(59 days)
The Immunalysis EDDP Specific Urine Enzyme Immunoassay is a homogeneous enzyme immunoassay with cutoffs of 100 ng/mL, 300n g/mL and 1000 ng/mL. The assay is intended for use in laboratories for the qualitative and semiquantitative analysis of EDDP in human urine with automated clinical chemistry analyzers. This assay is calibrated against EDDP. This in-vitro device is for prescription use only.
The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as GC-MS or permitting laboratories to establish quality control procedures.
The Immunalysis EDDP Specific Urine Enzyme Immunoassay Kit provides only a preliminary analytical test result. A more specific alternate 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 applied to any drug of abuse test result, particularly when preliminary positive results are used.
Immunalysis EDDP Urine Calibrators
The Immunalysis EDDP Urine Calibrators are used as calibrators in the Immunalysis EDDP Specific Urine Enzyme Immunoassay for the qualitative and semi-quantitative determination of EDDP in urine on automated clinical chemistry analyzers.
Immunalysis EDDP Urine Control Sets
The Immunalysis EDDP Urine Control Sets are used as control materials in Immunalysis EDDP Specific Urine Enzyme Immunoassay.
The assay consists of antibody/ substrate reagent and enzyme conjugate reagent. 1. The antibody/ substrate reagent includes recombinant fab antibodies to EDDP. glucose-6-phosphate (G6P) and nicotinamide adenine dinucleotide (NAD) in Tris buffer with Sodium Azide as a preservative. The enzyme conjugate reagent includes EDDP derivative labeled with glucose-6-phosphate dehydrogenase (G6PDH) in Tris buffer with Sodium Azide as a preservative.
2. All of the Immunalysis EDDP Calibrators and Controls are liquid and ready to use. These calibrators and controls do not have any especially unique technical characteristics. Each contains a known concentration of a specific drug analyte as a mixture.
The negative calibrator is a processed, drug-free synthetic urine matrix with sodium azide as a preservative. The Level 1, 2, 3 and 4 calibrators, as well as the LOW Control 1, HIGH Control 1, LOW Control 2 and HIGH Control 2, and LOW Control 3 and HIGH Control 3 are prepared by spiking known concentrations of EDDP into the negative calibrator matrix. These five calibrators and six controls are sold as individual bottles.
The provided document describes the Immunalysis EDDP Specific Urine Enzyme Immunoassay, along with its calibrators and control sets, and the studies conducted to demonstrate its substantial equivalence to a predicate device.
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1. Table of Acceptance Criteria and Reported Device Performance
For qualitative results, the acceptance criterion generally implies a high level of agreement with the confirmatory method, especially around the cutoff concentrations. For semi-quantitative results, similar high agreement is expected. Precision studies demonstrate the device's ability to consistently produce the same value. Specificity and interference studies aim to show that the device accurately identifies EDDP without significant false positives or negatives due to other compounds or physiological conditions.
Below is a table summarizing the reported device performance for the Qualitative and Semi-Quantitative Method Comparison studies, which are key to assessing acceptance criteria:
Table: Acceptance Criteria and Reported Device Performance (Method Comparison)
| Study Type | Cutoff (ng/mL) | Acceptance Criteria (Implicit from FDA submission standards) | Reported Device Performance (Agreement with LC/MS) | Additional Details |
|---|---|---|---|---|
| Qualitative Method Comparison | 100 | High agreement with LC/MS across known concentrations. | 98% Agreement | One discordant case (Test Device POS, LC/MS 97.0 ng/mL, cutoff 100 ng/mL) |
| Qualitative Method Comparison | 300 | High agreement with LC/MS across known concentrations. | 100% Agreement | No discordant cases reported. |
| Qualitative Method Comparison | 1000 | High agreement with LC/MS across known concentrations. | 100% Agreement | No discordant cases reported. |
| Semi-Quantitative Method Comparison | 100 | High agreement with LC/MS across known concentrations. | 98% Agreement | One discordant case (Test Device POS, LC/MS 97.0 ng/mL, cutoff 100 ng/mL) |
| Semi-Quantitative Method Comparison | 300 | High agreement with LC/MS across known concentrations. | 100% Agreement | No discordant cases reported. |
For Precision/Cutoff Characterization, the acceptance criteria are generally that samples below the cutoff are consistently negative and samples above the cutoff are consistently positive. Samples at the cutoff are expected to show a mix of positive and negative results, indicating the cutoff acts as a boundary. The device demonstrated this behavior across all cutoffs (100, 300, 1000 ng/mL) for both qualitative and semi-quantitative analysis. For example, at the 100 ng/mL cutoff, concentrations below 100 ng/mL yielded 80 negative results out of 80 determinations, while concentrations above 100 ng/mL yielded 80 positive results out of 80 determinations. At the 100 ng/mL cutoff itself, there were a mix of positive and negative results as expected (e.g., 43 Negative / 37 Positive for qualitative, 10 Negative / 70 Positive for semi-quantitative).
