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510(k) Data Aggregation

    K Number
    K212559
    Device Name
    CardioPhase® hsCRP
    Manufacturer
    Siemens Healthcare Diagnostics Products GmbH
    Date Cleared
    2022-12-16

    (490 days)

    Product Code
    NQD
    Regulation Number
    866.5270
    Type
    Special
    Panel
    Clinical Chemistry
    Reference & Predicate Devices
    K033908
    Predicate For
    K233242
    Why did this record match?
    Reference Devices :

    K033908

    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    CardioPhase® hsCRP is an in-vitro diagnostic reagent for the quantitative determination of C-reactive protein (CRP) in human serum, and heparin and EDTA plasma by means of particle enhanced immunonephelometry using the BN II and BN ProSpec® System. In acute phase response, increased levels of plasma proteins, including C-reactive protein, is observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurements of hsCRP, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes.

    Device Description

    The CardioPhase hsCRP assay is an in vitro diagnostic reagent for the quantitative determination C-reactive protein, in human serum, and heparinized and EDTA plasma by means of particle-enhanced immunoassay determination. Polystyrene particles coated with monoclonal antibodies specific to human CRP are aggregated when mixed with samples containing CRP. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the relevant protein in the sample. The result is evaluated by comparison with a standard of known concentration.

    AI/ML Overview

    This document describes the CardioPhase® hsCRP device, a C-reactive protein immunological test system, and a Special 510(k) submission for a change in its reference standard material from ERM-DA470 to ERM-DA474/IFCC.

    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 document doesn't explicitly state numerical acceptance criteria for all performance characteristics, but rather describes the studies performed and their satisfactory outcomes which imply meeting internal acceptance limits. For instance, for linearity, the stated ranges confirm the measuring range, implying that the observed linearity falls within acceptable deviations. For matrix comparison, high correlation coefficients and slopes close to 1 with intercepts close to 0 indicate acceptable equivalence.

    Performance CharacteristicAcceptance Criteria (Implicit/Explicit)Reported Device Performance
    Detection CapabilitiesLimit of Blank (LoB): Values below the respective Limit of Quantitation (LoQ). Limit of Detection (LoD): Greater than LoB and equal to or below LoQ. Limit of Quantitation (LoQ): An imprecision goal of less than 20% CV. (Specific numerical LoB/LoD not provided as acceptance criteria, but derived from the study.)LoB: All results measured on blank samples yielded results below the respective LoQ. LoD: Calculated parametrically, greater than LoB and equal to or below LoQ. LoQ: Set to 0.094 mg/L based on the sample/instrument/reagent lot combination with the highest imprecision observed in the study (<11% CV), meeting the <20% CV goal.
    LinearityDeviation between mean measured value and predicted value of weighted linear regression compared to predefined acceptance criteria. (Specific numerical acceptance criteria not explicitly stated).CRP sensitive (CRP2): Linear range 0.151 - 10.89 mg/L (confirming measuring range of 0.16-10 mg/L). CRP (CRP1): Linear range 1.478 – 224 mg/L (confirming measuring range of 3.1-100 mg/L). This implies that the predefined acceptance criteria were met.
    Method ComparisonThe predicted bias between the predicate and candidate assay should be within acceptable limits for intended use. (Specific numerical acceptance criteria not explicitly stated but implied by the reported bias values).CRP2: Predicted bias of 6.9% at 1 mg/L and 7.5% at 3 mg/L. CRP1: Predicted bias of 8.17% at 10 mg/L. These values are presented as satisfactory for demonstrating substantial equivalence.
    Matrix ComparisonEquivalence for serum vs. EDTA plasma and serum vs. heparin plasma, indicated by slope close to 1, intercept close to 0, and high Pearson Correlation Coefficient (r). (Specific numerical acceptance criteria for slope, intercept, and r not explicitly stated but implied by the conclusion of equivalence).CRP1: Slopes (0.972-1.018), Intercepts (-0.118-0.091), Pearson r (0.995-0.998). CRP2: Slopes (0.962-1.061), Intercepts (-0.132-0.072), Pearson r (0.970-0.983). Conclusion: Confirmed equivalence for serum and EDTA/lithium heparin plasma.
    TraceabilityCalibrator N Rheumatology Standard SL must be traceable to the IFCC European Reference Material ERM-DA474/IFCC.N Rheumatology Standard SL is traceable to Siemens internal Master Calibrator which is directly traceable to ERM-DA474/IFCC.
    Substantial EquivalenceThe modified device's performance should be substantially equivalent to the predicate device in terms of intended use, design, basic scientific principle, and performance, and the change should not affect safety and efficacy.The presented performance data and the conclusion that "The modified device, CardioPhase hsCRP traceable to ERM-DA474/IFCC, is substantially equivalent to the predicate device... based on intended use design, and basic scientific principle and performance."

