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510(k) Data Aggregation

    K Number
    K150606
    Device Name
    Emit II Plus Buprenorphine Assay, Emit II Plus Specialty Drug Calibrator/Control Level 1, Level 2 Level 3, Level 4, Emit II Plus Specialty Drug Control Negative, Emit II Plus Specialty Drug Control Positive
    Manufacturer
    SIEMENS HEALTHCARE DIAGNOSTICS, INC.
    Date Cleared
    2015-10-23

    (227 days)

    Product Code
    DJG,DLJ,LAS
    Regulation Number
    862.3650
    Type
    Traditional
    Panel
    Toxicology
    Reference & Predicate Devices
    K993755,K040316
    Predicate For
    K161216,K221605
    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay with a 5 ng/mL cutoff. The assay is intended for use in laboratories for the qualitative analyses of buprenorphine in human urine. Emit® II Plus assays are designed for use with a number of 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 LC/MS or Permitting laboratories to establish quality control procedures.

    The Emit® II Plus Buprenorphine Assay provides only a preliminary analytical test result. A more specific alternative chemical method(s) must be used to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry (GC/ MS) or LC/MS are the preferred confirmatory methods. Other chemical confirmation methods are available. Clinical consideration and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used.

    Emit® II Plus Specialty Drug Calibrator/Control Level 1, Emit® II Plus Specialty Drug Calibrator/Control Level 2, Emit® II Plus Specialty Drug Calibrator/Control Level 3, Emit® II Plus Specialty Drug Calibrator/Control Level 4

    The Emit® II Plus Specialty Drug Calibrators/Controls are used in the calibration of the Emit® II Plus Buprenorphine Assay. These products may also be used as quality control materials based on the Buprenorphine Assay cutoff.

    Emit® II Plus Specialty Drug Control Negative and Emit® II Plus Specialty Drug Control Positive

    The Emit® II Plus Specialty Drug Control Negative and Control Positive are for use with the Emit® II Plus Buprenorphine Assay.

    Device Description

    The Emit® II Plus Buprenorphine assay is a homogeneous enzyme immunoassay with a 5 ng/mL cutoff. The assay, used for the detection of Buprenorphine in human urine, utilizes a two-reagent system. The Antibody/Substrate Reagent 1 is a liquid ready-to-use product comprised of mouse monoclonal antibodies to buprenorphine, glucose-6-phosphate (G6P), and nicotinamide adenine dinucleotide (NAD) in a diluent containing bovine serum albumin (BSA), preservatives and stabilizers. The Enzyme Reagent 2 is a liguid. ready-to-use product containing norbuprenorphine labeled bacterial recombinant glucose-6 phosphate dehydrogenase (rG6PDH) in a diluent containing bovine serum albumin (BSA), Hepes buffer, preservatives and stabilizers.

    The assay kit consists of Reagent 1 and Reagent 2 in plastic containers and is available in three sizes: large kit (1L), small kit (115 mL), and 28 mL Emit® II Plus assays are designed for use with a number of chemistry analyzers.

    The Emit® II Plus Buprenorphine assay provides only a preliminary analytical test result. A more specific alternative chemical method must be used to obtain a confirmed analytical result.

    Emit® II Plus Specialty Drug Calibrators / Controls are in-vitro diagnostic products used in the calibration of the Emit® II Plus Buprenorphine assay. These products may also be used as quality control materials based on the Buprenorphine Assay cutoff. The matrix is pooled, drug-free, human urine based product containing buprenorphine, preservatives and surfactants. Each level of calibrator is packaged and sold separately, 1 plastic bottle per box, 10 mL in a 15 mL bottle. Values are nominal and are verified with urine based buprenorphine anchor pool and adjusted if needed. The anchor pool levels are verified by LC/MS/MS and are within 10% of nominal drug concentration for levels 2.5 and 5.0 ng/mL and within 5 % of nominal concentrations for levels 15 and 25 ng/mL.