The specificity and interference studies showed that many structurally non-similar compounds up to high concentrations did not interfere with the assay. Some structurally similar compounds (e.g., Methadone, Chlorpromazine, Methylphenidate, Diphenhydramine, (±)-alpha methadol) did show cross-reactivity at high concentrations, and these are noted in the labeling. Boric Acid was identified as an interferent and limitations added to the labeling. pH and Specific Gravity within tested ranges did not interfere.
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size (Method Comparison):
- For the 100 ng/mL cutoff: 80 unique clinical urine samples (40 positive by LC/MS and 40 negative by LC/MS). (Table 31)
- For the 300 ng/mL cutoff: 80 unique clinical urine samples (40 positive by LC/MS and 40 negative by LC/MS). (Table 34)
- For the 1000 ng/mL cutoff: 80 unique clinical urine samples (40 positive by LC/MS and 40 negative by LC/MS). (Table 36)
- Sample Size (Precision/Cutoff Characterization): For each cutoff (100, 300, 1000 ng/mL) and each concentration level relative to the cutoff (e.g., -100%, -75%, -50%, -25%, Cutoff, +25%, +50%, +75%, +100%), there were 80 determinations (20 days, 2 runs per day, in duplicate). This results in 9 concentration levels * 80 determinations = 720 determinations per cutoff. This was done for qualitative and semi-quantitative modes.
- Data Provenance: The Method Comparison study used "Unaltered, anonymous and discarded clinical urine samples obtained from clinical testing laboratories." This indicates the data is retrospective and its country of origin is not explicitly stated but is implicitly from the US given the FDA submission. The other studies (Precision, Specificity, Interference, Linearity/Recovery) appear to use spiked or prepared samples, not directly from patients.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
- The document does not mention the use of experts to establish ground truth for the test set.
- Instead, the ground truth for the method comparison study was established using a "more specific alternate chemical method," specifically Gas Chromatography/ Mass Spectrometry (GC-MS) or Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). These are analytical laboratory techniques, not human expert interpretation.
4. Adjudication Method for the Test Set
- Since the ground truth was established by LC/MS, there was no human adjudication process described for the test set results. The device's results were directly compared to the LC/MS confirmation.
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
- No MRMC comparative effectiveness study was done. This device is an in-vitro diagnostic assay (an enzyme immunoassay) for the detection of EDDP in urine, not an AI-based image analysis or diagnostic tool that involves human readers interpreting results with or without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Yes, the performance data presented is for the device operating in a standalone manner. The "Test Device" results were compared directly against the LC/MS confirmation. The assay is performed on automated clinical chemistry analyzers.
7. The Type of Ground Truth Used
- The primary ground truth used for performance verification (Method Comparison) was LC/MS (Liquid Chromatography/Tandem Mass Spectrometry) Confirmation. This is a highly accurate chemical analytical method considered the gold standard for drug confirmation.
- For other studies (Precision, Specificity, Interference, Linearity/Recovery), the ground truth was based on known concentrations of EDDP or other compounds in prepared urine matrices.
8. The Sample Size for the Training Set
- The document does not describe a "training set" in the context of machine learning or AI. This is a traditional immunoassay device. The assay development process involves optimization, but there isn't a "training set" in the way it's defined for AI/ML models. For traditional assays, development involves iterative testing and refinement of reagents and protocols using various samples, but this is distinct from training an algorithm.
9. How the Ground Truth for the Training Set Was Established
- As mentioned above, there is no explicit "training set" in the AI/ML sense. The "ground truth" for the calibrators and controls used in the assay itself is established by spiking known concentrations of EDDP into a synthetic urine matrix and verifying these concentrations through mass spectrometry.
§ 862.3620 Methadone test system.
(a)
Identification. A methadone test system is a device intended to measure methadone, an addictive narcotic pain-relieving drug, in serum and urine. Measurements obtained by this device are used in the diagnosis and treatment of methadone use or overdose and to determine compliance with regulations in methadone maintenance treatment.(b)
Classification. Class II (special controls). A methadone 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).