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510(k) Data Aggregation

    K Number
    K152227
    Device Name
    Elecsys Cortisol II, Cortisol II CalSet
    Manufacturer
    ROCHE DIAGNOSTICS
    Date Cleared
    2016-04-27

    (264 days)

    Product Code
    JFT,JIT
    Regulation Number
    862.1205
    Type
    Traditional
    Panel
    Clinical Chemistry
    Reference & Predicate Devices
    k070788
    Predicate For
    K202136
    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    Immunoassay for the in vitro quantitative determination of cortisol in human serum, and plasma. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

    Cortisol II CalSet is used for calibrating the quantitative Elecsys Cortisol II assay on the Elecsys and cobas e immunoassay analyzers.

    Device Description

    The Elecsys Cortisol II assay makes use of a competition test principle using a monoclonal antibody which is specifically directed against cortisol. Endogenous cortisol which has been liberated from binding proteins with danazol competes with exogenous cortisol derivative in the test which has been labeled with ruthenium complex for the binding sites on the biotinylated antibody.

    Results are determined via a calibration curve which is instrument specifically generated by 2point calibration and a master curve provided via reagent barcode.

    The reagent working solutions include:

    • rackpack (kit placed on instrument) .
      • Streptavidin coated microparticles, ş
      • Reagent 1 (Anti-cortisol-Ab~biotin) and ş
      • Reagent 2 (Cortisol-peptide~Ru(bpy)2+3). ş

    The Cortisol II CalSet is a lyophilized human serum with added cortisol in two concentration ranges.

    The CalSet includes:

    • Cal 1 (approximately 12.5 nmol/L cortisol in a human serum matrix) .
    • Cal 2 (approximately 1000 nmol/L cortisol in a human serum matrix) .
    AI/ML Overview

    The provided document describes the Elecsys Cortisol II immunoassay and its associated calibrator, Cortisol II CalSet. It details various non-clinical performance evaluations and one clinical performance evaluation.

    Here's an analysis of the acceptance criteria and the studies that prove the device meets them:

    1. A table of acceptance criteria and the reported device performance

    The document does not explicitly state acceptance criteria in a dedicated table for each technical performance study. Instead, it presents the results of these studies and implies that these results demonstrate the device's performance is acceptable and supports substantial equivalence to the predicate device. For analytical specificity and method comparison, the document includes tables comparing some key characteristics with the predicate device. For other studies like precision, linearity, and sensitivity, it reports the performance without directly listing a pre-defined acceptance criterion.

    However, I can extract the reported performance directly from the document for key metrics.

    Performance CharacteristicPredicate Device (Elecsys Cortisol - K070788) PerformanceCandidate Device (Elecsys Cortisol II) Reported Performance
    Measuring Range0.5 – 1750 nmol/L3.0 – 1750 nmol/L
    Precision (Within-run)Sample Mean (nmol/L) SD %CVHS 1: 208, 2.76, 1.3%HS 2: 561, 7.40, 1.3%HS 3: 1268, 14.0, 1.1%PCU* 1: 363, 5.08, 1.4%PCU* 2: 865, 8.54, 1.0%Sample Mean (nmol/L) SD CVHS 1: 3.09, 0.219, 7.1%HS 2: 35.8, 0.718, 2.0%HS 3: 283, 7.29, 2.6%HS 4: 548, 10.4, 1.9%HS 5: 1592, 29.3, 1.8%PCU* 1: 308, 4.33, 1.4%PCU* 2: 719, 10.4, 1.4%
    Precision (Total/Intermediate)Sample Mean (nmol/L) SD %CVHS 1: 208, 3.29, 1.6%HS 2: 561, 8.36, 1.5%HS 3: 1268, 19.9, 1.6%PCU* 1: 363, 5.67, 1.6%PCU* 2: 865, 12.5, 1.4%Sample Mean (nmol/L) SD CVHS 1: 3.09, 0.392, 12.7%HS 2: 35.8, 1.36, 3.8%HS 3: 283, 9.39, 3.3%HS 4: 548, 17.4, 3.2%HS 5: 1592, 42.7, 2.7%PCU* 1: 308, 8.35, 2.7%PCU* 2: 719, 18.0, 2.5%
    Analytical SensitivityLimit of Detection = <0.500 nmol/LLimit of Blank (LoB): = 1.0 nmol/mLLimit of Detection (LoD): = 1.5 nmol/mLLimit of Quantitation (LoQ): = 3.0 nmol/mL
    Linearity1 to 59.8 µg/dL3.0 to 1750 nmol/mL (implied as achieved, comparing to predicate)
    Bilirubin Interference<60 mg/dL unaffected≤ 25 mg/dL unaffected
    Hemolysis Interference<1.9 g/dL unaffected≤ 0.5 g/dL unaffected
    Lipemia Interference<2700 mg/dL unaffected≤ 1500 mg/dL unaffected
    Biotin Interference<30 ng/mL unaffected≤ 30 ng/mL unaffected
    Rheumatoid factors Interference<1100 IU/mL unaffected<600 IU/mL unaffected
    Method Comparison (vs. LC-MS)Not applicable (predicate compared to Enzymun-Test Cortisol)Passing/Bablok: 1.022 (slope), 2.92 (intercept), 0.930 (R)Deming Regression: 1.055 (slope), -6.10 (intercept), 0.993 (R)
    Reagent Stability (Onboard)On the Analyzers - 30 daysOn the Analyzers – 8 weeks (56 days)
    Reagent Stability (After Opening)After Opening at 2-8°C - 30 daysAfter Opening at 2-8°C - 12 weeks (84 days)
    Calibration IntervalOnce per lot (reagent), recommended renewed calibration after 28 days (same lot) / 7 days (same kit)Once per lot (reagent), recommended renewed calibration after 8 weeks (same lot) / 7 days (same kit)

