(241 days)
The CEDIA™ Benzodiazepine Assay is a homogeneous enzyme immunoassay intended for the qualitative and/or semi-quantitative determination of benzodiazepines in human urine at a cutoff concentration of 200 ng/mL.
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 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.
Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.
CEDIA™ technology uses recombinant DNA technology to produce a unique homogeneous enzyme immunoassay system. The assay is based on the bacterial enzyme ß-galactosidase, which has been genetically engineered into two inactive fragments, Enzyme acceptor (EA) and Enzyme Donor (ED). These fragments spontaneously re-associate to form fully active enzyme that, in the assay format, cleaves a substrate. This generates a color change that can be measured spectrophotometrically.
The assay consists of buffers (1 and 2) and lyophilized reagents (1a and 2a). The components include sheep polyclonal anti-benzodiazepine antibody, recombinant microbial "enzyme donor'' - benzodiazepine conjugate, "enzyme acceptor", chlorophenol red ß-Dgalactopyranoside, stabilizers and preservatives. Add ß-glucuronidase enzyme to the reconstituted EA solution before using the assay. All specimens must be tested with ßglucuronidase enzyme. This enzyme will hydrolyze the glucuronidated metabolites of benzodiazepines in the samples, thereby enabling the detection of benzodiazepine glucuronides.
The provided text describes the analytical performance of the CEDIA™ Benzodiazepine Assay, an in vitro diagnostic device, and does not contain information related to an AI/ML-based device. Therefore, a direct response to the request for acceptance criteria and study details for an AI/ML device is not possible based on the provided text.
However, I can extract and present the acceptance criteria and the reported device performance for this in vitro diagnostic device based on the provided document.
Acceptance Criteria and Study for CEDIA™ Benzodiazepine Assay (In Vitro Diagnostic Device)
The CEDIA™ Benzodiazepine Assay is an in vitro diagnostic device for the qualitative and/or semi-quantitative determination of benzodiazepines in human urine. The document details its analytical performance studies to establish substantial equivalence to a predicate device, not an AI/ML-based system.
Here's a summary of the acceptance criteria (implied by the reported precision and accuracy goals) and the reported device performance from the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for precision, accuracy, or other analytical performance metrics. Instead, it presents results intended to demonstrate that the device performs adequately and is substantially equivalent to a predicate device. For the purpose of this response, I will interpret the reported performance as meeting the implicit acceptance criteria for an in vitro diagnostic assay of this type.
Cut-off Concentration: 200 ng/mL
| Performance Metric | Implied Acceptance Criteria (Based on expected IVD performance) | Reported Device Performance |
|---|---|---|
| Precision | Qualitative Mode: Samples significantly below cutoff should be consistently negative. Samples significantly above cutoff should be consistently positive. Samples around cutoff show expected distribution. | Spiked Concentration 150 ng/mL (-25% of Cutoff): 80/80 Negative |
| Spiked Concentration 200 ng/mL (Cutoff): 6/74 Negative/Positive (i.e., 6 negative, 74 positive) | ||
| Spiked Concentration 250 ng/mL (+25% of Cutoff): 0/80 Negative/Positive (i.e., 0 negative, 80 positive) | ||
| Semi-Quantitative Mode: Similar to qualitative, with additional expectation of quantitative consistency. | Spiked Concentration 150 ng/mL (-25% of Cutoff): 79/1 Negative/Positive (i.e., 79 negative, 1 positive) | |
| Spiked Concentration 200 ng/mL (Cutoff): 1/79 Negative/Positive (i.e., 1 negative, 79 positive) | ||
| Spiked Concentration 250 ng/mL (+25% of Cutoff): 0/80 Negative/Positive (i.e., 0 negative, 80 positive) | ||
| Spike Recovery (Qualitative) | Samples spiked below cutoff should be negative; samples spiked above cutoff should be positive. | 150 ng/mL (below C/O): All 20 replicates Negative |
| 250 ng/mL (above C/O): All 20 replicates Positive | ||
| Analytical Recovery and Linearity | Average recovery should be close to 100% within the assay range (e.g., 90-110%). | Range of Recovery: 95.2 – 107.8% (for expected concentrations from 100 ng/mL to 800 ng/mL) |
| Method Comparison and Accuracy (vs. LC-MS/MS) | High concordance (agreement) with the reference method (LC-MS/MS), particularly for samples clearly positive or negative. | Overall Concordance: |
| 97% in Qualitative mode (for 200 ng/mL cutoff) | ||
