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510(k) Data Aggregation

    K Number
    K173195
    Device Name
    DRI Hydrocodone Assay
    Manufacturer
    Microgenics Corporation
    Date Cleared
    2018-02-13

    (134 days)

    Product Code
    DJG
    Regulation Number
    862.3650
    Type
    Traditional
    Panel
    Toxicology
    Reference & Predicate Devices
    K150502
    Predicate For
    N/A
    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    The DRI Hydrocodone Assay is a homogeneous enzyme immunoassay for the qualitative and/or semi-quantitative determination of the presence of hydrocodone and its metabolites in human urine at a cut-off concentration of 300 ng/mL. The assay is intended to be used in laboratories and provides a simple and rapid analytical screening procedure to detect hydrocodone and its metabolites in human urine. The assay is designed for use with a number of clinical chemistry analyzers.

    The semi-quantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as Liquid chromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establish quality control procedures.

    The assay provides only a preliminary analytical test result. A more specific alternative chemical method must be used to obtain a confirmed analytical result. Gas chromatography/ mass spectrometry (GC/MS) or Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is the preferred confirmatory method

    Device Description

    The DRI Hydrocodone assay is supplied as a liquid ready-to-use homogeneous enzyme immunoassay. The assay uses specific antibodies that can detect Hydrocodone and Hydromorphone and Hydromorphone glucuronide. The assay is based on competition between a drug labeled with glucose-6-phosphate dehydrogenase (G6PDH) and free drug from the urine sample, for a fixed amount of specific antibody binding sites. In the absence of free drug from the sample, the specific antibody binds the drug labeled with G6PDH and causes a decrease in enzyme activity. This phenomenon creates a direct relationship between the drug concentration in urine and enzyme activity. The enzyme activity is determined spectrophotometrically at 340 nm by measuring the conversion of nicotinamide adenine dinucleotide (NAD) to NADH.

    The assay consists of reagents (A and E).

    Reagent A contains mouse monoclonal anti-Hydrocodone antibody, glucose-6-phosphate (G6P), and nicotinamide adenine dinucleotide (NAD) in Tris buffer with sodium azide as a preservative.

    Reagent E: Contains Hydrocodone derivative labeled with glucose-6-phosphate dehydrogenase (G6PDH) in Tris buffer with sodium azide as a preservative.

    AI/ML Overview

    The provided document is a 510(k) premarket notification for a medical device called the DRI Hydrocodone Assay. This device is a homogeneous enzyme immunoassay designed for the qualitative and/or semi-quantitative determination of hydrocodone and its metabolites in human urine.

    Here's an analysis of the acceptance criteria and study proving the device meets those criteria, based on the provided text:

    Key Takeaway: This 510(k) is for a new instrument platform (Indiko Plus) for an already cleared assay (DRI Hydrocodone Assay, K150502). Therefore, much of the study focuses on showing comparable performance between the new instrument and the previous one. The acceptance criteria are implicitly met by demonstrating performance consistent with an already legally marketed predicate device.

    1. Table of Acceptance Criteria and Reported Device Performance

    Since this is a 510(k) for an existing assay on a new instrument, the "acceptance criteria" are not explicitly stated as quantitative targets (e.g., "sensitivity must be >95%"). Instead, the acceptance criteria are implicitly that the performance on the new analyzer (Indiko Plus) is comparable or equivalent to the performance on the predicate analyzer (AU 680). The study aims to demonstrate that the new device performs as intended and similarly to its predicate.

