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The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA is a homogeneous enzyme immunoassay for the qualitative analysis of carisoprodol metabolite, Meprobamate, at a cutoff of 280 ng/mL in human urine. The assay is intended for use in laboratories with automated clinical chemistry analyzers. This in vitro diagnostic device is for prescription use only.

The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA provides only a preliminary analytical test result. A more specific alternate chemical must be used in order 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. Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary positive results are used.

The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA is a sensitive in vitro diagnostic test intended for use in laboratories for the qualitative analysis of Meprobamate at a cutoff of 280 ng/mL in human urine with automated clinical chemistry analyzers.

Carisoprodol (N-isopropylmeprobamate, Soma, ingredient of Soma Compound, Somadril®) is a carbamate derivative first synthesized in 1959 and used clinically as a muscle relaxant and sedative. Carisoprodol is known to be metabolized to meprobamate and hydroxyl-meprobamate.

The assay is based on the competition of carisoprodol labeled enzyme glucose-6-phosphate dehydrogenase (G6PDH) and the free Meprobamate in the urine sample for the fixed amount of sheep anti-carisoprodol antibody binding sites. In the absence of the free Meprobamate in the sample, the antibody binds the drug enzyme conjugate and enzyme activity is inhibited. This creates a dose response relationship between drug concentration in the urine and enzyme activity. The enzyme G6PDH activity is determined at 340 nm spectrophotometrically by the conversion of nicotinamide adenine dinucleotide (NAD) to NADH.

The provided document describes the Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA, an in vitro diagnostic device for the qualitative analysis of carisoprodol metabolite, Meprobamate, in human urine. The acceptance criteria and the study proving the device meets these criteria are detailed in the "Performance Characteristics" section (G).

Here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

Based on the studies described, the acceptance criteria can be inferred from the reported performance. The document doesn't explicitly state "acceptance criteria" values in a separate table, but rather presents the study results which are implicitly considered acceptable for substantial equivalence.

2. Sample size used for the test set and the data provenance

• Precision/Cutoff Characterization: For each of the three product lots, 80 determinations were made at each concentration level across 10 days (2 runs/day, 4 replicates). Total for this study: 3 lots x 9 concentrations x 80 determinations/concentration = 2160 determinations (or 3 lots x 80 samples at each of 9 levels = 2160 total samples, if each replicate is considered a sample). The data provenance is not specified, but it involved "drug free urine" spiked with meprobamate. This suggests laboratory-prepared samples.
• Specificity and Cross-Reactivity: The sample size for each compound tested is not explicitly stated, but compounds were "spiked into drug free urine."
• Interference (Structurally Unrelated / Endogenous & Preservatives / pH / Specific Gravity): The sample size for each compound/condition is not explicitly stated, but compounds were "spiked into drug-free negative urine" containing meprobamate at specific concentrations.
• Urine Elimination Study: 10 subjects were used. The samples were "self-reported single dose users" and collected their own urine. Data provenance is not explicitly stated in terms of country, but implies prospective collection for the study.
• Method Comparison: 167 de-identified, unaltered leftover clinical urine samples. Data provenance is "obtained from clinical testing laboratories," indicating retrospective use of existing clinical samples. Country of origin is not specified.

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

For the quantitative results in the precision and method comparison studies, the ground truth was established by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), a highly accurate analytical chemistry method. This is a laboratory instrumental method, not dependent on human experts for qualitative interpretation in the way imaging studies might be. While trained laboratory personnel operate and validate LC-MS/MS, the "ground truth" itself is based on the chemical analysis, not expert consensus reading of a visual output.

For the qualitative interpretation of the Immunalysis assay results (Positive/Negative call at cutoff), this is determined automatically by the instrument based on the measured signal relative to the cutoff value, not by human experts adjudicating results.

Therefore, for this type of in vitro diagnostic device, the concept of "experts establishing ground truth for a test set" with qualifications like "radiologist with 10 years of experience" is not directly applicable.

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

Not applicable. This is an analytical immunoassay where the result (positive/negative) is determined by the instrument against an established cutoff, or by a confirmatory lab method (LC-MS/MS). There is no human interpretative step requiring adjudication.

5. 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

Not applicable. This is an IVD immunoassay, not an AI-assisted diagnostic imaging device that involves human reader interpretation.

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

Yes, the device's performance characteristics (precision, specificity, interference, calibration, stability) and the method comparison were evaluated for the "Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA" as a standalone analytical test. The device itself is an automated immunoassay intended for use with automated clinical chemistry analyzers. As an IVD, its function is essentially "algorithm only" in the sense that it relies on chemical reactions and optical readings, with the interpretation (positive/negative) being determined by the instrument based on programmed parameters (e.g., cutoff).

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

The ground truth for the quantitative concentration of meprobamate/carisoprodol in urine samples was established using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), which is considered the gold standard confirmatory method for drug testing. This falls under the category of a highly accurate, analytical laboratory test.