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

    • Detection Capabilities (LoB, LoD, LoQ):

      • LoB: Five (5) independent analyte-free samples. Conducted with one (1) BN ProSpec System, one (1) BNII System, three (3) different reagent lots, one (1) calibrator lot, five (5) individual aliquots of each sample, and determination on three (3) days. This protocol resulted in 75 measurements per reagent lot, a total of 450 measurements (including the two workflows) on each of the two (2) analyzers, resulting in 900 measurements overall.
      • LoD/LoQ: Serum samples with concentrations ranging from approximately 0.05 mg/L to 0.26 mg/L CRP. Five replicates of six patient samples were run once per day for five days using three hsCRP Reagent lots on one BNProSpec and one BN II, totaling 1080 determinations.
      • Data Provenance: Not explicitly stated (e.g., country of origin). The samples are referred to as "analyte-free" and "patient samples" (serum), implying clinical relevance and likely of human origin. The study appears to be prospective as it was specifically designed for this evaluation.

    • Linearity:

      • Sample Size: A high CRP serum pool was mixed with a low serum pool to generate 13 concentrations. Each level was tested in four-fold determination.
      • Data Provenance: Not explicitly stated (e.g., country of origin). The samples are described as "serum pool," implying human origin. The study appears to be prospective.

    • Method Comparison:

      • Sample Size: Native samples in the range of 0.27 and 11.90 mg/L for CRP2 and native samples in the range of 3.87 and 61.40 mg/L for CRP1. The exact number of samples is not explicitly given, but it implies a sufficient number to perform linear regression and bias calculations across the specified ranges.
      • Data Provenance: Not explicitly stated (e.g., country of origin). Native samples imply human origin. The study appears to be prospective for this comparison.

    • Matrix Comparison:

      • Sample Size: For each sample type (EDTA plasma and lithium heparin plasma compared to serum), a total of 60 native samples spanning the measuring range were evaluated.
      • Data Provenance: Not explicitly stated (e.g., country of origin). Native samples imply human origin. The study appears to be prospective.

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

    For this in-vitro diagnostic device (quantitative determination of C-reactive protein), "ground truth" is typically established by reference methods or gravimetrically prepared standards with known concentrations, or by comparison to a reference standard material.

    • Traceability and Standardization: The ground truth for this device is primarily established by its traceability to the IFCC European Reference Material ERM-DA474/IFCC, which is "certified for C-reactive protein measurements." This reference material serves as the "expert" or definitive standard.
    • No human expert panel for ground truth: Unlike image-based diagnostic devices, this type of immunoassay does not involve human experts establishing a "ground truth" based on interpretations (e.g., radiologists labeling images). The "ground truth" is analytical and defined by international reference standards.

    4. Adjudication Method for the Test Set

    Not applicable in the conventional sense. For an in-vitro diagnostic assay that measures a quantitative analyte, the "ground truth" is the certified value assigned to reference materials or the result from a highly accurate reference method. There is no subjective interpretation by multiple human adjudicators in the way there would be for an imaging diagnosis.

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

    No. This is an in-vitro diagnostic (IVD) device for quantitative measurement of a biomarker (CRP). MRMC studies are typically performed for devices that involve human interpretation, such as imaging AI applications, to assess how AI assistance impacts human reader performance. This device does not have a "human reader" component in that context.

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

    Yes, entirely. The entire performance evaluation (detection capabilities, linearity, method comparison, matrix comparison) demonstrates the standalone performance of the CardioPhase® hsCRP assay system (reagent and instrument) in measuring CRP levels. The device itself, once calibrated, provides a quantitative result without human-in-the-loop performance influencing the measurement. The human role is in operating the instrument and interpreting the numerical result in a clinical context, but not in directly influencing the measurement itself.

    7. Type of Ground Truth Used

    The ground truth used is primarily certified reference materials (ERM-DA474/IFCC) and comparative analysis against a previously cleared predicate device (which itself was traceable to ERM-DA470) which acts as a well-established reference. The "ground truth" for the calibrator N Rheumatology Standard SL is its traceability to the Siemens internal Master Calibrator, which in turn is directly traceable to ERM-DA474/IFCC.

    8. Sample Size for the Training Set

    Not applicable. This document describes the performance evaluation of a change to an existing in-vitro diagnostic reagent and its calibrator. This is not a machine learning or AI-based device that typically requires a "training set" in the context of model development. The characterization studies described are for analytical performance verification of the assay system, rather than training a computational algorithm.

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

    Not applicable, as there is no "training set" for this type of IVD device.

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