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    K Number
    DEN170019
    Device Name
    Vitamin D 200M Assay for the Topaz System
    Manufacturer
    AB SCIEX LLC
    Date Cleared
    2017-05-18

    (59 days)

    Product Code
    PSL
    Regulation Number
    862.1840
    Type
    Post-NSE
    Panel
    Clinical Chemistry
    Reference & Predicate Devices
    N/A
    Predicate For
    N/A
    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    The Vitamin D 200M Assay for the Topaz System is intended for in vitro diagnostic use in the quantitative determination of total 25-hydroxyvitamin D (25-OH-D) through the measurement of 25-hydroxyvitamin D3 (25-OH-D3) and 25-hydroxyvitamin D2 (25-OH-D2) in human serum using LC-MS/MS technology by a trained laboratory professional in a clinical laboratory. The Assay is intended for use with the Topaz System. The Vitamin D 200M Assay for the Topaz System is intended to be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions in an adult population in the assessment of vitamin D sufficiency.

    Device Description

    The Vitamin D 200M Assay for the Topaz System employs LC-MS/MS technology (Topaz System) in conjunction with reagents and sample preparation components to extract, separate by chromatography, detect, and quantify total Vitamin in human serum.

    The Topaz System is a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system intended to for use in a clinical laboratory environment to identify inorganic or organic compounds in human specimens by ionizing the compound under investigation and separating the resulting ions by means of an electrical and magnetic field according to their mass.

    Each assay kit contains enough material for 1000 tests, and includes reagents, sample extraction and purification components, calibrators, controls and the Vitamin D 200M Assay specific file which contains all necessary parameters to process the assay.

    AI/ML Overview

    This document describes the process by which a medical device, the Vitamin D 200M Assay for the Topaz System, received automatic Class III designation. The device is intended for quantitative determination of total 25-hydroxyvitamin D (25-OH-D) to assist clinicians in assessing vitamin D sufficiency.

    Here's a breakdown of the acceptance criteria and the study proving the device meets them:

    1. Table of Acceptance Criteria and Reported Device Performance

    The acceptance criteria are derived from the special controls defined in 21 CFR 862.1840 for Total 25-hydroxyvitamin D Mass Spectrometry Test Systems. The reported device performance is extracted from the "Performance Characteristics" section of the document.

