(125 days)
The Lin-Zhi International (LZI) Buprenorphine Enzyme Immunoassay is intended for the qualitative and semi-quantitative determination of norbuprenorphine (buprenorphine metabolite) in human urine, at a cutoff value of 5 and 10 ng/mL. The assay is designed for professional use with a number of automated clinical chemistry analyzers.
The Norbuprenorphine Drugs of Abuse (DAU) Calibrators are for use as calibrators in the qualitative and semi-quantitative calibration of the Lin-Zhi International (LZI) Buprenorphine Enzyme Immunoassay.
The Norbuprenorphine Drugs of Abuse (DAU) Controls are for use as assayed quality control materials to monitor the precision of the Lin-Zhi International (LZI) Buorenorphine Enzyme Immunoassay.
The assay provides only a preliminary analytical result. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Chromatography/mass spectrometry (GC/MS or LC/MS) is the preferred confirmatory method). Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary test result is positive.
The LZI Buprenorphine assay is a homogeneous enzyme immunoassay with ready-to-use liquid reagent. The assay is based on competition between drug in the sample and drug labeled with the enzyme glucose-6-phosphate dehydrogenase (G6PDH) for a fixed amount of antibody in the reagent. Enzyme activity decreases upon binding to the antibody, and the drug concentration in the sample is measured in terms of enzyme activity. In the absence of drug in the sample, buprenorphine-labeled G6PDH conjugate is bound to antibody, and the enzyme activity is inhibited. On the other hand, when free drug is present in the sample, antibody would bind to free drug, the unbound buorenorphine-labeled G6PDH then exhibits its maximal enzyme activity. Active enzyme converts nicotinamide adenine dinucleotide (NAD) to NADH, resulting in an absorbance change that can be measured spectrophotometrically at 340 nm
Here's an analysis of the acceptance criteria and study as presented in the provided document:
Acceptance Criteria and Device Performance
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state formal "acceptance criteria" for the study. Instead, it presents performance characteristics (Precision, Semi-Quantitative/Qualitative Positive/Negative Results, Detection Limit, Linearity, and Method Comparison) which are presumably used to demonstrate substantial equivalence to the predicate device. For the purpose of this response, I will interpret the performance goals shown in the predicate device's characteristics (implicitly matching or improving upon them) and the presented "agreement" percentages with the GC/MS method as the de-facto acceptance criteria.
| Acceptance Criteria | Reported Device Performance (LZI Buprenorphine Enzyme Immunoassay) |
|---|---|
| Precision (Semi-Quantitative, ng/mL): | Achieved |
| Range of %CV for various concentrations (0.5 to 20 ng/mL) within run and total precision. (No explicit target values are given, but the device reports detailed %CV values). | Within Run %CV: 3.0 - 116.1% |
| Total Precision %CV: 3.7 - 121.4% | |
| (Note: The high %CV for "Negative" samples (0.5 ng/mL mean) is expected due to very low concentration near the detection limit.) | |
| Precision (Qualitative, mA/min): | Achieved |
| Range of %CV for various concentrations (0 to 20 ng/mL) within run and total precision. (No explicit target values are given, but the device reports detailed %CV values). | Within Run %CV: 0.6 - 0.8% |
| Total Precision %CV: 0.8 - 1.3% | |
| Semi-Quantitative Positive/Negative Results (5 ng/mL Cutoff): | Achieved |
| Ability to correctly classify samples at concentrations below, at, and above the cutoff with a certain number of determinations. (No explicit percentage agreement target, but implies high accuracy). | -100% (0 ng/mL): 88/88 Negative (100%) |
| -50% (2.5 ng/mL): 88/88 Negative (100%) | |
| 100% (5.0 ng/mL): 62/88 Positive, 26/88 Negative (70.5% Positive) - This indicates the cutoff itself is where ambiguity is expected. | |
| +50% (7.5 ng/mL): 88/88 Positive (100%) | |
| +100% (10.0 ng/mL): 88/88 Positive (100%) | |
| Semi-Quantitative Positive/Negative Results (10 ng/mL Cutoff): | Achieved |
| Ability to correctly classify samples at concentrations below, at, and above the cutoff with a certain number of determinations. | -100% (0 ng/mL): 88/88 Negative (100%) |
| -75% (2.5 ng/mL): 88/88 Negative (100%) | |
| -50% (5.0 ng/mL): 88/88 Negative (100%) | |
| -25% (7.5 ng/mL): 88/88 Negative (100%) | |
| 100% (10.0 ng/mL): 47/88 Positive, 41/88 Negative (53.4% Positive) - Again, ambiguity at the cutoff. | |
| +25% (12.5 ng/mL): 88/88 Positive (100%) | |
| +50% (15.0 ng/mL): 88/88 Positive (100%) | |
| +75% (17.5 ng/mL): 88/88 Positive (100%) | |
| +100% (20.0 ng/mL): 88/88 Positive (100%) | |
| Qualitative Positive/Negative Results (5 ng/mL Cutoff): | Achieved |
| Ability to correctly classify samples at concentrations below, at, and above the cutoff with a certain number of determinations for qualitative assessment. | -100% (0 ng/mL): 88/88 Negative (100%) |
| -50% (2.5 ng/mL): 88/88 Negative (100%) | |
| 100% (5.0 ng/mL): 43/88 Positive, 45/88 Negative (48.9% Positive) | |
| +50% (7.5 ng/mL): 88/88 Positive (100%) | |
| +100% (10.0 ng/mL): 88/88 Positive (100%) | |
| Qualitative Positive/Negative Results (10 ng/mL Cutoff): | Achieved |
| Ability to correctly classify samples at concentrations below, at, and above the cutoff with a certain number of determinations for qualitative assessment. | -100% (0 ng/mL): 88/88 Negative (100%) |
| -75% (2.5 ng/mL): 88/88 Negative (100%) | |
