(195 days)
The MEDTOX Buprenorphine Test uses immunochromatographic test strips for the rapid, qualitative detection of buprenorphine and its metabolites in human urine. It is intended for prescription use only. The MEDTOX Buprenorphine Test is not for overthe-counter sale. It is not intended for use in point-of-care settings.
MEDTOX Buprenorphine detects buprenorphine and its metabolites at the following cutoff concentrations:
Buprenorphine (Buprenorphine) BUP 10 ng/mL
The MEDTOX Buprenorphine Test provides only a preliminary analytical test result. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. Liquid chromatography/tandem mass spectrometry (LC/MS/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be applied to any test result.
The MEDTOX® Buprenorphine Test is a rapid, single use, one-step qualitative immunochromatographic screening assay for the detection of Buprenorphine and its metabolites in human urine.
Acceptance Criteria and Device Performance for MEDTOX® Buprenorphine Test
This document outlines the acceptance criteria and the studies conducted to demonstrate the performance of the MEDTOX® Buprenorphine Test, a rapid, qualitative immunochromatographic screening assay for Buprenorphine and its metabolites in human urine.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are derived from various studies detailed in the submission, primarily focusing on analytical sensitivity, specificity, and accuracy around the defined cutoff. Due to the qualitative nature of the test and the reporting style, acceptance criteria are inferred from the study design and expected performance for a screening device.
For the purposes of this summary, the primary acceptance criterion for a diagnostic test like this is typically to correctly identify drug-positive samples at or above the cutoff and drug-negative samples below the cutoff, with minimal false positives or false negatives.
| Performance Metric | Acceptance Criteria (Inferred) | Reported Device Performance |
|---|---|---|
| Analytical Sensitivity (Precision): | For a qualitative test around a cutoff, there should be a clear distinction between negative and positive results between 50% and 150% of the cutoff concentration. Specifically, samples below the cutoff should be predominantly negative, and samples above the cutoff should be predominantly positive. Ideally, 100% agreement at 0 ng/mL and 150% of cutoff, and a gradient of positive detection between 75% and 125% of cutoff. | At Cutoff of 10 ng/mL: |
- 0 ng/mL: 45/45 Negative (100%)
- 2.5 ng/mL (25%): 45/45 Negative (100%)
- 5.0 ng/mL (50%): 45/45 Negative (100%)
- 7.5 ng/mL (75%): 28 Negative, 17 Positive (37.8% Positive)
- 12.5 ng/mL (125%): 4 Negative, 41 Positive (91.1% Positive)
- 15.0 ng/mL (150%): 45/45 Positive (100%)
This demonstrates appropriate sensitivity around the cutoff. |
| Analytical Specificity (Cross-Reactivity): | The device should generally not cross-react with structurally similar compounds at high concentrations, or with common medications/endogenous substances, to avoid false positives. Related Buprenorphine metabolites are expected to show some level of cross-reactivity. | Related Compounds:
- Buprenorphine-glucuronide: Positive at 7.5 ng/mL (133% cross-reactive)
- Norbuprenorphine: Positive at 50 ng/mL (20% cross-reactive)
- Norbuprenorphine-glucuronide: Positive at 75 ng/mL (13% cross-reactive)
Non-Reacting Opiates: All listed (Codeine, Diacetylmorphine, Hydrocodone, etc.) showed "None Detected" at 100,000 ng/mL (or highest level tested). These non-reactive opiates also did not affect expected results when spiked with Buprenorphine at 5 ng/mL and 15 ng/mL.
Non-Crossreactive Endogenous Compounds & Common Drugs: None of the 13 endogenous compounds or 16 common drugs tested at high concentrations (typically 100 µg/mL) affected the expected Buprenorphine results at 5 ng/mL and 15 ng/mL. This indicates high specificity. |
| Interference (pH & Specific Gravity): | The device's performance should not be significantly affected by variations in urine pH or specific gravity within typical physiological ranges encountered in clinical samples. | pH: No interference observed; samples fortified to 5 ng/mL (negative) and 15 ng/mL (positive) gave expected results across pH 5.0, 6.0, 7.0, and 8.0.
Specific Gravity: No interference observed; samples fortified to 5 ng/mL (negative) and 15 ng/mL (positive) gave expected results across specific gravity 1.003, 1.015, and 1.030. |
| Clinical Accuracy/Agreement (with LC/MS/MS): | High agreement expected with a confirmatory method (LC/MS/MS), particularly for samples near and above the cutoff. Low false positive rate for negative samples. | Overall Agreement: - Positive Agreement: 100% (72 High Positive + 8 Near Cutoff Positive = 80 samples correctly identified as Positive).