    Emit® II Plus Specialty Drug Control Negative and Emit® II Plus Specialty Drug Control Positive are in-vitro diagnostic products are for use with the Emit® II Plus Buprenorphine assay. The matrix is pooled, drug-free, human urine based product containing buprenorphine, preservatives and surfactants. The Control Negative and Control Positive are packaged separately in 15 mL plastic vials with a 10 mL fill per vial. Values are nominal and are verified with urine based buprenorphine anchor pool and adjusted if needed. Anchor pool levels are verified by LC/MS/MS.

    AI/ML Overview

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

    Device: Emit® II Plus Buprenorphine Assay, Emit® II Plus Specialty Drug Calibrator/Control Level 1-4, Emit® II Plus Specialty Drug Control Negative/Positive.

    Acceptance Criteria and Reported Device Performance

    The acceptance criteria are not explicitly stated as numbered or bulleted points in the provided document. However, based on the performance data presented, we can infer the criteria that the device aimed to meet for substantial equivalence. The document primarily focuses on demonstrating performance against expected standards for an in vitro diagnostic device for drug screening, particularly a qualitative and semi-quantitative assay.

    Here's a table summarizing the inferred acceptance criteria and the device's performance:

    Acceptance Criteria Category/Inferred CriteriaReported Device Performance
    Precision (Qualitative Analysis) - Agreement near cutoff - Consistent classification (Negative/Positive) for concentrations significantly below/above cutoff. - Acceptable level of concordant/discordant results near the cutoff for both qualitative and semi-quantitative modes.Precision: Qualitative Analysis (5 ng/mL cutoff) - 0, 2.5, 3, 3.75 ng/mL (below cutoff): 80 Negative out of 80 results (100% agreement). - 5 ng/mL (cutoff): 25 Negative / 55 Positive (68.75% positive, 31.25% negative). This indicates some variability at the exact cutoff, which is typical for immunoassays. - 6.25, 7, 7.5, 10 ng/mL (above cutoff): 80 Positive out of 80 results (100% agreement). - Additional Precision Study: - 1.25 ng/mL (-75% cutoff): 80 Negative out of 80 results (100% agreement). - 8.75 ng/mL (+75% cutoff): 80 Positive out of 80 results (100% agreement). Overall, good precision away from the cutoff, expected variability at the cutoff.
    Precision (Semi-quantitative Analysis) - Agreement near cutoff - Consistent classification (Negative/Positive) and semi-quantitative results for concentrations significantly below/above cutoff.Precision: Semi-quantitative Analysis (5 ng/mL cutoff) - 0, 2.5, 3, 3.75 ng/mL (below cutoff): 80 Negative out of 80 results (100% agreement). - 5 ng/mL (cutoff): 25 Negative / 55 Positive (68.75% positive, 31.25% negative). - 6.25, 7, 7.5, 10 ng/mL (above cutoff): 80 Positive out of 80 results (100% agreement). - Additional Precision Study: - 1.25 ng/mL (-75% cutoff): 80 Negative out of 80 results (100% agreement). - 8.75 ng/mL (+75% cutoff): 80 Positive out of 80 results (100% agreement). Results mirror qualitative analysis, demonstrating consistent semi-quantitative performance.
    Specificity and Cross-reactivity - Buprenorphine Metabolites - Appropriate cross-reactivity with buprenorphine and its primary active metabolite (norbuprenorphine). - Low to no cross-reactivity with inactive glucuronide metabolites.Buprenorphine Metabolite Recovery - Buprenorphine (5 ng/mL): 103.2% recovery (5.2 ng/mL). - Norbuprenorphine (5 ng/mL): 92.6% recovery (4.6 ng/mL). - Buprenorphine Glucuronide (1000 ng/mL): 0.1% cross-reactivity (0.9 ng/mL). - Norbuprenorphine Glucuronide (1000 ng/mL): 0.1% cross-reactivity (1.2 ng/mL). Demonstrates good detection of buprenorphine and norbuprenorphine, minimal interference from inactive glucuronide metabolites.
