrics:

• Precision (Human Sera):
  • Internal: Seven-member panel (5 patient samples, 2 controls). Tested in single determination, 4 aliquots, over 21 operating days. Total measurements: 7 samples * 4 aliquots/day * 21 days = 588 measurements (at least, assuming single determination each aliquot).
  • External: Two replicates of each control (PC TM 1 & 2) and six human serum samples per run, two runs per day for 20 days at three external sites. Total measurements: (2 controls + 6 HS) * 2 replicates * 2 runs/day * 20 days * 3 sites = 1,920 measurements.
  • Provenance: Not explicitly stated, but common for such studies to use mixtures of human serum/controls which could be sourced from various regions due to ethical and availability considerations. Prospective data collection for these specific tests.
• Limit of Blank (LoB): 5 analyte-free serum samples. 60 measuring points collected (implies 5 samples * 2-fold determination/run * 6 runs = 60).
• Limit of Detection (LoD): 5 low-level human serum samples. 60 measuring points collected (implies 5 samples * 2-fold determination/run * 6 runs = 60).
• Limit of Quantitation (LoQ): 8 spiked human serum samples. 200 measuring points collected (implies 8 samples * 5 runs * single determination = 40, assuming some dilutions).
• Linearity: Six dilution series (3 serum, 3 plasma), each with at least 11 dilutions.
• Endogenous Interferences: Three human serum samples (low, mid, high CYFRA 21-1) for each of six interfering substances.
• HAMA Effect: One HAMA serum and one control serum, both spiked to two different analyte concentrations. Each concentration had 11 dilutions, measured in duplicate.
• High-Dose Hook Effect: Human serum pools spiked up to 2,470ng/mL.
• Exogenous Interferences - Drugs: Two human serum samples, spiked with 27 pharmaceutical compounds. Samples tested in three-fold determination.
• Serum/Plasma Comparison: At least 44 serum/plasma pairs per sample type. For Serum/Plasma Separation Tube comparison, 5 samples in duplicate.
• Clinical Performance (Monitoring): 83 patients with lung cancer, 398 samples measured (86 baseline, 315 monitoring values). Patients had ≥ 3 blood draws over time.
  • Provenance: Not explicitly stated, but implies clinical samples from lung cancer patients, likely retrospective from a patient cohort or collected prospectively for the study.
• Expected Values (Normal Population):
  • 240 apparently healthy men and women (equally divided into smokers and non-smokers).
  • 195 benign disease conditions.
  • 440 cancer cases (including 120 lung cancer, 40 bladder, breast, cervical, ESCC, GI tract, head and neck, prostate, and ovarian cancer each).
  • Provenance: This data represents cohort studies, likely retrospective collection from various institutions.

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

For this type of immunoassay, "ground truth" is typically defined by the actual analyte concentration in the samples or by established clinical diagnoses/disease progression based on a combination of clinical assessment, imaging, and potentially pathology.

• Clinical Performance (Monitoring): The document states that clinical effectiveness was assessed by "comparing changes in CYFRA 21-1 levels in serial serum samples from 83 patients compared to changes in disease status." The "disease status" would be the ground truth for clinical progression. However, the number and qualifications of experts (e.g., oncologists, radiologists) establishing this disease status ground truth are NOT specified in the provided text.

4. Adjudication Method for the Test Set

Not applicable in the typical sense for an immunoassay. The clinical performance study relies on a comparison of assay values to "disease status," which is a clinical endpoint rather than an adjudicated radiological finding or similar interpretation. The judgment of disease progression would be based on standard clinical practice for lung cancer, likely involving follow-up imaging, biopsy results, and physician assessment, but no specific adjudication panel or method (e.g., 2+1) is described for the clinical endpoint data.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

Not applicable. This is an in-vitro diagnostic device for quantitative measurement of a biomarker, not an AI for image interpretation that augments human readers. Therefore, an MRMC study comparing human readers with and without AI assistance is not relevant to this device's evaluation.

6. Standalone Performance Study (Algorithm Only Without Human-in-the-Loop Performance)

Yes, the entire submission is a standalone performance study of the Elecsys CYFRA 21-1 immunoassay. The device generates quantitative results (ng/mL) without human interpretation as part of its primary function. The clinical performance section assesses how these quantitative results_correlate_ with disease status, but the assay itself doesn't have a "human-in-the-loop" component in its operation.

7. Type of Ground Truth Used

• Analytical Studies (Precision, LoB, LoD, LoQ, Linearity, Interference, Calibration, Stability): The ground truth is the actual concentration of the analyte (CYFRA 21-1) in spiked samples, known concentrations in controls, or the absence of the analyte in blank/interferent-free samples. This is established through highly controlled laboratory procedures and reference methods.
• Clinical Performance (Monitoring): The ground truth is the "disease status" (progression or no progression) of lung cancer patients. The method for establishing this status is not detailed beyond "changes in disease status," but it inherently relies on a combination of medical evidence and clinical assessment over time.
• Expected Values (Normal Population & Cancer/Benign Cohorts): The ground truth is the clinical diagnosis/health status of the individuals in those cohorts (e.g., "apparently healthy," "benign lung disease," "lung cancer").

8. Sample Size for the Training Set

For an immunoassay, the concept of a "training set" as understood in machine learning (where an algorithm learns from labeled data) doesn't directly apply. However, the development and optimization of the assay (e.g., antibody selection, reagent formulation, instrument parameters) would involve extensive internal testing. The submission here focuses on validation, demonstrating performance on independent (test) samples. The assay itself has pre-defined chemical and electrical principles, not an adaptive learning algorithm.

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

As explained above, "training set" doesn't directly apply. However, during the initial development and optimization phase, the ground truth would be established through:

• Reference materials: Samples with precisely known concentrations of CYFRA 21-1 (traceable to internal or international standards).
• Clinical samples: Use of various clinical samples (e.g., from healthy individuals, various disease states) to understand the assay's behavior and define preliminary measuring ranges and expected values. This preliminary testing would inform the design of the formal validation studies presented in the 510(k). The "Enzymun-Test CYFRA 21-1 method" is mentioned as a method against which the Elecsys CYFRA 21-1 has been standardized, indicating a reference for comparison during development.

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