    Test CategoryAcceptance Criteria (Implicit)Reported Device Performance (DRI Hydrocodone Assay on Indiko Plus)
    PrecisionConsistent and reliable results across replicates and days, reflecting expected performance relative to the cutoff. For qualitative mode, no overlap in 2SD ranges between critical concentrations (e.g., -25% and 100% of cutoff, and 100% and +25% of cutoff).Qualitative Mode:- Lot #1: - -100% to -25% of cutoff: 80/80 Negative results. - 100% of cutoff (300 ng/mL, LC-MS/MS 318.50): 22 Negative / 58 Positive. - +25% to +100% of cutoff: 80/80 Positive results.- Lot #2: - -100% to -25% of cutoff: 80/80 Negative results. - 100% of cutoff (300 ng/mL, LC-MS/MS 318.50): 4 Negative / 76 Positive. - +25% to +100% of cutoff: 80/80 Positive results.Semi-quantitative Mode:- Lot #1: - -100% to -25% of cutoff: 80/80 Negative results. - 100% of cutoff (300 ng/mL, LC-MS/MS 318.50): 24 Negative / 56 Positive. - +25% to +100% of cutoff: 80/80 Positive results.- Lot #2: - -100% to -25% of cutoff: 80/80 Negative results. - 100% of cutoff (300 ng/mL, LC-MS/MS 318.50): 7 Negative / 73 Positive. - +25% to +100% of cutoff: 80/80 Positive results.Spike Recovery: No ± 2SD overlap between 300 ng/mL samples and 225 ng/mL (all 20 replicates negative) and 375 ng/mL (all 20 replicates positive). Conclusion: Meets Acceptance Criteria.
    Analytical Recovery and Dilution LinearityExpected: % Recovery should be within an acceptable range (e.g., 80-120%). Dilution should demonstrate linearity.Samples run in replicates of five in semi-quantitative mode. % Recovery ranged from 91.1% (at 1000 ng/mL) to 110.3% (at 300 ng/mL for one lot, 200 ng/mL for another). Conclusion: Meets Acceptance Criteria.
    Method Comparison and AccuracyHigh overall concordance with the confirmatory method (LC-MS/MS). Discordant samples should be explainable.Overall concordance with LC-MS/MS: 82.4%.- Qualitative & Semi-Quantitative Mode (combined table in document): - True Negatives: 42 - False Positives (immunoassay positive, LC-MS/MS <150 ng/mL or 150-299.9 ng/mL): 7+17 = 24 discordant samples (e.g., Immmunoassay positive, LC-MS/MS 126 ng/mL, 179 ng/mL hydromorphone-3β-glucuronide). - True Positives (immunoassay positive, LC-MS/MS >=300 ng/mL): 9+48 = 57 - False Negatives (immunoassay negative, LC-MS/MS <150 ng/mL or 150-299.9 ng/mL): 3+10 = 13 - False Negatives (immunoassay negative, LC-MS/MS >=300 ng/mL): 0Explanation for discordant samples: Cross-reactivity of immunoassay to hydromorphone and hydromorphone-3β-glucuronide.
    Specificity (Cross-reactivity)Known related compounds should show expected cross-reactivity. Structurally unrelated compounds should show minimal or no cross-reactivity, especially at critical concentrations.Hydrocodone & Metabolites:- Hydrocodone: 100% cross-reactivity at 300 ng/mL (cutoff).- Hydromorphone: 92% cross-reactivity at 325 ng/mL.- Hydromorphone-3β-glucuronide: 162% cross-reactivity at 185 ng/mL (higher than 100% suggests higher potency than Hydrocodone in the assay).- Norhydrocodone: 2% at 13,000 ng/mL.- Dihydrocodeine: 2% at 12,500 ng/mL.Opiates & Structurally Related: Most showed <0.1% to <0.4% cross-reactivity at high concentrations (e.g., Codeine <0.2% at 150,000 ng/mL), indicating minimal/negligible assay interference from standard opiates at typical physiological levels relative to hydrocodone. Some showed higher e.g., Levorphanol (1.4% at 22,000 ng/mL), Naloxone (1.8% at 17,000 ng/mL), Naltrexone (0.4% at 75,000 ng/mL), Noroxycodone (0.3% at 110,000 ng/mL), Oxycodone (2.1% at 14,000 ng/mL), Oxymorphone-beta-D-glucuronide (2.1% at 14,000 ng/mL), Oxymorphone (2.1% at 140,000 ng/mL).Structurally Unrelated Compounds: All tested compounds (e.g., Acetaminophen, Ibuprofen, Amphetamine, Caffeine) showed no interference; samples spiked with Low Control (225 ng/mL hydrocodone) remained negative, and those with High Control (375 ng/mL hydrocodone) remained positive.
    Interference (pH, Endogenous Substances)No significant interference from common urinary pH variations or endogenous substances at physiologically relevant concentrations.Interference Substances: No interference observed for common substances (e.g., Acetaminophen, Creatinine, Glucose, Hemoglobin, Urea) at specified concentrations. Low Control remained Negative, High Control remained Positive.pH: No interference observed across pH 4-10. Low Control remained Negative, High Control remained Positive.
    Specific GravityNo significant interference from varying specific gravity of urine samples.No interference observed for specific gravity ranging from 1.003 to 1.031. Low Control remained Negative, High Control remained Positive.
    StabilityAssay reagents should maintain performance over claimed shelf-life and on-board stability periods.Open Vial Stability: 60 days (validated in predicate submission K150502).Reagent On-Board Stability: 60 days.Real Time Stability: 2 years at 2-8°C, with Low Control remaining negative and High Control remaining positive, and recoveries within 80-120%. Current shelf-life claim is 18 months, which is supported.
    TraceabilityCalibrators and controls should be traceable to a reliable reference standard.Primary controls and calibrators are traceable to 1 mg/mL Hydrocodone stock solution (99.9% purity) from a commercial source. Confirmed by LC-MS/MS from three independent laboratories.