| 96% in Semi-Quantitative mode (for 200 ng/mL cutoff) |
Qualitative Mode:
Agreement among Positives: 100% (68/68)
Agreement among Negatives: 93% (56/60)
Semi-Quantitative Mode:
Agreement among Positives: 99% (67/68)
Agreement among Negatives: 93% (56/60) |
| Specificity (Cross-reactivity) | Minimal to no interference from structurally unrelated compounds. Relevant benzodiazepines and metabolites should show expected reactivity. | Structurally unrelated compounds (e.g., Acetaminophen, Amphetamine, Caffeine, Codeine etc. at high concentrations up to 100,000 ng/mL) showed no significant cross-reactivity, maintaining expected results for spiked low/high controls. Data provided for 30+ benzodiazepines and metabolites, showing varying cross-reactivity percentages. |
| Interference (pH, Endogenous/Exogenous Substances) | No interference from common physiological substances or varying pH levels. | Various compounds (e.g., Acetone, Ascorbic Acid, Glucose, Hemoglobin, Human Serum Albumin, Urea) and pH levels (3-11) showed no interference, maintaining expected results for spiked low/high controls. |
| Specific Gravity Interference | No interference from varying specific gravity of urine samples. | Urine samples with specific gravity from 1.002 to 1.029 showed no interference, maintaining expected results for spiked low/high controls. |
2. Sample sizes used for the test set and the data provenance
-
Precision Study:
- Samples were tested in replicates of 2, twice per day for 20 days.
- Total n=80 for each spiked concentration level (0 to 400 ng/mL).
- Data Provenance: Not explicitly stated, but the study was performed at the manufacturer's site. "Drug free urine" was used for spiking. It is implied to be laboratory-controlled samples, not patient data from a specific country or retrospective/prospective collection.
-
Spike Recovery Study:
- 20 replicates for each concentration (150 ng/mL and 250 ng/mL).
- Data Provenance: "Drug free urine" was used for spiking. Implied laboratory-controlled samples.
-
Method Comparison and Accuracy Study:
- Sample Size: One hundred and twenty-eight (128) samples.
- Data Provenance: Not explicitly stated. The samples were "treated with ß-glucuronidase reagent prior to analysis". This suggests potentially patient-derived urine samples, but their origin (country, retrospective/prospective collection) is not mentioned.
-
Specificity (Cross-reactivity) & Interference Studies:
- Samples made by adding known amounts of compounds to "drug-free negative urine" or "Oxazepam spiked" urine.
- Data Provenance: Laboratory-controlled samples.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
Not applicable for this type of in vitro diagnostic device study. The "ground truth" (or reference method) for the method comparison study was established by Liquid Chromatography/tandem mass spectrometry (LC-MS/MS), which is a highly accurate chemical analytical method. It does not involve human expert interpretation in the way AI/ML systems for medical imaging, for example, would.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. Ground truth was established by LC-MS/MS, an objective chemical analytical method, not by human expert consensus 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 in vitro diagnostic assay, not an AI/ML-based device that would assist human readers/operators in interpretation. Its performance is measured directly against a reference analytical method.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, in the context of an IVD, the CEDIA™ Benzodiazepine Assay's performance is inherently standalone in the sense that the assay's output (positive/negative/concentration) is directly measured and compared against the LC-MS/MS reference method. There is no human interpretative step within the 'device' itself, nor is its primary purpose to augment human interpretation.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for the method comparison study was Liquid Chromatography/tandem mass spectrometry (LC-MS/MS) results, which is a gold standard chemical analytical method for drug concentration determination.
8. The sample size for the training set
Not applicable. This document describes an in vitro diagnostic assay, which is a chemical and biological reagent-based system, not an AI/ML algorithm that requires a "training set" in the computational sense. Its formulation and calibration are based on chemical principles and standard laboratory practices.
9. How the ground truth for the training set was established
Not applicable, as there is no "training set" for this type of device. The assay is developed and optimized as a chemical system.
§ 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).