    Specificity and Cross-reactivity - Structurally Related Compounds - No significant false positives from a panel of common opioids and other structurally related compounds at high concentrations.Cross-reactivity with Structurally Related Compounds - Over 20 common opioids and related compounds (e.g., 6-acetylcodeine, codeine, heroin, morphine, oxycodone) were tested at 100,000 ng/mL. - All tested compounds showed "Negative" qualitative results and "<0.01%" cross-reactivity (semi-quantitative). Excellent specificity, not cross-reacting with a wide range of other opioids at very high concentrations, which is critical for drug screening assays.
    Interference - Structurally Unrelated Compounds - No false positive or false negative results from a panel of common medications and other substances expected in urine at clinically relevant concentrations.Interference of Structurally Unrelated Compounds - Over 50 structurally unrelated compounds (e.g., acetaminophen, amoxicillin, caffeine, ibuprofen, fluoxetine, methadone, naproxen, phencyclidine, THC) were tested. - Each interferent was spiked into urine pools at -40% cutoff (3 ng/mL buprenorphine) and +40% cutoff (7 ng/mL buprenorphine). - At the stated concentration for each interferent, all "-40% Cutoff" samples remained Negative and all "+40% Cutoff" samples remained Positive, for both qualitative and semi-quantitative results. Demonstrates good resistance to interference from a broad range of common drugs and substances.
    Interference - Endogenous Substances - No false positive or false negative results due to endogenous substances, pH, or specific gravity variations.Endogenous Substances Interference, pH, and Specific Gravity - 15 endogenous substances (e.g., acetone, ascorbic acid, bilirubin, creatinine, ethanol, glucose, hemoglobin, urea) were tested at high concentrations. - pH range (pH 3 to pH 11) and Specific Gravity range (1.002 to 1.035) were tested. - For all endogenous substances, pH levels, and specific gravity levels, the -40% cutoff samples remained Negative, and the +40% cutoff samples remained Positive, for both qualitative and semi-quantitative results. Indicates robust performance across a range of physiological conditions and common urine constituents.
    Recovery/Linearity - Accurate semi-quantitative recovery of buprenorphine across a range of concentrations.Recovery/Linearity - Tested nine concentrations of buprenorphine from 2 ng/mL to 25 ng/mL. - % Recovery ranged from 92.5% to 105.0%. Demonstrates good linearity and accurate recovery of buprenorphine concentrations over the tested range.
    Method Comparison (Qualitative and Semi-quantitative) - Agreement with Reference Method - High agreement with a more specific, confirmatory method (LC/MS/MS). - Acceptable number of discordant results, with plausible explanations for any discrepancies.Method Comparison (Emit® II Plus Buprenorphine Assay vs. LC/MS/MS) - Total Samples: 127 unaltered human urine samples. - Qualitative Agreement: 90% positive agreement, 98% negative agreement. - Overall Agreement (from 2x2 table): (65 + 54) / 127 = 119 / 127 = 93.7%. - Discordant Results (8 samples): - 7 samples were Emit® Positive but LC/MS/MS Negative (concentration between 3.86-4.97 ng/mL, below 5 ng/mL cutoff for LC/MS/MS buprenorphine/norbuprenorphine sum). These are typically considered "near cutoff" false positives for a screening assay. - 1 sample was Emit® Negative but LC/MS/MS Positive (buprenorphine at 5.12 ng/mL). This is a single false negative near the cutoff. High overall agreement with LC/MS/MS, with expected discordance at concentrations close to the cutoff, demonstrating performance comparable to drug screening immunoassays.