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

    • Precision:
      • Qualitative & Semi-quantitative Modes: Samples prepared by spiking hydrocodone into drug-free urine at cutoff, ±25%, ±50%, ±75%, and -100% (0 ng/mL hydrocodone).
      • Sample Size: For each of the two reagent lots, each concentration was tested in replicates of 2, twice per day for 20 days.
        • Total n = 80 determinations per concentration per lot.
    • Analytical Recovery and Dilution Linearity:
      • Sample Size: 10 intermediate dilution levels generated from a high calibrator (1000 ng/mL) spiked in drug-free urine. Each sample run in replicates of five. (Therefore, 11 concentrations total * 5 replicates = 55 measurements per lot, though not explicitly stated if multiple lots were used here).
    • Method Comparison and Accuracy:
      • Sample Size: One hundred and thirty six (136) patient samples.
      • Data Provenance: Not explicitly stated (e.g., country of origin), but implied to be from a laboratory setting. The terms "patient samples" suggest real-world samples, but it's not specified if they were retrospectively collected or prospectively collected. Given that it's compared against LC-MS/MS, it's likely retrospective.
    • Specificity (Cross-reactivity) & Interference & Specific Gravity:
      • Sample Size:
        • Hydrocodone and its Metabolites: Tested using varying concentrations of each compound, with results given as concentrations achieving cutoff-equivalent response. Number of replicates per concentration not explicitly stated but implied multiple for curve fitting.
        • Opiates and Structurally Related Compounds: Tested at single high concentrations.
        • Structurally Unrelated Compounds: Spiked into 225 ng/mL or 375 ng/mL hydrocodone urine. Tested in 5 replicates for each compound and concentration.
        • Interference Substances & pH & Specific Gravity: Tested at single concentrations/pH values. Replicates not explicitly stated for these specific tests but implied by general "analytical performance" section to follow CLSI protocol, which often involves replicates.
      • Data Provenance: Controlled laboratory experiments using spiked drug-free urine.

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

    • Ground Truth Method: LC-MS/MS (Liquid Chromatography/Tandem Mass Spectrometry) is used as the preferred confirmatory method for hydrocodone and its metabolites.
    • Experts: LC-MS/MS is a highly precise and definitive analytical chemical method, considered the gold standard for drug quantification in urine. Therefore, the "ground truth" is established by the analytical method itself, not by human experts interpreting results. The document notes that external laboratories confirmed the concentration of primary control and calibrator stocks by LC-MS/MS, adding a layer of external validation to the method's accuracy.

    4. Adjudication Method for the Test Set

    • Adjudication: Not applicable. The "ground truth" is established by an objective, quantitative laboratory assay (LC-MS/MS), not by human interpretation requiring adjudication. Discordant results are analyzed against this LC-MS/MS truth and explained (e.g., cross-reactivity).

    5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

    • MRMC Study: No. This device is an immunoassay for drug detection, where the output is a chemical reaction read by an analyzer to provide a qualitative or semi-quantitative result. It does not involve human readers interpreting images or complex data in the same way an AI for radiology would. Therefore, an MRMC study is not relevant or applicable.

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

    • Standalone Performance: Yes, in essence. The studies for precision, analytical recovery, specificity, and interference evaluate the assay's performance independent of human interpretation for the final qualitative/quantitative determination. The device's output (positive/negative, or semi-quantitative concentration) is directly compared to the LC-MS/MS ground truth. Human involvement is limited to sample preparation, loading the instrument, and reviewing automated results, not interpreting raw data or making diagnostic decisions without the device's output.

    7. The Type of Ground Truth Used

    • Type of Ground Truth: The ground truth for this device's performance studies is definitive analytical chemistry data, specifically Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) results. This is considered the gold standard for confirming and quantifying drug concentrations in biological samples. It's a highly objective and quantitative method.

    8. The Sample Size for the Training Set

    • Training Set: Not explicitly mentioned or applicable in the context of this traditional immunoassay. This is not a machine learning/AI device that requires a distinct "training set" in the computational sense. Immunoassays leverage established biochemical principles and reagents. The "training" for such devices involves reagent formulation, calibration curve development, and optimization by the manufacturer, rather than machine learning on a dataset. The precision study uses two lots of reagents, which implies a level of manufacturing consistency, but these are not 'training sets' in the AI sense.

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

    • Ground Truth for Training/Development: Not applicable as there is no computational "training set" in the AI sense. The development and optimization of the immunoassay reagents rely on known chemical properties, antibody specificity, and the relationship between drug concentration and enzyme activity. Calibrators and controls are used during development and routine use, and their concentrations are traceable to LC-MS/MS confirmed stock solutions (as noted in section 1g, "Traceability"). This analytical method ensures the accuracy of the calibrators used to establish the assay's performance curve.
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