(189 days)
Benzodiazepines II (BNZ2) is an in vitro diagnostic test for the qualitative and semiquantitative detection of benzodiazepines in human urine on cobas c systems at cutoff concentrations of 100 ng/mL, and 300 ng/mL. Semiquantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program.
Semiquantitative assays are intended to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas chromatography/mass spectrometry (GC-MS), or Liquid Chromatography coupled with Tandem Mass Spectrometry (LC-MS/MS).
Benzodiazepines II provides only a preliminary analytical test result. A more specific alternical method must be used in order to obtain a confirmed analytical result. Gas chromatography/mass spectrometry (GC-MS) or Liquid Chromatography coupled with 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 Benzodiazepines II assay is an in vitro diagnostic test for the qualitative and semi-quantitative detection of benzodiazepines in human urine on automated clinical chemistry analyzers at cutoff concentrations of 100 ng/mL and 300 ng/mL. The semi quantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program.
The device consists of two wet reagents which contain the key components of the immunoassay: monoclonal/ polyclonal antibody against the drug, substrate, and enzyme-labeled drug (conjugate).
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:
Acceptance Criteria and Device Performance for ONLINE DAT Benzodiazepines II
1. Table of Acceptance Criteria and Reported Device Performance
The direct "acceptance criteria" for performance are not explicitly listed in a single table, but rather demonstrated through various performance studies. The table below summarizes the key performance aspects tested and the results obtained for the ONLINE DAT Benzodiazepines II.
Device Name: ONLINE DAT Benzodiazepines II
Intended Use: Qualitative and semiquantitative detection of benzodiazepines in human urine on cobas c systems at cutoff concentrations of 100 ng/mL, 200 ng/mL, and 300 ng/mL.
| Performance Characteristic | Acceptance Criteria (Implied/Demonstrated) | Reported Device Performance (ONLINE DAT Benzodiazepines II) |
|---|---|---|
| Precision (Repeatability & Intermediate) | Low CV% for semiquantitative results; >95% agreement for qualitative results around specified cutoffs. | 100 ng/mL Cutoff (SQ): Repeatability CV: 1.8-5.7%; Intermediate Precision CV: 2.0-6.2%. 100 ng/mL Cutoff (Qualitative): >95% negative reading for -50%, -25% samples; >95% positive reading for +25%, +50% samples. 200 ng/mL Cutoff (SQ): Repeatability CV: 0.8-2.5%; Intermediate Precision CV: 1.5-3.1%. 200 ng/mL Cutoff (Qualitative): >95% negative reading for -50%, -25% samples; >95% positive reading for +25%, +50% samples. 300 ng/mL Cutoff (SQ): Repeatability CV: 1.2-2.9%; Intermediate Precision CV: 1.6-3.5%. 300 ng/mL Cutoff (Qualitative): >95% negative reading for -50%, -25% samples; >95% positive reading for +25%, +50% samples. |
| Analytical Recovery and Linearity | Acceptable percent recovery across the assay range, demonstrating linearity. | 100 ng/mL Cutoff: Recovery generally within 94-116% across various concentrations (0-1000 ng/mL). 200 ng/mL Cutoff: Recovery generally within 95-119% across various concentrations (0-1000 ng/mL). 300 ng/mL Cutoff: Recovery generally within 92-117% across various concentrations (0-3000 ng/mL). |
| Analytical Specificity/Cross-Reactivity | Appropriate cross-reactivity with common benzodiazepines and metabolites, and minimal cross-reactivity with structurally unrelated compounds. | Cross-reactivity with Benzodiazepines and Metabolites: Varies (e.g., Nordiazepam: 98-101%, Alprazolam: 109-115%, Oxazepam: 104-113%, Lorazepam Glucuronide: 56-58%, 7-Acetamidonitrazepam: 0.3-0.5%). No Interference (Structurally Unrelated Compounds): None of the tested compounds (e.g., Acetone, Ascorbic Acid, Creatinine, Ethanol, Glucose, Hemoglobin, Ibuprofen, Morphine, Nicotine, etc.) at high concentrations caused positive or negative interference. |
| Endogenous Interferences | No interference from common endogenous compounds at specified concentrations. | None of the listed endogenous compounds (e.g., Acetone, Ascorbic Acid, Calcium, Creatinine, Ethanol, Glucose, Hemoglobin, Human Albumin, Urea, Uric Acid) caused interference at the tested concentrations. |
| Interference Drugs | No interference from common drugs at specified concentrations, with noted exceptions. | Most tested drugs (e.g., Acetaminophen, Aspirin, Amitryptyline, Caffeine, Codeine, Ibuprofen, Morphine, Nicotine) caused no interference at very high concentrations. Exception: Oxaprozin may yield falsely elevated results when present with benzodiazepine at negative control levels due to cross-reactivity (13% at 100 ng/mL cutoff, 6% at 200 ng/mL cutoff, 10% at 300 ng/mL cutoff). |
| Specific Gravity and pH Interference | Proper recovery of results across specified pH and specific gravity ranges. | Urine samples with pH 4.0-9.0 and specific gravities 1.001-1.034 resulted in proper recovery in both semi-quantitative and qualitative modes. |
| Method Comparison to Predicate (Clinical Correlation) | High agreement with LC-MS/MS, especially for negative and confirmed positive samples; acceptable performance near cutoff. | 100 ng/mL Cutoff: 100% negative agreement with normal urines. 100% positive agreement with confirmed positive samples. Overall good agreement with LC-MS/MS with few discrepancies near cutoff. 200 ng/mL Cutoff: 100% negative agreement with normal urines. 100% positive agreement with confirmed positive samples. Overall good agreement with LC-MS/MS with few discrepancies near cutoff. 300 ng/mL Cutoff: 100% negative agreement with normal urines. 100% positive agreement with confirmed positive samples. Overall good agreement with LC-MS/MS with few discrepancies near cutoff. |
| Stability (On-board Stability) | Stable performance (agreement, mean, SD, CV) over 12 weeks of on-board use after transport stress. | 100/200/300 ng/mL Cutoffs (SQ & Qualitative): 100% agreement for negative and positive controls and clinical samples for 91 days (13 weeks) onboard after transport stress. Mean, SD, and CV values remained consistent and within acceptable ranges over the 91-day period. |
Study Details:
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Sample Size used for the test set and the data provenance:
- Precision Study: 84 determinants (n=84) for each cutoff concentration (100, 200, 300 ng/mL) in both qualitative and semi-quantitative modes. These samples were drug-free negative urine spiked with Oxazepam. Data provenance is internal to Roche Diagnostics, as samples were prepared for the study.