    Acceptance Criteria (from 21 CFR 862.1840 Special Controls)Reported Device Performance
    (1) The device must have initial and annual standardization verification by a certifying vitamin D standardization organization deemed acceptable by FDA.Traceability: The assigned 25-hydroxyvitamin D of the Vitamin D 200M Assay for the Topaz System is certified with the CDC Vitamin D Standardization-Certification Program (VDSCP). (Source: CDC website link provided, last accessed May 18, 2017).
    (2) The 21 CFR 809.10(b) compliant labeling must include detailed descriptions of performance testing conducted to evaluate precision, accuracy, linearity, interference, including the following:Detailed descriptions are provided in the "L. Performance Characteristics" section and other sections of the document.
    (i) Performance testing of device precision must, at a minimum, use intended sample type with Vitamin D concentrations at medically relevant decision points. At least one sample in the precision studies must be an unmodified patient sample. This testing must evaluate repeatability and reproducibility using a protocol from an FDA-recognized standard.Reproducibility/Precision: Data was analyzed according to the multi-site evaluation study outlined in CLSI EP05-A3 guideline. The study was performed at three sites. Five serum samples were assayed on five calendar days, with one run per day and five replicates per sample. The analyte concentrations of the samples approximated both low and high levels, as well as medical decision points. The sixth sample was a native patient sample (unmodified).
    (ii) Performance testing of device accuracy must include a minimum of 115 serum or plasma samples that span the measuring interval of the device and compare results of the new device to results of a reference method or a legally marketed standardized mass spectrometry based vitamin D assay. The results must be described in the 21 CFR 809.10(b)(12) compliant labeling of the device.Method comparison with reference method: The sponsor performed an accuracy study to the CDC Vitamin D Standardization-Certification Program (VDSCP). The sample set contained 118 unique natural patient serum samples which were purchased and value assigned by CDC with total 25-OH-vitamin D concentrations ranging from 5.6 ng/mL to 133 ng/mL. Twelve specimens were contrived (10.2%). The comparison data was analyzed to find the Pearson correlation coefficient and an estimate of the bias using the slope of the line from the Passing-Bablok fit.
    (iii) Interference from vitamin D analogs and metabolites including vitamin D2, vitamin D3, 1-hydroxyvitamin D2, 1-hydroxyvitamin D3, 3-Epi-25-Hydroxyvitamin D2, 3-Epi-25-Hydroxyvitamin D3, 1,25-Dihydroxyvitamin D2, 1,25-Dihydroxyvitamin D3, 3-Epi-1,25-Dihydroxyvitamin D2, and 3-Epi-1,25-Dihydroxyvitamin D3, 25, 26-Dihydroxyvitamin-D3, 24 (R), 25-dihydroxyvitamin-D3, 23 (R), 25-dihydroxyvitamin-D3 must be described in the 21 CFR 809.10(b)(7) compliant labeling of the device.Analytical specificity: The design of the analytical specificity study was based on CLSI EP07-A2 guideline. A total of 79 potential interferents, at high and low concentrations, were spiked into samples with high and low concentrations of analyte (~37 ng/mL and ~11 ng/mL). Each of the four concentration combinations was tested in triplicate: low analyte/low interferent, low analyte/high interferent, high analyte/low interferent, and high analyte/high interferent, and was compared to control samples spiked with solvent instead of interferent. None of the potential endogenous and exogenous interfering substances or collection tubes tested in this study was found to cause interference with the analyte of interest greater than a 10% difference between the test and control samples. A comprehensive table listing substances and their highest concentration tested without significant interference is provided in the document. This list includes the specific vitamin D analogs and metabolites mentioned in the acceptance criteria.
    (3) The 21 CFR 809.10(b) compliant labeling must be supported by a reference range study representative of the performance of the device. The study must be conducted using samples collected from apparently healthy male and female adults at least 21 years of age and older from at least 3 distinct climatic regions within the United States of America in different weather seasons. The ethnic, racial, and gender background of this study population must be representative of the US population demographics.Expected Values: A reference range study was conducted with reference to the CLSI EP28-A3 guideline. A total of 404 serum samples from apparently healthy male and female adults 21 years of age and older from 3 different geographic regions were analyzed. The inner 95% Reference interval of 25(OH) vitamin D concentrations found in this population was 8.6 to 49 ng/mL. (Note: The document states "3 different geographic regions" which addresses the "distinct climatic regions" without explicitly stating "United States of America" or "different weather seasons". It also does not explicitly detail the "ethnic, racial, and gender background" as being "representative of the US population demographics" within this specific section, though it is a general requirement for such studies).
    (4) The results of the device as provided in the 21 CFR 809.10(b) compliant labeling and any test report generated must be reported as only total 25-hydroxyvitamin D.Indications For Use: The assay is intended for in vitro diagnostic use in the quantitative determination of total 25-hydroxyvitamin D (25-OH-D) through the measurement of 25-hydroxyvitamin D3 (25-OH-D3) and 25-hydroxyvitamin D2 (25-OH-D2). Test Principle: "Total Vitamin D concentrations is calculated as a total of the concentrations of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2." This directly supports reporting only total 25-hydroxyvitamin D.
    Linearity/Assay Reportable Range:A linearity study was performed according to CLSI EP06-A to assess the linearity of the Vitamin D 200M Assay across the assay measuring range (4 to 140 ng/mL). The results of the linear regression analyses were: y = 0.9974x + 1.1737 R2 = 0.9984. The linearity study data support the claimed measuring range of 4.0 to 140 ng/mL.
    Detection Limit:The lower limit of the measuring interval (LLMI) for this assay was determined to be 2.9 ng/mL for total 25-OH-Vitamin D. This was determined as the lowest concentration of analyte that achieved both the bias and precision goals (<20% bias and <20% CV).
    Carryover:Studies were performed at a single internal site using 3 instruments and 3 kit lots over a period of 1 day. There was no carry-over demonstrated in the study. This study was sufficient to demonstrate that there was no significant carry-over.

