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The 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 and/or semiquantitative analyses of buprenorphine in human urine. Emit® II Plus assays are designed for use with a number of chemistry analyzers.

The semiquantitative 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/Mass Spectrometry (LC/MS) or permitting laboratories to establish quality control procedures.

The Emit® II Plus Burrenorphine 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.

For Professional Use.

Caution: Federal (USA) law restricts this device to sale by or on the order of a licensed healthcare professional.

For in vitro diagnostic use.

The Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay technique used for the analysis of specific compounds in human urine. The assay is based on competition between drug in the specimen and drug labeled with the recombinant glucose-6-phosphate dehydrogenase (rG6PDH) for antibody binding sites. Enzyme activity decreases upon binding to the antibody, so the drug concentration in the specimen can be measured in terms of enzyme activity. Active enzyme converts nicotinamide adenine dinucleotide (NAD) to NADH in the presence of glucose-6phosphate (G6P), resulting in an absorbance change that is measured spectrophotometrically. Endogenous serum G6PDH does not interfere because the coenzyme NAD functions only with the bacterial (Leuconostoc mesenteroides) enzyme employed in the assay.

The Emit® II Plus Buprenorphine Assay reagents are provided liquid, ready to use and may be used directly from the refrigerator. The product is sold in three (3) kit sizes: 28 mL, 115 mL, and 1000 mL. Reagents 1 and 2 are provided as a matched set. They should not be interchanged with components of kits with different lot numbers.

Antibody/Substrate Reagent 1: Mouse monoclonal antibodies to buprenorphine (0.53 µg/mL)*.NAD (6.9 mM), G6P (10.9 mM), bovine serum albumin, preservatives, and stabilizers. *The antibody titer and enzyme conjugate activity may vary from lot to lot.

Enzyme Reagent 2: Norbuprenorphine labeled with bacterial rG6PDH (0.50 µg/mL), HEPES buffer, bovine serum albumin, preservatives, and stabilizers, where the antibody titer and enzyme conjugate activity may vary from lot to lot.

The marketing submission for the Siemens Healthineers Emit® II Plus Buprenorphine Assay (K221605) demonstrates that the device meets its acceptance criteria through various performance studies. Below is a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as strict numerical thresholds in the provided document, but rather demonstrated through the qualitative agreement and recovery percentages, as well as precision and specificity profiles. Based on the "Method Comparison" results, the implicit acceptance criterion for qualitative agreement against LC/MS/MS is a high percentage, and for recovery, it's generally close to 100%. For specificity, it's low or negligible cross-reactivity with other substances (ideally less than the cutoff concentration when tested at high concentrations). For precision, it's low coefficient of variation (CV).

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

• Method Comparison: 120 native urine individual patient samples. The samples were collected from external suppliers, received frozen, and thawed before testing. 21% were within -50% of the cutoff and 19% within +50% of the cutoff. The provenance is not explicitly stated in terms of country of origin but implies human urine samples from external suppliers. The study design is retrospective, using previously collected samples.
• Recovery: 9 urine samples prepared by spiking buprenorphine into negative urine pools.
• Precision (Repeatability and Within-Lab): 11 urine samples prepared by spiking buprenorphine into negative urine pools.
• Precision (Reproducibility): 3 urine samples (Negative Control, Cutoff Calibrator, Positive Control from Emit II Plus Specialty Drug Control line).
• Limit of Detection: 4 blank samples and 4 low-level samples (buprenorphine spiked into drug-free urine). A minimum of 60 replicate measurements per sample set.
• Specificity and Cross-reactivity: The number of unique compounds tested is substantial (listed in Tables 9, 10, and 11), with samples assayed in five replicates for each compound.
• Interference: Various endogenous and exogenous substances, as well as pH and specific gravity variations, were tested at specified concentrations. Samples were assayed in five replicates.

3. 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). This is a highly specific and sensitive analytical method considered the gold standard for drug confirmation testing. No human experts are explicitly described as establishing the ground truth; it's based on the instrumental analytical results.
• For Recovery, the ground truth (nominal value) for spiked samples was determined gravimetrically based on stock concentration and confirmed by LC/MS/MS.
• For Precision, Limit of Detection, Specificity, and Interference, the ground truth is based on the known concentrations of spiked substances or the known characteristics of the samples (e.g., drug-free urine, specific pH levels). Instrumental analysis is used to determine the device's measurement against these known values.

4. Adjudication Method for the Test Set

• For the qualitative analysis in the Method Comparison, the results from the Emit® II Plus Buprenorphine Assay on DxC 500 AU were compared directly against the results from LC/MS/MS. A 2x2 box plot was used to assess qualitative agreement. There is no mention of a human adjudication method (e.g., 2+1 or 3+1), as the comparison is between two analytical methods.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No MRMC comparative effectiveness study was done. This device is an in vitro diagnostic assay, not an AI-assisted interpretation device that would involve human readers.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Yes, the entire performance evaluation presented is a standalone study of the analytical performance of the Emit® II Plus Buprenorphine Assay on the DxC 500 AU Clinical Chemistry Analyzer. There is no human-in-the-loop component for interpreting the assay's results; the device produces qualitative or semi-quantitative analytical results directly.

7. Type of Ground Truth Used

• Analytical Ground Truth:
  • LC/MS/MS (Liquid Chromatography/Mass Spectrometry/Mass Spectrometry) for method comparison and as a reference for recovery studies.
  • Known concentrations of spiked urine samples (gravimetrically determined nominal values) for recovery, precision, limit of detection, specificity, and interference studies. This involves preparing samples with precisely known amounts of the analyte or interfering substances.
  • Drug-free urine pools for negative controls and spiking experiments.

8. Sample Size for the Training Set

• The document describes performance evaluation studies for a device, not a machine learning algorithm that requires a "training set." Therefore, there is no mention of a training set or its sample size in the context of this device's regulatory submission.

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

• As this is not a machine learning-based device, there is no training set and thus no ground truth established for a training set. The studies focus on demonstrating the analytical performance of the immunoassay against recognized analytical standards and spiked samples with known concentrations.

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