- Analytical Recovery and Linearity Study: 17 levels per cutoff, run in triplicate, for three reagent lots. Samples were "prepared" (implied internal spiking/dilution).
- Analytical Specificity/Cross-Reactivity Study: Concentration series prepared for each cross-reactant by spiking drug-free urine. Data provenance is internal.
- Endogenous Interferences: Two sets of samples per interferent, containing benzodiazepine and/or glucuronidated benzodiazepine. Data provenance is internal.
- Interference Drugs: Samples spiked with benzodiazepine in the presence of potentially interfering drugs. Data provenance is internal.
- Specific Gravity and pH Interference: Urine samples prepared with varying pH and specific gravities, spiked with benzodiazepine. Data provenance is internal.
- Method Comparison (Clinical Correlation) Study:
- 100 ng/mL Cutoff: 137 native human unaltered samples in total (48 screened negative, 54 screened preliminary positive/confirmed, 8 near cutoff negative by LC-MS/MS, 7 near cutoff positive by LC-MS/MS).
- 200 ng/mL Cutoff: 134 native human unaltered samples in total (56 screened negative, 57 screened preliminary positive/confirmed, 12 near cutoff negative by LC-MS/MS, 9 near cutoff positive by LC-MS/MS).
- 300 ng/mL Cutoff: 114 native human unaltered samples in total (40 screened negative, 45 screened preliminary positive/confirmed, 17 near cutoff negative by LC-MS/MS, 12 near cutoff positive by LC-MS/MS).
- Data Provenance: Samples were "purchased from clinical laboratories" and "obtained from a clinical laboratory," implying a retrospective collection of clinical urine samples from the United States or a jurisdiction with similar clinical laboratory practices.
- Stability Study: Two control samples per cutoff, the cutoff calibrator, and two clinical samples (pooled urine from individual donors). Data provenance is internal.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- No human experts were explicitly used to establish a ground truth in the sense of clinical interpretation for this in vitro diagnostic device study.
- The "ground truth" for the method comparison study was established by a confirmatory analytical method: Liquid Chromatography coupled with Tandem Mass Spectrometry (LC-MS/MS), which is considered the gold standard for drug confirmation. This is an objective analytical measurement, not an expert opinion.
- For the precision, linearity, and interference studies, the ground truth was based on precisely prepared spiked samples with known concentrations.
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Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- There was no adjudication method described for the test set in the conventional sense of expert review for image-based diagnostics.
- The method comparison data used LC-MS/MS as the reference method. Discrepant samples in the method comparison were cross-referenced against the LC-MS/MS values, which served as the definitive reference.
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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 MRMC comparative effectiveness study was performed or described. This device is an in vitro diagnostic (IVD) immunoassay for detecting substances in urine. It does not involve human readers interpreting images with or without AI assistance. Therefore, this question is not applicable.
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If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, the primary performance evaluation is a standalone (algorithm only) performance. The device itself is an automated chemical analyzer (cobas c systems) that performs the immunoassay and generates a result (qualitative or semi-quantitative concentration). There is no "human-in-the-loop" performance component for the direct operation or result generation of the device. The results are then used by clinical laboratories.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For the method comparison study, the primary ground truth was Liquid Chromatography coupled with Tandem Mass Spectrometry (LC-MS/MS), which is an objective chemical confirmatory method.
- For other analytical performance studies (precision, linearity, cross-reactivity, interferences, stability), the ground truth was based on known concentrations in spiked samples prepared in the laboratory.
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The sample size for the training set:
- The document describes performance evaluation studies (validation studies) for a cleared device. It does not explicitly mention a "training set" or its size, as such devices are typically developed and optimized by the manufacturer using internal data and then validated through these types of pre-market performance studies. The presented data represents the validation of the final product.
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How the ground truth for the training set was established:
- As no "training set" is explicitly mentioned in the context of device development or machine learning in this submission, the method for establishing its ground truth is not provided. For an IVD like this, ground truth during development would typically involve similarly prepared spiked samples with known concentrations and/or analysis by definitive reference methods like LC-MS/MS.
§ 862.3170 Benzodiazepine test system.
(a)
Identification. A benzodiazepine test system is a device intended to measure any of the benzodiazepine compounds, sedative and hypnotic drugs, in blood, plasma, and urine. The benzodiazepine compounds include chlordiazepoxide, diazepam, oxazepam, chlorzepate, flurazepam, and nitrazepam. Measurements obtained by this device are used in the diagnosis and treatment of benzodiazepine use or overdose and in monitoring levels of benzodiazepines to ensure appropriate therapy.(b)
Classification. Class II (special controls). A benzodiazepine test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).