    2. Sample sizes used for the test set and the data provenance

    • Precision (Human Serum)
      • Test Set Sample Size: 5 human serum samples (native, diluted, spiked) and 2 controls (PC Universal).
      • Data Provenance: Not explicitly stated, but implies laboratory testing internal to the manufacturer (Roche Diagnostics).
    • Limit of Blank (LoB)
      • Test Set Sample Size: 5 blank samples. A total of n = 60 LoB measurements were made.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Limit of Detection (LoD)
      • Test Set Sample Size: 5 low-level human serum samples (diluted). A total of n = 60 LoD measurements were made.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Limit of Quantitation (LoQ)
      • Test Set Sample Size: 9 human serum samples.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Linearity (Serum and Plasma)
      • Test Set Sample Size: 19 concentrations (thereof 17 dilutions) prepared from a high analyte serum/plasma sample. Each assayed in 3-fold determination within a single run.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Analytical Specificity (Serum/Plasma)
      • Test Set Sample Size: Two human serum sample pools.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Endogenous Interferences
      • Test Set Sample Size: Three human serum samples (low, mid, high cortisol concentrations) for each interfering substance.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • HASA Effect
      • Test Set Sample Size: Two serum samples with cortisol concentrations of 173 and 789 nmol/L. Aliquots spiked with DASA and diluted in 10% increments.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Exogenous Interferences - Drugs
      • Test Set Sample Size: Two human serum samples (native, diluted, spiked) for 16 pharmaceutical compounds; each tested in 3-fold determination.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Exogenous Interferences - Anticoagulants
      • Test Set Sample Size: Minimum of 48 serum/plasma pairs per sample material (Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma primary tubes and Li-Heparin Plasma Gel Separation Tubes). Each tested in duplicate.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Method Comparison 1: Elecsys Cortisol II vs. LC-MS (Reference Method)
      • Test Set Sample Size: 208 human serum samples (all native single donors).
      • Data Provenance: UZ Gent, Lab voor Klinische Biologie (Gent, Belgium); implies prospective collection for the study or a well-characterized archive.
    • Method Comparison 2: Elecsys Cortisol II vs. Cortisol I (K070788)
      • Test Set Sample Size: 536 human serum samples (all native single donors).
      • Data Provenance: UZ Gent, LMU Großhadern, Uni Klinik Leipzig and Labor Limbach; implies prospective collection for the study or a well-characterized archive from multiple European sites.
    • Reagent Stability (Onboard and After First Opening)
      • Test Set Sample Size: 5 human serum samples (native, diluted, spiked) and 2 controls.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Reagent Stability (Real-time, ongoing)
      • Test Set Sample Size: PreciControl Universal (Level 1 and 2) and human serum samples. Data for time-points at 0, 13, 16, 19 months (MP lot) and 0, 7, 16, 19 months (P2 and P3 lot)
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Sample Stability (2-8°C, Room Temperature, -15 to -25°C)
      • Test Set Sample Size: Twelve human serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma samples (all single donors, native, spiked, diluted) for each study.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Calibration Stability (Lot and On-board)
      • Test Set Sample Size: Five human serum samples (native, diluted, spiked) and two control samples.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Calibrator studies (Reconstitution, Stability)
      • Test Set Sample Size: Not explicitly stated beyond "two sets of Cortisol II CalSet" for reconstitution, and "on-test and reference materials" for stability. PreciControl Universal used to assess CalSet stability.
      • Data Provenance: Not explicitly stated, implies internal laboratory testing.
    • Clinical Performance Evaluation (Reference Range)
      • Test Set Sample Size: 296 individuals for 6-10 am sample collection, 300 individuals for 4-8 pm sample collection.
      • Data Provenance: Three sites in the United States (one site in St Louis, Missouri for evaluation). These are prospective clinical samples.
    • Training Set Sample Size: The document does not specify a separate "training set" for the Elecsys Cortisol II device. Immunoassays are not typically "trained" in the machine-learning sense with a distinct training dataset. Instead, they are developed, optimized, and then validated with performance studies. The "value assignment" for calibrators, and the master curves are part of the setup, but not a "training set" in the context of AI.

