(93 days)
CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine is a rapid test for the qualitative detection of Nortriptyline (a major metabolite of Tricyclic Antidepressants) and Buprenorphine in human urine at a cutoff concentration of 1000ng/mL and 10ng/mL, respectively. The test is the first step in a two-step process. The second step is to send the sample for laboratory testing if preliminary positive results are obtained. The test is intended for over-the-counter and for prescription use.
The test may yield preliminary positive results even when prescription drugs including Tricyclic Antidepressants and Buprenorphine are ingested, at prescribed doses; it is not intended to distinguish between prescription use or abuse of these drugs. There are no uniformly recognized cutoff concentration levels for Nortriptyline in urine. The test provides only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. GC/MS is the preferred confirmatory method. Clinical consideration and professional iudgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.
For in vitro diagnostic use only.
The CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine test uses immunochromatographic assays for nortriptyline and buprenorphine. The test is a lateral flow, one step system for the qualitative detection of nortriptyline and buprenorphine in human urine.
Here's an analysis of the provided text to extract the acceptance criteria and study details for the CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine device:
Acceptance Criteria and Device Performance for CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" for precision or accuracy using specific numerical thresholds. Instead, it presents the raw performance data from various studies. For the purpose of this analysis, I will infer the implicit acceptance criteria from the observed performance and the nature of drug screening tests (i.e., high agreement around cutoff, 100% detection for significantly positive, 100% negative for significantly negative).
Analytical Performance (Precision/Cut-off Verification)
| Criterion Type | Acceptance Criteria (Implied) | Reported Device Performance (Nortriptyline - TCA) | Reported Device Performance (Buprenorphine - BUP) |
|---|---|---|---|
| Precision | Should show 100% negative results at concentrations significantly below the cutoff (-50%, -75%, -100%) and 100% positive results at concentrations significantly above the cutoff (+50%, +75%, +100%). At the cutoff and near-cutoff concentrations (-25%, +25%), some variability is expected and acceptable, but a clear trend towards positive above cutoff and negative below cutoff should be observed. | -100%, -75%, -50% cut-off: 50-/0+ (100% Negative)-25% cut-off: 50-/0+ (100% Negative)Cut-off: 43-44+/6-7 (86-88% Positive)+25%, +50%, +75%, +100% cut-off: 50+/0- (100% Positive) | -100%, -75%, -50% cut-off: 50-/0+ (100% Negative)-25% cut-off: 50-/0+ (100% Negative)Cut-off: 42-43+/7-8 (84-86% Positive)+25%, +50%, +75%, +100% cut-off: 50+/0- (100% Positive) |
| Cut-off | Device should consistently classify samples at or above +25% of the cutoff as positive and samples at or below -25% of the cutoff as negative. | All positive at +25% and +50% cut-off. All negative at -25% and -50% cut-off. | All positive at +25% and +50% cut-off. All negative at -25% and -50% cut-off. |
| Interference | No interference from tested endogenous or exogenous substances at specified concentrations (100 µg/mL). | All listed compounds showed no interference at 100 µg/mL. | All listed compounds showed no interference at 100 µg/mL. |
| Specificity | Should demonstrate expected cross-reactivity with drug metabolites and related compounds, reflecting the immunological basis of the test, and minimal cross-reactivity with unrelated substances. | Nortriptyline: High cross-reactivity with Nordoxepine (100%), Desipramine (500%), Imipramine (250%). Lower cross-reactivity with Amitriptyline, Promazine, Doxepine, Maprotiline, Trimipramine, Clomipramine, Promethazine. | Buprenorphine: High cross-reactivity with Buprenorphine-3-D-Glucuronide (67%), Norbuprenorphine (50%). Very low cross-reactivity with Norbuprenorphine-3-D-Glucuronide (5%), Morphine, Oxymorphone, Hydromorphone (90-95%) with GC/MS for clearly negative (e.g., -100%, -75%, -50% below cutoff) and clearly positive samples (e.g., +50%, +75% above cutoff). Reasonable agreement (e.g., >80%) in near-cutoff regions, acknowledging the inherent variability and intended screening nature of the device. For OTC use, acceptable agreement demonstrates that lay users can correctly interpret results following instructions. |
| Ease of Use (Lay User Study) | Lay users should indicate that instructions are easy to follow, and the reading grade level of instructions should be appropriate for OTC use. | All lay users indicated instructions were easy to follow. Flesch-Kincaid score indicated a reading grade level less than 7. | All lay users indicated instructions were easy to follow. Flesch-Kincaid score indicated a reading grade level less than 7. |
The study demonstrates that the device performs as expected for a qualitative drug screening test, with high accuracy for samples well outside the cutoff and reasonable performance near the cutoff, which is acceptable given its intended "first step in a two-step process" role where preliminary positives require laboratory retesting.
2. Sample Sizes Used for the Test Set and Data Provenance
Analytical Performance (Precision, Cut-off, Interference, Specificity, Specific Gravity/pH):
- Precision:
- For each of 9 concentration levels, for both Nortriptyline and Buprenorphine: 50 tests were performed (2 runs per day for 25 days).
- Total tests for precision: 9 concentrations * 2 drugs * 50 tests/concentration = 900 tests.
- Cut-off Verification:
- 125 Nortriptyline samples and 125 Buprenorphine samples, equally distributed at -50%, -25%, cut-off, +25%, +50% of their respective cut-offs. (Total 250 samples).