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

    • Test Set Sample Size:

      • Precision/Reproducibility: 6 serum samples (5 spiked/diluted, 1 native patient). Each sample was assayed on 5 calendar days, with 1 run per day and 5 replicates per sample.
      • Linearity: 9 serum samples (serially diluted from a high concentration sample).
      • Accuracy/Method Comparison: 118 unique natural patient serum samples. 12 specimens (10.2%) were contrived.
      • Analytical Specificity/Interference: 79 potential interferents, spiked into samples with high and low analyte concentrations. Each of four concentration combinations was tested in triplicate.
      • Reference Range Study: 404 serum samples.

    • Data Provenance: The document does not explicitly state the country of origin for all data.

      • For the Accuracy/Method Comparison, the samples were "purchased and value assigned by CDC" and "CDC Vitamin D Standardization-Certification Program (VDSCP)," which implies US-based reference and potentially US-derived samples.
      • For the Reference Range Study, samples were from "3 different geographic regions" and are described in the context of being "representative of the US population demographics," strongly implying US-based retrospective or prospective collection.
      • The Precision study was "performed at three sites," which could be internal or external but is not specified beyond that.
      • All studies appear to be prospective in nature, as they are described as "studies performed" or "study was performed" to evaluate the device's characteristics.

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

    This device is an in vitro diagnostic (IVD) assay for quantitative measurement, not an image-based AI device requiring expert human readers for ground truth.

    • Ground Truth for Accuracy/Method Comparison: The ground truth for the 118 patient samples was established by the CDC Vitamin D Standardization-Certification Program (VDSCP), which acts as a reference method. The specific "experts" or their qualifications within the CDC program are not detailed in this document, but their role as a "standardization organization" implies high-level analytical expertise.
    • For other analytical performance characteristics (precision, linearity, detection limit, analytical specificity), the ground truth is based on the known concentrations of spiked analytes or the intrinsic properties of the samples used, not on expert human interpretation.

    4. Adjudication Method for the Test Set

    Not applicable in the context of a quantitative IVD device. Ground truth for the method comparison was established by a reference method (CDC VDSCP), not through human adjudication of differing interpretations. Analytical performance studies rely on measured values against known concentrations or statistical methods defined by CLSI guidelines.

    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 is an in vitro diagnostic (IVD) assay, not an AI-assisted diagnostic imaging device that involves human reader interpretation. No MRMC study was performed.

    6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

    Yes, the entire performance characterization described in the document is for the standalone device (the Vitamin D 200M Assay on the Topaz System) without human-in-the-loop performance influencing the measurement itself. The device performs the LC-MS/MS analysis and provides a quantitative result. Human involvement is primarily in operating the system, preparing samples, and using the results in conjunction with other clinical data. The performance metrics (precision, accuracy, linearity, etc.) are solely for the device's technical capabilities.

    7. The Type of Ground Truth Used

    • Accuracy/Method Comparison: The ground truth was established by a reference method (CDC Vitamin D Standardization-Certification Program (VDSCP)). This is equivalent to an external, highly standardized, and validated method.
    • Precision, Linearity, Detection Limit, Analytical Specificity: Ground truth was based on the known concentrations of analytes in prepared samples (spiked or diluted samples) or intrinsic properties of native samples, following established CLSI guidelines. This falls under a form of "designed experimental data with known parameters."
    • Reference Range Study: Ground truth for this was the actual measured 25-OH-D concentrations in the serum samples of "apparently healthy" individuals, which were then used to define the expected reference interval. This is based on outcomes data in a healthy population.

    8. The Sample Size for the Training Set

    Not applicable. This document describes an IVD assay, not a machine learning or AI-based device that requires a distinct "training set" in the computational sense. The device's underlying principles are based on LC-MS/MS technology and established chemical/physical properties, not on training a model with data.

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

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

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