(150 days)
BioSieve™ Fentanyl FIA Test Kit is a fluorescence immunoassay (FIA) for the qualitative determination of fentanyl in human urine at a cutoff concentration of 1.0 ng/mL. The assay is intended for use with BioSieve™ ToxiSmart FIA Reader.
It is for in vitro diagnostic use only. It is intended for prescription use.
The tests provide only preliminary results. A more specific alternative chemical must be used in order 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 exercised with any drug test result, particularly when the preliminary test result is positive.
BioSieve™ ToxiSmart FIA Reader is a portable fluorescence instrument for in vitro diagnostic use only. The Reader is designed to perform in vitro diagnostic tests on urine specimens. This Reader can be used in a laboratory or in a point-of-care setting.
This test uses a lateral flow design with location-dependent lines and zones. BioSieve™ ToxiSmart FIA Reader scans the test strip and displays results. The sample is added to the sample well of the test card, and the sample is drawn by capillary action into and through the fluorescent labeled pad, through the nitrocellulose strip and into the adsorption pad. Within the fluorescent labeled pad, the specimen comes into contact with antibodies conjugated with fluorescent microspheres. During this interaction, if the amount of fentanyl antigen in the sample is greater than or equal to the cutoff value, the antigen in the sample and the fluorescence-labeled antibody bind to the FTY antigenantibody complex when the sample passes through a pad of fluorescence-microbead-labeled antibody conjugate. As the sample flows and reaches the FTY antigen coated by the T-line of nitrocellulose membrane, the FTY antigen coated by the T-line antigen in the sample competitively bind the FTY antibody labeled with fluorescence, then the T-line captures fluorescence signal is weaker than the cutoff fluorescence signal. When the samples do not contain fentanyl antigen or levels below the cutoff value, as the sample flow, fluorescent microsphere labeled antibody to nitrocellulose membrane T line captures fluorescent signal is stronger than the cutoff fluorescence signal. Whether or not FTY antigen was present in the sample, the rabbit IgG fluorescent microsphere conjugate not bound to the test line continued to flow with the rest of the sample and soon encountered a control line composed of goatanti-rabbit IgG. The position of C-line will accumulate fluorescence signal. The C-line control area was scanned to confirm that adequate sample flow had occurred. High resolution, narrow band SMD LED was used as light source in the Immunofluorescence Analyzer. The central wavelength of the excitation spectrum is 365nm. The central response wavelength is 610nm.
The provided text describes the acceptance criteria and the study that proves the device meets those criteria for the BioSieve™ Fentanyl FIA Test Kit and BioSieve™ ToxiSmart FIA Reader.
Here's an analysis of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are not explicitly stated as distinct pass/fail thresholds in a table format. However, the performance characteristics tested and summarized imply the criteria for acceptable performance. The study aims to demonstrate that the device performs as expected for a qualitative immunoassay for fentanyl in urine, particularly around the 1.0 ng/mL cutoff.
The reported device performance is presented in several sections:
| Performance Metric | Implied Acceptance Criteria (Based on typical immunoassay requirements) | Reported Device Performance |
|---|---|---|
| Precision | High agreement for samples well below and well above cutoff; reasonable agreement near cutoff. | For -100%, -75%, -50% cutoff, all 60 tests for each lot were negative (60-/0+). For +25%, +50%, +75%, +100% cutoff, all 60 tests for each lot were positive (60+/0-). For -25% cutoff, 58-59 negative and 1-2 positive out of 60. For cutoff (1.0 ng/mL), 28-29 negative and 31-32 positive out of 60. |
| Stability | Device remains effective under specified storage conditions for its shelf life. | Stable at 2-30°C for 24 months based on accelerated stability study; real-time ongoing. |
| Interference | No significant interference from common substances found in urine. | Numerous compounds (e.g., Acetaminophen, Ethanol, Glucose) at specific concentrations showed no interference. |
| Specificity (Cross-Reactivity) | Low or no cross-reactivity with other related compounds or metabolites not intended to be detected, especially at clinically relevant concentrations. | Lists various fentanyl-related compounds and their cross-reactivity percentages (e.g., Acetyl fentanyl 83.33%, Carfentanil 0.20%). Many opiate compounds showed no cross-reactivity at 100 µg/mL. |
| Effect of Urine Specific Gravity and pH | Performance should be robust across a physiological range of urine specific gravity and pH. | Samples spiked at -50% and +50% Cut-Off levels across specific gravity 1.000-1.035 and pH 4-9 showed expected negative and positive results respectively. |
| Method Comparison (Clinical Samples) | High concordance with a reference method (LC-MS/MS), especially for samples far from the cutoff. Acceptable levels of discordance near the cutoff. | Site 1: 0 False Positives (FP) from negative, 0 FP from low negative, 4 FP from near cutoff negative. 1 False Negative (FN) from near cutoff positive, 0 FN from high positive. |
| Site 2: 0 FP from negative, 0 FP from low negative, 3 FP from near cutoff negative. 2 FN from near cutoff positive, 0 FN from high positive. | ||
| Site 3: 0 FP from negative, 0 FP from low negative, 2 FP from near cutoff negative. 1 FN from near cutoff positive, 0 FN from high positive. | ||
| Discordant Results: Specific sample numbers and their LC-MS/MS vs. BioSieve results are listed, showing cases where the device gave a positive result for a true negative near the cutoff, and a negative result for a true positive near the cutoff. |
2. Sample Size Used for the Test Set and Data Provenance
- Precision Study Test Set: For each of 9 concentrations (e.g., -100% cutoff, cutoff, +100% cutoff), 6 runs per day for 10 days per device lot were performed. With 3 lots, this suggests: 9 concentrations * 6 tests/run * 10 days * 3 lots = 1620 individual tests (results reported as sums across these).
