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    K Number
    K233454
    Device Name
    ONLINE TDM Methotrexate
    Manufacturer
    Roche Diagnostics Operations
    Date Cleared
    2024-02-20

    (123 days)

    Product Code
    LAO
    Regulation Number
    N/A
    Type
    Traditional
    Panel
    Toxicology
    Reference & Predicate Devices
    k111904
    Predicate For
    N/A
    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    ONLINE TDM Methotrexate is an in vitro test for the quantitative determination of methotrexate in human serum and plasma on cobas c systems. The determination of methotrexate is used for monitoring levels of methotrexate to ensure appropriate therapy.

    Device Description

    The ONLINE TDM Methotrexate assay is an in vitro test for the quantitative determination of methotrexate in human serum and plasma on cobas c systems. The determination of methotrexate is used for monitoring levels of methotrexate to ensure appropriate therapy.

    The ONLINE TDM MTX assay is a two-reagent system used for the detection of methotrexate in serum and plasma. In this technology drug hapten attached to the enzyme glucose 6 phosphate dehydrogenase (G6PDH) serves as the binding partner to anti-methotrexate antibody. A competitive reaction to a limited amount of specific anti-methotrexate antibody takes place between the enzyme bound hapten and free methotrexate in the sample. Enzyme activity is reduced with bound antibody. Only active enzymes reduce NAD+ to NADH. The rate of NADH formation during the reaction correlates to the methotrexate concentration and is measured photometrically.

    The ONLINE TDM MTX assay is a homogeneous enzyme-immunoassay.

    Reagents - working solutions

    R1: Anti-methotrexate antibody (rabbit monoclonal), 3 µg/mL; NAD, G6P, bovine serum albumin in water, pH 6.3; preservative

    R3: Methotrexate hapten conjugated to G6PDH, 0.3 µg/mL; bovine serum albumin in buffer, pH 7.8; preservative

    AI/ML Overview

    The provided document describes the analytical performance evaluation of the "ONLINE TDM Methotrexate" assay. This is an in vitro diagnostic device used for the quantitative determination of methotrexate in human serum and plasma. The study aims to demonstrate that the device meets predefined acceptance criteria.

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

    1. Table of Acceptance Criteria & Reported Device Performance:

    The document doesn't explicitly present a single table of "acceptance criteria" alongside "reported device performance" in a comparative format for all tests. Instead, it states for each section: "All acceptance criteria were met," and then provides the results. We can infer the acceptance criteria from the context and the reported successful outcomes.

    Here is a reconstructed table based on the provided text, indicating the acceptance criteria (inferred from the "All acceptance criteria were met" statements and industry standards implicitly followed) and the reported performance.

    Performance CharacteristicAcceptance Criteria (inferred/implied)Reported Device Performance
    PrecisionCV (Coefficient of Variation) within acceptable limits for repeatability & intermediate precision (e.g., generally lower CVs for higher concentrations).Repeatability:- Control 1 (0.0863 µmol/L): 4.4% CV- Control 2 (0.485 µmol/L): 0.9% CV- Control 3 (0.849 µmol/L): 0.7% CV- Human Serum 1 (0.0872 µmol/L): 4.0% CV- Human Serum 2 (0.526 µmol/L): 0.8% CV- Human Serum 3 (0.889 µmol/L): 0.7% CV- Human Serum 4 (4.85 µmol/L): 1.0% CV- Human Serum 5 (44.2 µmol/L): 4.0% CV- Human Serum 6 (449 µmol/L): 3.7% CV- Human Serum 7 (1334 µmol/L): 3.1% CVIntermediate Precision:- Control 1 (0.0737 µmol/L): 10.9% CV- Control 2 (0.487 µmol/L): 1.2% CV- Control 3 (0.841 µmol/L): 0.8% CV- Human Serum 1 (0.0752 µmol/L): 11.2% CV- Human Serum 2 (0.526 µmol/L): 1.3% CV- Human Serum 3 (0.889 µmol/L): 1.1% CV- Human Serum 4 (4.91 µmol/L): 2.0% CV- Human Serum 5 (44.2 µmol/L): 5.3% CV- Human Serum 6 (449 µmol/L): 6.3% CV- Human Serum 7 (1316 µmol/L): 5.1% CVAll stated to have met acceptance criteria.
    Analytical SensitivityLoB, LoD, LoQ within predefined thresholds to ensure accurate measurement at low concentrations.LoB: ≤ 0.0250 µmol/L (claim in labeling)LoD: < 0.0350 µmol/L (claim in labeling)LoQ: 0.0400 µmol/L (claim in labeling)All stated to have met acceptance criteria.
    Linearity/Reportable RangeAssay results must be linear across the claimed measuring range.Confirmed for the measuring range of 0.0400 – 1.20 µmol/L.All stated to have met acceptance criteria.
    DilutionExpected recovery of concentration from diluted samples.Post-dilution checks performed, supporting instrument and/or manual dilution for samples above the measuring range. (Implied acceptance criteria met, as no issues reported).
    Endogenous InterferencesNo significant interference from common endogenous substances at specified concentrations.No interference claims for: Icterus (up to I index of 60/~1026 µmol/L bilirubin), Hemolysis (up to H index of 1000/~621 µmol/L hemoglobin), Lipemia (up to L index of 1000), Albumin (60 g/L), Immunoglobulin G (60 g/L), Total protein (2-12 g/dL), Rheumatoid factors (1000 IU/mL).All predefined acceptance criteria were met.
    Analytical Specificity/ Cross-ReactivityExpected cross-reactivity with structurally similar compounds.DAMPA cross-reactivity: 87.6% at 0.1 µmol/L MTX, 64.6% at 1.0 µmol/L MTX.DAMPA can cross-react between 50% and 150% (This range implies the acceptance criteria for DAMPA cross-reactivity).
    Exogenous Interferences (Drugs)No significant interference from commonly used pharmaceuticals.A long list of common and special pharmaceuticals were tested with no significant interference (implicitly meaning acceptance criteria were met).
    Sample Matrix ComparisonAcceptable correlation between different sample matrices (serum vs. various plasma types).Correlation (Pearson r) with Serum vs.:- Li-Heparin plasma: 0.998 - K2-EDTA plasma: 0.999 - K3-EDTA plasma: 0.998 - Na-Heparin plasma: 0.998 Slopes are close to 1, intercepts close to 0.All predefined acceptance criteria were met, supporting the claims for acceptable sample types.
    Method ComparisonAcceptable correlation/agreement with a validated comparator method (LC-MS/MS).Deming Regression: y = 1.032x + 0.000831 µmol/LCorrelation (r): 0.997(Implied acceptance criteria met, as close agreement shown).
    StabilityDevice must maintain performance throughout its claimed shelf life and on-board stability.Stability studies were conducted to support Roche Diagnostic's claims as reported in the package labeling. (Implied acceptance criteria met).

