(269 days)
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.
| Performance Characteristic | Acceptance Criteria (Inferred from Study Design & Results) | Reported Device Performance |
|---|---|---|
| Precision/Cutoff Characterization | All samples at -100%, -75%, -50%, +25%, +50%, +75%, +100% of cutoff should yield 100% agreement (Negative or Positive). At cutoff, approx. 50% Negative/50% Positive. | Lot #1: |
| -100% to -25%: 80/80 Negative | ||
| Cutoff (280 ng/mL): 40 Negative/40 Positive | ||
| +25% to +100%: 80/80 Positive | ||
| Lot #2: | ||
| -100% to -25%: 80/80 Negative | ||
| Cutoff (280 ng/mL): 38 Negative/42 Positive | ||
| +25% to +100%: 80/80 Positive | ||
| Lot #3: | ||
| -100% to -25%: 80/80 Negative | ||
| Cutoff (280 ng/mL): 39 Negative/41 Positive | ||
| +25% to +100%: 80/80 Positive | ||
| Specificity and Cross-Reactivity | Compounds not structurally similar to meprobamate should show = 280 ng/mL):** 107 samples | |
| Agreement Immunalysis HEIA Positive vs. LC-MS/MS Positive: 100% (107/107) | ||
| Agreement Immunalysis HEIA Negative vs. LC-MS/MS Negative: 92% (55/60) | ||
| False Positives: 5 samples (all contained carisoprodol and were considered clinically acceptable/not a concern). |
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).
§ 862.3590 Meprobamate test system.
(a)
Identification. A meprobamate test system is a device intended to measure meprobamate in human specimens. Measurements obtained by this device are used to detect the presence of meprobamate to diagnose the use or overdose of meprobamate or structurally-related drug compounds (e.g., prodrugs).(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include:
(i) Robust data demonstrating the accuracy of the device when used in the intended specimen matrix. The accuracy data must include a comparison between the meprobamate test system results and meprobamate results that are measured on an FDA-accepted measurement method that is specific and accurate (e.g., gas or liquid chromatography combined with tandem mass spectrometry).
(ii) Robust analytical data demonstrating the performance characteristics of the device, including, but not limited to, specificity, cross-reactivity to relevant endogenous and exogenous substances, and the reproducibility of analyte detection around the cutoff(s).
(2) The intended use of the device must not include an indication for use in monitoring therapeutic drug concentrations or informing dosing adjustment decisions.
(3) Your 21 CFR 809.10 labeling must include the following:
(i) If indicated for use as a screening test to identify preliminary results for further confirmation, the intended use must state “This 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.”
(ii) A limiting statement that reads as follows: “This test should not be used to monitor therapeutic drug concentrations or to inform dosing adjustment decisions.”