- Interference Study Test Set: Numerous interfering substances were tested with 3 batches of each device for drug-free urine and target fentanyl urine at -50% and +50% Cut-Off levels. The exact number of tests per substance is not specified, but it implies a substantial number.
- Specificity (Cross-Reactivity) Test Set: Various drug metabolites and opioid compounds were tested using three batches of device. The number of individual tests per compound is not explicitly stated.
- Effect of Urine Specific Gravity and pH Test Set: Urine samples across the specified ranges were spiked at -50% and +50% Cut-Off. Tested by three different operators per lot of device, with a total of three lots. The exact number of individual tests is not specified.
- Method Comparison Test Set: 80 unaltered clinical samples (40 negative and 40 positive based on an internal classification) were used per site across three different testing sites. This totals 240 clinical samples.
- Data Provenance: The document does not explicitly state the country of origin for the samples. It mentions "unaltered clinical samples" for the method comparison study, implying they were retrospective if they were already collected clinical samples. The precision study samples were "prepared by spiking fentanyl in negative samples," indicating these were artificially contrived samples, not naturally occurring clinical specimens, and were conducted in a controlled lab setting.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
- For the Precision Study, "Each fentanyl concentration was confirmed by LC/MS-MS." LC/MS-MS (Liquid Chromatography/Mass Spectrometry) is a highly accurate analytical chemistry method, typically considered a gold standard for quantifying substances in biological samples. This method itself provides the "ground truth" and does not typically involve human "experts" in the sense of clinicians or radiologists reading results.
- For the Method Comparison Study, "The samples were blind labeled and compared to LC-MS/MS results." Again, LC-MS/MS is the ground truth. No human experts (e.g., radiologists) were used to establish the ground truth; it was established by an analytical instrument method.
- No information is provided about the qualifications of the operators who performed the tests on the BioSieve™ device at the three sites, nor is there mention of a panel of experts for subjective adjudication.
4. Adjudication Method for the Test Set
- None in the context of human expert adjudication. The ground truth for quantitative accuracy and comparative performance was established by LC-MS/MS, a definitive analytical method, not by human consensus or adjudication. The BioSieve™ device provides a qualitative result (positive/negative), which is then compared against the quantitative LC-MS/MS value relative to the 1.0 ng/mL cutoff.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC study was not done. This device is a quantitative/qualitative immunoassay read by an instrument (BioSieve™ ToxiSmart FIA Reader), not interpreted by human readers in the same way an imaging AI would be. The "operators" in the method comparison study are likely technicians performing the test, not interpreting complex outputs. Therefore, a study on human reader improvement with AI assistance is not applicable.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
- Yes, in essence. The BioSieve™ ToxiSmart FIA Reader is an automated instrument that reads the test strip and displays results. The results presented for precision, interference, specificity, and comparison studies demonstrate the standalone performance of the BioSieve™ Fentanyl FIA Test Kit and the BioSieve™ ToxiSmart FIA Reader system. The device produces a qualitative result directly from the sample, without human interpretation of the signal beyond observing the final positive/negative display.
7. Type of Ground Truth Used
- LC-MS/MS (Liquid Chromatography/Mass Spectrometry): This highly accurate analytical method was used to confirm fentanyl concentrations in precision samples and as the reference method for clinical samples in the method comparison study. It provides objective, quantitative biochemical data, which is then translated to the qualitative positive/negative ground truth based on the 1.0 ng/mL cutoff.
8. Sample Size for the Training Set
- Not specified. The document describes performance validation studies for regulatory submission (510(k)). It does not provide details about a specific "training set" for an AI algorithm because the BioSieve™ ToxiSmart FIA Reader is not described as an AI-powered device in the typical sense of a deep learning model that requires a labeled training dataset. It's a fluorescence immunoassay reader. The "development modes" refer to how the test is run (Standard vs. Quick), not algorithmic training.
9. How the Ground Truth for the Training Set Was Established
- Not applicable. As noted above, the device is an immunoassay system and reader, not explicitly an AI/machine learning algorithm requiring a training set with established ground truth in the context of typical AI development. The document describes analytical validation, not algorithmic training.
§ 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).