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

    • Precision (Repeatability & Intermediate Precision):
      • Repeatability: n = 84 measurements (total across all samples/controls).
      • Intermediate Precision: Not explicitly stated as a single 'n'. It involved 2 aliquots per run, 2 runs per day, over 21 days for controls and human serum samples.
    • Analytical Sensitivity (LoB, LoD, LoQ):
      • LoB: One analyte-free sample measured with three reagent lots, in 6 runs, each with 10-fold determination, distributed over 3 days.
      • LoD: 5 serum samples measured on three lots with 2-fold determination per run, across 6 runs distributed over 3 days.
      • LoQ: 5 serum samples measured with three reagent lots, across 6 runs distributed over 3 days.
    • Linearity/Assay Reportable Range:
      • A dilution series spanning ≥ 9 levels, assayed on one analyzer using 3 reagent lots and 4 replicates per sample.
    • Endogenous Interferences: Not explicitly stated as a numerical sample size but implies a study design for each substance.
    • Analytical Specificity/Cross-Reactivity (DAMPA):
      • Two human serum sample pools.
    • Exogenous Interferences (Drugs): Not explicitly stated as a numerical sample size but implies a study design for each drug.
    • Sample Matrix Comparison:
      • ≥ 50 samples compared across serum and various plasma types.
    • Method Comparison:
      • 105 native human plasma and serum samples.

    Data Provenance: The studies were conducted on "human serum" and "human plasma" samples. No specific country of origin is mentioned for the samples. The studies are retrospective in nature, as they involve testing existing samples (or creating spiked samples from existing matrices) within a laboratory setting to characterize the device performance. This is a typical approach for IVD device validation.

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

    This information is not provided in the document. The type of device (in vitro diagnostic for quantitative determination of a drug) means that "ground truth" is typically established via a reference method (like LC-MS/MS), not by expert human graders.

    4. Adjudication Method for the Test Set:

    This information is not applicable for this type of in vitro diagnostic device study. Adjudication methods (like 2+1, 3+1) are typically used in clinical studies where human readers evaluate medical images and their interpretations need to be reconciled. For a quantitative assay like this, the 'ground truth' is established by a reference analytical method.

    5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done and Effect Size:

    No, a MRMC comparative effectiveness study was not done. This type of study is relevant for AI-powered devices that assist human interpretation (e.g., radiologists reading images). This device is a fully automated in vitro diagnostic assay, so human interpretation assistance is not part of its function.

    6. If a Standalone (algorithm only without human-in-the-loop performance) was done:

    Yes, this entire study describes the standalone performance of the "ONLINE TDM Methotrexate" assay. It is an automated laboratory test that measures methotrexate levels, meaning it operates "without human-in-the-loop performance" during the measurement process. The results are quantitative values generated directly by the instrument using the assay's reagents.

    7. The Type of Ground Truth Used:

    The primary type of "ground truth" used for performance evaluation, particularly for method comparison and potentially for linearity/dilution studies, is a validated comparator method, specifically LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry). This is a highly accurate and precise analytical technique often considered a reference method for drug quantification. The document explicitly states: "The target value was determined with the LC-MS/MS" for dilution checks and "A method comparison of the ONLINE TDM Methotrexate on the cobas c 503 analyzer versus a validated comparator method on LC-MS/MS was completed."

    For other tests like precision, sensitivity, interference, matrix comparison, ground truth is established by the known concentrations of controls, spiked samples, or comparison against established acceptable ranges as per CLSI (Clinical and Laboratory Standards Institute) guidelines.

    8. The Sample Size for the Training Set:

    The document does not provide any details about a training set. This is expected because this device is an in vitro diagnostic reagent assay, not an AI/Machine Learning model that undergoes a "training" phase. The assay relies on established biochemical reactions (homogeneous enzyme-immunoassay) and instrumental calibration rather than iterative learning from a dataset.

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

    As there is no training set for this type of IVD device (it's not an AI/ML product), this question is not applicable. The "ground truth" for the performance evaluation (test set) relied on validated analytical methods and known sample concentrations.

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