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The ARK Fentanyl II Assay is an immunoassay intended for the qualitative detection of fentanyl in human urine at a cutoff concentration of 1.0 ng/mL. The assay is intended for use in laboratories with automated clinical chemistry analyzers. This in vitro diagnostic device is for prescription use only.

The ARK Fentanyl II Assay provides only a preliminary analytical result. A more specific alternative chemical method must be used in order to obtain a confirmed positive analytical result. Gas Chromatography/Mass Spectrometry (GC/MS) or Liquid Chromatography/tandem Mass Spectrometry (LC-MS/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug test result, particularly when the preliminary test result is positive.

The ARK Fentanyl II Assay is a homogeneous enzyme immunoassay technique used for the analysis of a specific compound in human urine. The assay is based on competition between drug in the specimen and drug labeled with recombinant glucose-6-phosphate dehydrogenase (rG6PDH) for antibody binding sites. As the latter binds antibody, enzyme activity decreases. In the presence of drug from the specimen, enzyme activity increases and is directly related to the drug concentration. Active enzyme converts nicotinamide adenine dinucleotide (NAD) to NADH in the presence of glucose-6-phosphate (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 enzyme used in the assay.

The ARK Fentanyl II Assay consists of reagents R1 anti-fentanyl monoclonal antibodies with substrate and R2 fentanyl derivative labeled with bacterial recombinant G6PDH enzyme.

1. Acceptance Criteria and Reported Device Performance for ARKTM Fentanyl II Assay

The provided text details the performance characteristics of the ARKTM Fentanyl II Assay, which is an immunoassay for the qualitative detection of fentanyl in human urine at a cutoff concentration of 1.0 ng/mL. The study evaluates precision, analytical specificity (cross-reactivity with structurally similar compounds and lack of interference from structurally unrelated compounds and endogenous substances), and method comparison with LC-MS/MS.

Here's a table summarizing the acceptance criteria (implied by the data presentation for each test) and the reported device performance:

Study Details:

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

   • Precision Study: N=160 for each of 9 concentration levels (total 1440 measurements). The samples were drug-free human urine supplemented with fentanyl. Data provenance is not explicitly stated as country of origin, but described as "drug-free, negative human urine", implying laboratory-prepared samples.
   • Analytical Specificity (Cross-reactivity/Interference): Samples were drug-free, negative human urine spiked with various compounds and fentanyl. Specific sample sizes for each compound tested are not provided, but generally involve multiple replicates for dose-response evaluation or testing with fentanyl-spiked urine.
   • Method Comparison: A total of 147 unaltered clinical urine specimens were used. The data provenance is not explicitly mentioned as country of origin, but it is stated these were "unaltered clinical urine specimens that are not individually identifiable." This suggests a retrospective collection of clinical samples.

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

   • The ground truth for the method comparison study was established by LC-MS/MS (Liquid Chromatography/tandem Mass Spectrometry), which is described as the "preferred confirmatory method" and was performed by a "licensed reference laboratory." This is an objective, analytical method, not reliant on human expert interpretation for the quantitative values. Therefore, individual human "experts" in the traditional sense (e.g., radiologists) were not used to establish the ground truth in this context. The expertise lies in the certified analytical process and the laboratory standards.

3. Adjudication method for the test set:

   • No adjudication method (e.g., 2+1, 3+1) was applicable or mentioned, as the ground truth was established by quantitative analytical methods (LC-MS/MS), not by human expert review requiring consensus.

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:

   • This is an in vitro diagnostic immunoassay and not an AI-powered image analysis or medical device that involves human readers/interpreters in its primary function. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance was not conducted and is irrelevant to this device type. The device provides a direct analytical result.

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

   • Yes, the performance presented is a standalone performance of the immunoassay system. It measures the algorithm's (immunoassay's) ability to detect fentanyl in urine samples independently of human intervention for result interpretation. The results are generated by an "automated clinical chemistry analyzer."

6. The type of ground truth used:

   • For the method comparison study, the ground truth was quantitative analytical data from LC-MS/MS (Liquid Chromatography/tandem Mass Spectrometry). This is a highly specific and sensitive confirmatory laboratory method.

7. The sample size for the training set:

   • This document describes a premarket notification (510(k)) for an in vitro diagnostic device (immunoassay). For such devices, internal development and optimization (which can be considered analogous to "training") occur during the assay design and reagent formulation phases. However, the FDA 510(k) submission typically focuses on the validation (test set) of the finalized device rather than detailed disclosure of the "training set" in the context of machine learning. The document does not specify a sample size for a training set in the way it would for a machine learning algorithm. The "training" here would involve iterative testing and refinement of antibody characteristics, enzyme conjugates, and reagent formulations using proprietary in-house samples until the desired performance (specificity, sensitivity, dynamic range) is achieved.

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

   • As mentioned above, the concept of a "training set" with established ground truth in the machine learning sense is not directly applicable to this traditional immunoassay. The development process would involve:
     • Synthesizing or acquiring known concentrations of fentanyl and its metabolites.
     • Evaluating various antibody candidates and enzyme conjugates against these known concentrations.
     • Spiking drug-free human urine to create samples with precisely known concentrations of analytes.
     • Using highly accurate analytical methods (like GC/MS or LC-MS/MS) internally to confirm the concentrations of prepared samples or to guide dose-response adjustments during reagent formulation.
   • Ultimately, the ground truth for any "training" or optimization would be based on known chemical concentrations of the target analyte and potential interferents, confirmed by reference analytical methods.

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