- Negative Agreement: 96.1% (70 No Drug + 4 Near Cutoff Negative = 74 samples correctly identified as Negative). The report indicates 3 "Near Cutoff Negative" samples (between -50% and cutoff, i.e., between 5 and 10 ng/mL) were reported as positive by the device (potentially false positives or very low positives for a screening test). The three specific discordant samples were: total buprenorphine at 5 ng/mL, 7 ng/mL, and 9 ng/mL, all reported as positive by the MEDTOX test. Since the cutoff is 10 ng/mL, detecting positives below the cutoff represents a level of sensitivity for a screening test. The device had 0 false positives for samples with no drug. |
2. Sample Sizes and Data Provenance
-
Analytical Sensitivity (Precision) Test Set:
- Sample Size: 6 concentrations x 45 observations (triplicate testing on 5 different intervals by 3 operators) = 270 total observations.
- Data Provenance: Drug-free urine spiked with standard drug solutions. This is laboratory-controlled, not human patient data.
-
Analytical Specificity (Cross-Reactivity) Test Set:
- Sample Size:
- Cross-reacting metabolites: Tested with standards, results expressed as minimum concentration for positive result.
- Non-reacting opiates: Tested at 100,000 ng/mL, then spiked into Buprenorphine-containing urine (5 ng/mL and 15 ng/mL) in triplicate by in-house operators.
- Endogenous Compounds & Common Drugs: Spiked into Buprenorphine-containing urine (5 ng/mL and 15 ng/mL) in triplicate by in-house operators.
- Data Provenance: Laboratory-controlled samples using reference standards and drug-free urine.
- Sample Size:
-
Interference (pH & Specific Gravity) Test Set:
- Sample Size: 4 pH levels x 3 replicates; 3 specific gravity levels x 3 replicates. Each fortified with Buprenorphine at 5 ng/mL and 15 ng/mL.
- Data Provenance: Laboratory-controlled samples.
-
Clinical Accuracy Test Set:
- Sample Size: Total not explicitly stated, but derived from the table: 70 (No Drug) + 7 (Near Cutoff Negative) + 8 (Near Cutoff Positive) + 72 (High Positive) = 157 clinical urine samples.
- Data Provenance: Retrospective clinical urine samples obtained from MEDTOX® Laboratories. The country of origin is not specified but implicitly assumed to be the USA, given the FDA submission.
3. Number of Experts for Ground Truth and Qualifications
- Analytical Studies: "in-house operators" are mentioned. Their specific qualifications (e.g., years of experience, specific certifications) are not detailed.
- Clinical Accuracy Study: The ground truth was established by LC/MS/MS results. While LC/MS/MS is a highly precise analytical method, the interpretation of these results might involve expert toxicologists or lab personnel. The number and qualifications of such "experts" for LC/MS/MS confirmation are not provided, as the method itself serves as the objective reference standard.
4. Adjudication Method for the Test Set
- Analytical Studies: No formal "adjudication" is described beyond reporting the direct visible results observed by "in-house operators."
- Clinical Accuracy Study: No multi-reader adjudication method (like 2+1 or 3+1) was used for the device's interpretation. The device's visual results were compared directly against the LC/MS/MS results. The "in-house operators" interpreted the results visually at five (5) minutes, and also at 15 minutes with identical results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was performed or described. This submission focuses on the standalone performance of the device relative to established analytical methods. Therefore, no effect size for human readers improving with AI vs. without AI assistance can be provided.
6. Standalone Performance
Yes, extensive standalone performance was done. All studies described (analytical sensitivity, specificity, interference, and clinical accuracy) evaluate the algorithm's (in this case, the immunochromatographic test strip's visual output) performance without human-in-the-loop assistance in the sense of a diagnostic interpretation aid. The "in-house operators" merely read and recorded the visible bands, they were not "assisted" by an algorithm for diagnosis. The device itself is a standalone screening tool.
7. Type of Ground Truth Used
- Analytical Studies (Sensitivity, Specificity, Interference): Laboratory-prepared spiked samples with known concentrations of Buprenorphine and other substances.
- Clinical Accuracy Study: Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS) results, which is a highly sensitive and specific confirmatory analytical method for drug detection.
8. Sample Size for the Training Set
The document does not describe explicit "training" of an algorithm in the modern sense of machine learning. For an immunochromatographic assay, the "training" (development and optimization) would involve experimental iterative refinements of the test strip components (antibodies, reagents, membrane) based on laboratory performance data. No specific sample size for such an iterative development process is provided, nor is it typically reported for this type of device. The reported studies represent the validation of the final device.
9. How the Ground Truth for the Training Set was Established
As noted above, no explicit "training set" with ground truth in the context of an algorithm or AI is described. The development of such a device relies on established chemical and immunological principles, with performance optimized through iterative laboratory testing using known concentrations of analytes and controls (similar to how the analytical studies were conducted for validation).
§ 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).