    Study Details:

    1. Sample Size used for the test set and data provenance:

      • Precision/Cutoff Characterization: For the main precision study, 8 urine pools were tested (0, 2.5, 3, 3.75, 5, 6.25, 7, 7.5, 10 ng/mL). Each pool was analyzed in duplicate twice a day for 20 days, resulting in 80 replicates per concentration level (total 720 replicates) for the main study. An additional precision study used 2 urine pools (1.25 and 8.75 ng/mL), with 80 replicates each (total 160 replicates). The urine was "drug-free human urine" spiked with buprenorphine.
      • Specificity and Cross-reactivity (Metabolites): Each metabolite was tested at n=5 replicates.
      • Specificity and Cross-reactivity (Structurally Related Compounds): Each compound was tested at n=5 replicates.
      • Interference (Structurally Unrelated Compounds): Each interferent was tested at n=5 replicates (at both -40% and +40% cutoff levels).
      • Interference (Endogenous Substances): Each endogenous substance, pH level, and specific gravity level was tested (N=not explicitly stated, but typically n=5 replicates as above).
      • Recovery/Linearity: Nine concentrations were analyzed in replicates of N=5.
      • Method Comparison: 127 unaltered human urine samples were used.
      • Data Provenance: The document states studies were conducted at "Siemens Healthcare Diagnostics Inc." and used "human urine" (drug-free or unaltered). No specific country of origin is mentioned. It is an internal, retrospective study using banked samples or samples collected for the purpose of the study.

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

      • For the Method Comparison study, the ground truth was established by LC/MS/MS (Liquid Chromatography/Mass Spectrometry/Mass Spectrometry), which is a highly specific and sensitive analytical method considered a "confirmatory method." This is a laboratory-based instrumental method, not established by human experts in the traditional sense of medical image interpretation or clinical diagnosis. The "experts" would be the laboratory personnel operating and interpreting the LC/MS/MS results, qualified in analytical chemistry and toxicology testing. Their number and specific qualifications are not specified in this document.

    3. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

      • For the method comparison, the ground truth was established by LC/MS/MS as a single, definitive reference method. There was no multi-expert adjudication mentioned as would be common in diagnostic imaging studies. The LC/MS/MS result serves as the "gold standard."

    4. 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:

      • No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay (a chemical test) and operates independently of human "readers" or "AI assistance" in the way that imaging devices or AI-driven diagnostic software would. The output is a numerical value or a qualitative (positive/negative) result generated by an automated analyzer.

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

      • Yes, the provided performance data represents standalone performance. The Emit® II Plus Buprenorphine Assay is an automated immunoassay designed for use on chemistry analyzers. All precision, specificity, interference, linearity, and method comparison data reflect the assay's performance without "human-in-the-loop" interpretation beyond running the assay and recording the results. The ultimate interpretation and clinical judgment for drug-of-abuse test results might involve a human, but the analytical performance presented is the measurement device's standalone capability.

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

      • The ground truth for the performance studies, particularly the crucial method comparison, was established by LC/MS/MS (Liquid Chromatography/Mass Spectrometry/Mass Spectrometry). This is an analytical reference method considered the gold standard for confirming drug presence and concentration in toxicology.

    7. The sample size for the training set:

      • This document describes performance characteristics of a diagnostics assay for regulatory submission. It does not refer to a "training set" in the context of machine learning. The "training" of such a device primarily involves the development and optimization of the reagent formulation and assay parameters during the product development phase, which isn't typically quantified by a distinct "training set sample size" like in AI/ML development. The precision studies use spiked urine, which could be considered part of the characterization but not a "training set" in the modern AI sense.

    8. How the ground truth for the training set was established:

      • Given that this is not an AI/ML device but a chemical immunoassay, the concept of a "ground truth for a training set" as typically understood in AI/ML performance studies does not directly apply. The calibration and control materials are manufactured to known (targeted) concentrations, and their values are "verified with urine based buprenorphine anchor pool and adjusted if needed," with anchor pool levels "verified by LC/MS/MS." This implies that the 'true' concentrations for calibrators and controls used to define the assay's performance characteristics are established via LC/MS/MS.
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