    3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

    This information is not applicable or explicitly stated in the document for this type of medical device (an in-vitro diagnostic immunoassay). For immunoassays, ground truth (or reference values) is typically established through:

    • Reference methods: Like LC-MS (Liquid Chromatography-Mass Spectrometry) as used in Method Comparison 1. These are highly accurate analytical techniques, not dependent on expert interpretation.
    • Spiking studies/Dilution linearity: Known concentrations are added to samples, which serves as the "ground truth" for evaluating recovery and linearity.
    • Clinical context: For reference ranges, the "truth" is derived statistically from a population of healthy individuals.
    • Previous assay values: For comparative studies, the predicate device's results are used as a comparison point.

    There are no mentions of human experts establishing "ground truth" in terms of interpreting clinical findings or images.

    4. Adjudication method for the test set

    Not applicable. This is not a device where human interpretation or adjudication is used to establish "ground truth" for the test results. The device measures a biomarker concentration.

    5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

    Not applicable. This document describes an immunoassay and calibrator, not an AI device that assists human readers in interpreting cases. There is no mention of human readers or AI assistance.

    6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

    This refers to an immunoassay, which is by nature a standalone analytical system. The Elecsys Cortisol II assay determines the quantitative concentration of cortisol in human serum and plasma directly. There is no human-in-the-loop performance component in the measurement process itself, although clinical interpretation of the results by a healthcare professional is expected.

    7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

    The types of "ground truth" or reference standards used in the studies include:

    • Reference Method LC-MS: For Method Comparison 1, the Elecsys Cortisol II was compared against LC-MS, which serves as a highly accurate reference method for cortisol quantification.
    • Predicate Device: For Method Comparison 2, the Elecsys Cortisol II was compared against the predicate Elecsys Cortisol (K070788) assay.
    • Known Spiked/Diluted Concentrations: For studies like linearity, analytical specificity, and interference, known amounts of analyte or interfering substances were added to samples, establishing controlled "ground truth" for evaluation.
    • Statistical Normative Data: For establishing the reference ranges, the results from a large cohort of self-reported healthy individuals were used to statistically define normal limits.
    • Assigned Values: For calibrator and control stability, "assigned values" from independent measurements (e.g., using multiple analyzers and lots) were used as the reference.

    8. The sample size for the training set

    The document does not specify a "training set" in the context of machine learning for this immunoassay. Immunoassays typically involve development and optimization phases for reagent formulation, antibody selection, and instrument parameters, which could be seen as analogous to "training" in a broad sense, but not with a distinct training data set size as in AI/ML validation studies. Instead, the assay relies on a master curve (provided via reagent barcode) and 2-point calibration.

    9. How the ground truth for the training set was established

    As there is no distinct "training set" in the AI/ML sense, this question is not directly applicable. However, for the reference values that define the assay's performance and calibration, the following methods are mentioned:

    • Master curve: Provided via reagent barcode for quantitative determination.
    • Calibration: Results are determined via a calibration curve that is instrument specifically generated by 2-point calibration.
    • Traceability: The Elecsys Cortisol II assay has been standardized against the IRMM (Institute for Reference Materials and Measurements)/IFCC 451 panel (ID GC/MS, isotope dilution-gas chromatography/mass spectrometry), which serves as a highly accurate reference.
    • Calibrator Value Assignment: For the Cortisol II CalSet, target values are chosen for the best fit with the Master Calibration Curve and Rodbard curve parameters. Calibrators are run in duplicate on multiple analyzers (at least 3 cobas e 411 and at least 3 cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers) with all available reagent lots. The assigned value is the mean over at least six runs on at least three analyzers.
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