- Interference & Specificity & Effect of Specific Gravity and pH:
- Number of samples not explicitly stated beyond "tested for each condition (drug-free, 25% below cut-off, 25% above cut-off)" against a long list of potential interferents/cross-reactants.
- Data Provenance: The document does not explicitly state the country of origin for these analytical samples. They appear to be spiked samples developed in a laboratory setting for controlled testing rather than clinical samples. The studies are prospective in nature in that samples were prepared and then tested.
Clinical/Method Comparison Study (vs. GC/MS):
- Sample Size: 80 "unaltered clinical samples" for Nortriptyline and 80 "unaltered clinical samples" for Buprenorphine. (Total 160 clinical samples).
- Data Provenance: Not explicitly stated, but described as "clinical samples," implying human origin. The study was performed "in-house," and the samples were "unaltered," and "masked and randomized," indicating a prospective evaluation of existing or collected clinical samples.
Lay-User Study:
- Sample Size: 260 lay persons, using urine samples (20 drug-free, 120 nortriptyline, 120 buprenorphine).
- For Nortriptyline and Buprenorphine, each: 20 samples were tested at -100% (drug-free), -75%, -50%, -25%, +25%, +50%, +75% of the cutoff. (7 concentrations * 20 samples/concentration = 140 samples * 2 drugs = 280 samples for the lay user study, but the text says 20 drug-free, 120 nortriptyline, 120 buprenorphine, summing to 260 samples).
- Data Provenance: Urine samples were "spiked drug(s) into drug free-pooled urine specimens." The concentrations were confirmed by GC/MS. This indicates laboratory-prepared, prospectively tested samples, not necessarily from patients with the conditions. Lay users had diverse educational and professional backgrounds from 21 to >50 years of age.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
- Analytical Ground Truth: For precision, cut-off, interference, specificity, specific gravity/pH studies, the ground truth was established by preparing samples with known concentrations of analytes (e.g., standard solutions, spiked urine). The "experts" are the laboratory personnel who accurately prepare these samples and use calibrated instrumentation.
- Clinical/Method Comparison Ground Truth: The ground truth for the 160 "unaltered clinical samples" was established by GC/MS (Gas Chromatography/Mass Spectrometry), which is stated as "the preferred confirmatory method." The number of experts interpreting the GC/MS results is not specified, but GC/MS involves trained laboratory professionals.
- Lay-User Study Ground Truth: The ground truth for the spiked samples was established by preparing samples with known concentrations and confirmed by GC/MS.
4. Adjudication Method for the Test Set
- Analytical Studies (Precision, Cut-off, Interference, Specificity, Specific Gravity/pH):
- In some cases, samples were tested using "three different lots by three different operators." The results were then summarized. No formal expert adjudication method (e.g., 2+1) is explicitly described for discrepancies in these analytical studies. It implies direct data recording and analysis.
- Clinical/Method Comparison Study:
- "Three laboratory assistants" ran the samples. The obtained results were compared to GC/MS results. The results are presented for "Viewer A, Viewer B, Viewer C," suggesting individual interpretations. The discordant tables list individual viewer's results against the GC/MS result. There is no mention of an adjudication process among the three viewers for their interpretations. The ground truth (GC/MS) is presented as definitive.
- Lay-User Study:
- Each participant was given one blind-labeled sample and a device. The participants' results were then compared to the GC/MS confirmed concentration of the sample. No adjudication was explicitly performed for the lay users' interpretations; their results were simply recorded and compared to the established ground truth.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a traditional MRMC comparative effectiveness study comparing human readers with AI assistance versus without AI assistance was not done. This device is a rapid drug screening test and not an imaging AI device. The method comparison study involved "three laboratory assistants" (human readers) interpreting the device results and comparing them to a gold standard (GC/MS), but it did not involve an AI component or evaluate the "effect size of how much human readers improve with AI vs without AI assistance."
6. Standalone Performance Study
Yes, the analytical performance studies (Precision, Cut-off, Interference, Specificity, Specific Gravity/pH) and the "Comparison Studies" (method comparison with GC/MS) represent standalone (algorithm only, without human-in-the-loop performance), as the performance of the device (its ability to detect the substances) is characterized independently. While human operators perform the test and read the result line, the inherent accuracy of the device's chemical assay is what is being evaluated in these sections. The lay-user study then assesses whether an untrained human can properly interpret the standalone device's output.
7. Type of Ground Truth Used
- Analytical Studies: Known concentrations of target analytes (spiked samples) and confirmed by GC/MS for lay-user study samples. This is a form of reference standard ground truth.
- Clinical/Method Comparison Study: GC/MS (Gas Chromatography/Mass Spectrometry) results. This is considered a definitive laboratory reference method or gold standard for drug detection and quantification.
8. Sample Size for the Training Set
The document does not mention a training set for an algorithm or AI. This device is an immunochromatographic assay (lateral flow immunoassay), which is a chemical/biological test, not a software algorithm that requires training data.
9. How the Ground Truth for the Training Set Was Established
As there is no training set for an algorithm, this question is not applicable. The device operates based on antigen-antibody reactions, not a learned model.
§ 862.3910 Tricyclic antidepressant drugs test system.
(a)
Identification. A tricyclic antidepressant drugs test system is a device intended to measure any of the tricyclic antidepressant drugs in serum. The tricyclic antidepressant drugs include imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, and doxepin. Measurements obtained by this device are used in the diagnosis and treatment of chronic depression to ensure appropriate therapy.(b)
Classification. Class II (special controls). A tricyclic antidepressant drugs 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).