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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

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.

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.

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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The DRI® Hydrocodone Assay is intended for the qualitative and semi-quantitative detection and estimation of Hydrocodone and its metabolites in human urine at a cutoff of 300 ng/mL. The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of specimen for confirmatory method such as LC-MS/MS or GC-MS and permitting laboratories to establish quality control measures.

This assay provides a preliminary analytical test result. A more specific alternative chemical method must be used in order to confirm an analytical result. Gas chromatography/mass spectrometry (GC/MS) and Liquid Chromatography/ tandem mass spectrometry (LC-MS/MS) are the preferred confirmatory methods. Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary positive results are used.

The DRI® Hydrocodone Assay Calibrators are intended for the DRI® Hydrocodone Assay. For In Vitro Diagnostic Use Only.

The DRI® Hydrocodone Controls are unassayed quality control material intended for use in the DRI Hydrocodone Assay to detect and monitor systematic deviations from accuracy resulting from reagent or instrument defects. For In Vitro Diagnostics Use Only

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 its metabolites without any significant cross-reactivity to other opiate compounds. 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. In the presence of free drug, the free drug occupies the antibody binding sites, allowing the drug bound G6PDH to interact with the substrate, resulting 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 DRI® Hydrocodone Assay is a kit comprised of two reagents, Reagent A and Reagent E, which are bottled separately but sold together within the same kit.

The Reagent A solution contains: mouse monoclonal anti-hydrocodone antibody, glucose-6phosphate (G6P) and nicotinamide adenine dinucleotide (NAD) in Tris buffer with Sodium Azide (≤0.09%) as a preservative). The Reagent E solution contains: glucose-6-phosphate dehydrogenase (G6PDH) in Tris buffer with Sodium Azide (≤0.09%) as preservative.

The DRI® Hydrocodone Enzyme Immunoassay calibrators designated for use at the 300 ng/mL cutoff contain 0 (negative), 100, 300, 500, and 1,000 ng/mL of hydrocodone in human urine matrix with sodium azide (≤0.09%) as preservative. The controls are provided at a concentration of 225 and 375 ng/mL. The calibrators are sold separately and the two controls are sold as a kit.

Here's a breakdown of the acceptance criteria and study information for the DRI® Hydrocodone Assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Precision Studies: 80 replicates (tested twice per day for 20 days, n=80) for each spiked concentration level (0, 75, 150, 225, 300, 375, 450, 525, 600 ng/mL).
• Accuracy Study (Patient Samples): 100 patient samples.
• Linearity Study: 5 replicates for each spiked concentration level (12 levels including 0).
• Specificity & Cross-Reactivity: Not explicitly stated but implied to be multiple tests for each substance and concentration.
• Interference (pH, Endogenous Substances, Specific Gravity): Not explicitly stated, but "controls were detected accurately" implies sufficient testing for each condition.

Data Provenance: The document does not explicitly state the country of origin for the data or whether the studies were retrospective or prospective. Given it's a 510(k) submission to the FDA, it can be inferred the data was generated under conditions suitable for regulatory review, likely from laboratory settings. The "patient samples" for the accuracy study would be clinical specimens.

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

• For the Accuracy study, the ground truth for the 100 patient samples was established using LC-MS/MS (Liquid Chromatography/tandem mass spectrometry), which is specified as the "preferred confirmatory method" and is an analytical chemical method, not based on expert consensus. Therefore, no human experts were used to establish the ground truth in this context. LC-MS/MS itself is considered a highly sensitive and specific gold standard for drug confirmation.
• For the Precision study, ground truth was based on the known spiked concentrations using LC-MS/MS for confirmation.
• For the Linearity study, ground truth was based on the known spiked concentrations confirmed with LC-MS/MS data.
• For Specificity, Cross-Reactivity, and Interference studies, ground truth was based on known concentrations of spiked substances.

4. Adjudication Method for the Test Set

Not applicable. The ground truth for the accuracy study was established by LC-MS/MS, an objective analytical method. There was no need for human expert adjudication of results against another human interpretation.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay for detecting substances in urine, not an imaging or diagnostic AI tool that assists human readers.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, the studies presented are all standalone performance evaluations of the assay system (device and analyzer) without human-in-the-loop performance influencing the primary analytical result. The assay directly reports qualitative (positive/negative) or semi-quantitative results. Clinical interpretation and professional judgment are advised after the preliminary analytical test result.

7. The Type of Ground Truth Used

The primary ground truth used for performance evaluation (e.g., accuracy, precision, linearity) was the objective analytical measurement by LC-MS/MS (Liquid Chromatography/tandem mass spectrometry), which is considered a gold standard confirmatory method (sometimes referred to as a "Reference Method"). For spiked samples, the ground truth was the known spiked concentration confirmed by LC-MS/MS.

8. The Sample Size for the Training Set

This document does not specify a separate "training set" or its size. In the context of an immunoassay, the concept of a training set as used in machine learning (where algorithms learn from data) is typically not applicable in the same way. The development of an immunoassay involves optimizing reagent formulations, antibody specificity, and assay conditions rather than training a predictive algorithm on a dataset.

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

Since a "training set" in the machine learning sense is not explicitly mentioned or applicable for this type of immunoassay development, the method for establishing its ground truth is not described. The manufacturer would have performed extensive R&D and optimization during method development to achieve the desired performance characteristics which were then validated in the studies described.

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