8. The sample size for the training set

The document does not describe a separate "training set" for the device development. This is typical for an immunoassay where the assay's chemical formulation, antibody properties, and cutoff are developed based on laboratory analytical studies and calibration, rather than on a large dataset of patient samples in the way a machine learning algorithm is trained. The studies described are performance validation studies.

9. How the ground truth for the training set was established

As there's no explicitly described "training set" in the context of an algorithm or machine learning, the concept of establishing ground truth for such a set is not applicable here. The ground truth for the analytical and validation studies was established through precisely prepared spiked samples (for precision, specificity, interference) and confirmatory LC-MS/MS analysis for clinical samples (method comparison, urine elimination study).

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The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is intended for the qualitative and semi-quantitative determination of carisoprodol metabolite (meprobamate) in human urine at a cutoff value of 100 ng/mL when calibrated against meprobamate. The assay is designed for prescription use with a number of automated clinical chemistry analyzers.

The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for verification by a confirmatory method such as GC/MS, LC/MS or permitting laboratories to establish quality control procedures.

The assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive.

The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is a homogeneous enzyme immunoassay with ready-to-use liquid reagents. The assay is a kit comprised of two reagents (antibody/substrate reagent R1 and enzyme-drug conjugate reagent R2), which are bottled separately but sold together within the kit. The Ri solution contains mouse monoclonal anti-meprobamate antibody, glucose-6- phosphate (G6P), nicotinamide adenine dinucleotide (NAD), stabilizers, and sodium azide (0.09 %) as a preservative. The R2 solution contains meprobamate-labeled glucose-6-phosphate dehydrogenase (G6PDH) in buffer with sodium azide (0.09 %) as a preservative.

Here's a breakdown of the acceptance criteria and the study details for the LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay, based on the provided document:

Acceptance Criteria and Reported Device Performance

Study Details

2. Sample size used for the test set and the data provenance

• Sample Size for Test Set:

  • Precision Study: 88 determinations per concentration level for
    each of 8 concentrations (a total of 704 determinations for qualitative and 704 for semi-quantitative).
  • Method Comparison Study: 127 clinical urine samples.
  • Linearity Study: Each sample run in 10 replicates across 11 concentrations.
  • Analytical Specificity (Endogenous, Preservatives, pH, Specific Gravity, Unrelated Compounds): Samples tested in duplicate.
  • Cross-reactivity (Structurally Related Compounds): Not explicitly stated, but typically involves multiple runs.

• Data Provenance: Retrospective clinical urine samples "from subjects that were (b) (4) taking prescribed or nonprescribed Carisoprodol." The origin country is not explicitly stated, but given this is an FDA submission, it's likely primarily US-based or from regions with comparable medical practices.

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

• The ground truth for the test set was established by Gas Chromatography/Mass Spectrometry (GC/MS) or Liquid Chromatography/Mass Spectrometry (LC/MS). These are established analytical methods for drug confirmation. There is no mention of "experts" in the sense of medical professionals (e.g., radiologists) establishing ground truth, as this is an in vitro diagnostic device. The "experts" in this context would be the technicians/scientists operating and interpreting the GC/MS/LC/MS results, who are implied to be qualified in their field based on the use of these validated methods.

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

• There was no human adjudication process described. The reference method (GC/MS or LC/MS) provided the definitive "ground truth" for each sample.

5. 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, this was not a multi-reader multi-case (MRMC) comparative effectiveness study. This device is an automated enzyme immunoassay for chemical analysis, not an imaging-based AI system that would typically involve human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here.

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

• Yes, this was a standalone (algorithm only) performance study. The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is an automated system designed to provide a preliminary analytical result without human interpretation of the assay itself. Human involvement comes in confirming positive results with alternative chemical methods and clinical judgment, as stated in the intended use.

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

• The ground truth used was confirmatory analytical methods, specifically Gas Chromatography/Mass Spectrometry (GC/MS) or Liquid Chromatography/Mass Spectrometry (LC/MS). These methods are considered the gold standard for drug quantification and identification in urine.

8. The sample size for the training set

• The document does not explicitly describe a separate "training set" for the device. As an enzyme immunoassay, the "training" (calibration) involves using known calibrator concentrations (0, 50, 100, 200, and 400 ng/mL meprobamate, as mentioned in the linearity section) to establish the standard curve against which unknown samples are measured. There isn't an "algorithm" in the conventional AI sense that undergoes training with a large dataset. The performance characteristics described are related to the analytical validation of the assay itself.

9. How the ground truth for the training set was established

• As there isn't a traditional "training set" in the AI sense, the concept of ground truth for it doesn't directly apply. The "ground truth" for the calibrators used in the assay system would be their known, precisely manufactured concentrations of meprobamate, traceable to a commercially available meprobamate source material with 99% analytical purity (as mentioned in section L.1.c).

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