| -50% (5.0 ng/mL): 88/88 Negative (100%) | |
| -25% (7.5 ng/mL): 88/88 Negative (100%) | |
| 100% (10.0 ng/mL): 59/88 Positive, 29/88 Negative (67.0% Positive) | |
| +25% (12.5 ng/mL): 88/88 Positive (100%) | |
| +50% (15.0 ng/mL): 88/88 Positive (100%) | |
| +75% (17.5 ng/mL): 88/88 Positive (100%) | |
| +100% (20.0 ng/mL): 88/88 Positive (100%) | |
| Detection Limit: | Achieved |
| Differentiable from negative urine with 95% confidence. | 2 ng/mL |
| Linearity (Regression equation and correlation): | Achieved |
| Good correlation between device and target values over a range. | y=1.0026x + 0.9053, r²=0.991 (over 2-70 ng/mL) |
| Method Comparison (5 ng/mL Cutoff): | Achieved |
| High agreement with GC/MS for positive and negative samples. (Implied target is high agreement). | 96.4% agreement with positive samples |
| 100.0% agreement with negative samples | |
| Method Comparison (10 ng/mL Cutoff): | Achieved |
| High agreement with GC/MS for positive and negative samples. | 95.1% agreement with positive samples |
| 98.0% agreement with negative samples |
2. Sample Size and Data Provenance for the Test Set
- Sample Size for Precision Studies (Semi-Quantitative and Qualitative): N=88. These samples were tested across 4 runs (22 determinations per run to reach 88 total determinations) to assess "Total Precision" and "Within Run" precision. The description implies these are spiked samples (e.g., "0 ng/mL", "2.5 ng/mL", etc.).
- Sample Size for Method Comparison against GC/MS: 90 clinical unaltered samples.
- Data Provenance: Not explicitly stated (e.g., country of origin). The samples for the method comparison are described as "clinical unaltered samples," suggesting they were collected from patients, which would typically be retrospective or prospective clinical samples. The precision samples appear to be laboratory-prepared or spiked samples.
3. Number of Experts and Qualifications for Ground Truth
- Number of Experts: Not applicable. The ground truth for the method comparison study was established through a "more specific alternative chemical method," specifically Chromatography/mass spectrometry (GC/MS or LC/MS).
- Qualifications of Experts: Not applicable, as GC/MS is an analytical instrument-based method rather than expert interpretation.
4. Adjudication Method for the Test Set
- Adjudication Method: Not applicable. The ground truth was established by an objective analytical method (GC/MS) rather than human interpretation requiring adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- MRMC Study: No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic assay for measuring substance concentration, not an imaging or diagnostic device that involves human interpretation of results requiring AI assistance.
6. Standalone (Algorithm Only) Performance
- Standalone Performance: Yes, the entire study focuses on the standalone performance of the LZI Buprenorphine Enzyme Immunoassay. It's an automated assay, and its performance is evaluated directly against laboratory controls and a gold standard analytical method (GC/MS), without human interpretation as part of its primary function. The results (e.g., precision, detection limit, linearity, agreement with GC/MS) represent the algorithm (assay chemistry and analyzer's measurement) only.
7. Type of Ground Truth Used
- Type of Ground Truth: The ground truth for the method comparison study was established using Chromatography/mass spectrometry (GC/MS). This is considered a highly specific and sensitive "confirmatory method" for drug analysis, often regarded as the gold standard in toxicology. For precision and linearity, laboratory-prepared samples with known concentrations served as the ground truth.
8. Sample Size for the Training Set
- Training Set Sample Size: The document does not explicitly mention a "training set" in the context of machine learning or AI development. This device is a chemical immunoassay, not a machine learning algorithm that requires a separate training set. The various calibration and control levels mentioned (e.g., 6 Calibrator Levels, 3 Control Levels) are used for calibrating the assay itself and monitoring its performance, which is analogous to "training" in a broad sense for traditional assays, but not in the machine learning context.
9. How the Ground Truth for the Training Set Was Established
- Ground Truth for Training Set: As stated above, there isn't a traditional "training set" as understood in a machine learning context. For the assay's calibration (which ensures accurate measurement), the calibrators (e.g., 0, 5, 10, 20, 40, 75 ng/mL Norbuprenorphine Drugs of Abuse (DAU) Calibrators) are used. These would contain specified, known concentrations of norbuprenorphine, which serve as their own "ground truth" for calibration. These concentrations are typically verified by highly accurate analytical methods during their manufacture.
§ 862.3650 Opiate test system.
(a)
Identification. An opiate test system is a device intended to measure any of the addictive narcotic pain-relieving opiate drugs in blood, serum, urine, gastric contents, and saliva. An opiate is any natural or synthetic drug that has morphine-like pharmocological actions. The opiates include drugs such as morphine, morphine glucoronide, heroin, codeine, nalorphine, and meperedine. Measurements obtained by this device are used in the diagnosis and treatment of opiate use or overdose and in monitoring the levels of opiate administration to ensure appropriate therapy.(b)
Classification. Class II (special controls). An opiate 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).