(132 days)
cobas c Acetaminophen Gen.2 assay:
The cobas c Acetaminophen Gen.2 assay is an in vitro diagnostic test for the quantitative determination of acetaminophen in serum and plasma for use in the diagnosis of acetaminophen overdose in serum and plasma on Roche/Hitachi cobas c systems.
ACET2 calibrator:
The ACET2 calibrator is for use in the calibration of the Acetaminophen Gen.2 Roche assay.
The cobas c Acetaminophen Gen.2 assay is based on a homogeneous enzyme immunoassay technique used for the quantitative analysis of acetaminophen in human serum and plasma.
Reagents are packaged in a cassette labeled with their instrument positioning R1 (Reagent 1) and R2 (Reagent 2).
R1 contains anti-acetaminophen antibody (sheep polyclonal), G6P, NAD, bovine serum albumin, preservatives and stabilizers.
R2 contains acetaminophen labeled with bacterial G6PDH, Tris buffer, preservatives, bovine serum albumin, and stabilizers.
The ACET2 calibrator contains a known quantity of acetaminophen. The cobas c 501 analyzer dilutes the ACET2 calibrator on-board the analyzer with NaCl diluent, in order to create five concentration levels, and level 1 is water. This results in a six-level calibrator set, and the calibrator set is then used to establish a standard curve. The ACET2 calibrator contains acetaminophen, phosphate buffer, and preservatives.
The provided document describes the analytical performance of the cobas c Acetaminophen Gen.2 assay and ACET2 Calibrator. It outlines various studies conducted to demonstrate the device's characteristics, which can serve as acceptance criteria.
Here's the requested information:
1. A table of acceptance criteria and the reported device performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Precision (Repeatability) | |
| Control 1 SD (µg/mL) | 0.4 µg/mL |
| Control 2 SD (µg/mL) | 0.9 µg/mL |
| Control 3 SD (µg/mL) | 2 µg/mL |
| Human Serum 1 SD (µg/mL) | 0.2 µg/mL |
| Human Serum 2 SD (µg/mL) | 1.7 µg/mL |
| Human Serum 3 SD (µg/mL) | 4 µg/mL |
| Human Serum 4 SD (µg/mL) | 4 µg/mL |
| Human Serum 5 SD (µg/mL) | 4 µg/mL |
| Precision (Intermediate Precision) | |
| Control 1 SD (µg/mL) | 0.5 µg/mL |
| Control 2 SD (µg/mL) | 1.0 µg/mL |
| Control 3 SD (µg/mL) | 3 µg/mL |
| Human Serum 1 SD (µg/mL) | 0.3 µg/mL |
| Human Serum 2 SD (µg/mL) | 1.9 µg/mL |
| Human Serum 3 SD (µg/mL) | 4 µg/mL |
| Human Serum 4 SD (µg/mL) | 5 µg/mL |
| Human Serum 5 SD (µg/mL) | 6 µg/mL |
| Method Comparison to Predicate (Deming Regression Weighted) | |
| Slope (y = mx + b) | 1.02 |
| Y-intercept (y = mx + b) | -0.699 µg/mL |
| Correlation Coefficient (r) | 0.997 |
| Linearity (Serum) | |
| Linear Regression Equation (y = mx + b) | y = 1.014x - 0.248 |
| Pearson correlation coefficient (R) | 0.998963 |
| In-range percentage recovery (between 5 and 200 µg/mL) | 94% - 98% (for spiked concentrations of 24-240 µg/mL or more broadly, 92-98% for plasma and 94-98% for serum) |
| Linearity (Plasma) | |
| Linear Regression Equation (y = mx + b) | y = 1.011x - 0.193 |
| Pearson correlation coefficient (R) | 0.999010 |
| In-range percentage recovery (between 5 and 200 µg/mL) | 90% - 95% (for spiked concentrations of 24-240 µg/mL) |
| Detection Limits | |
| Limit of Blank (LoB) | 1.5 µg/mL |
| Limit of Detection (LoD) | 3 µg/mL |
| Limit of Quantitation (LoQ) | 5 µg/mL |
| Analytical Specificity - Cross Reactivity | |
| % cross reactivity for listed compounds (e.g., Acetaminophen cysteine, glucuronide, mercapturate, sulfate, Cysteine, N-Acetylcysteine, Phenacitin) | Generally low, with most noted as "not detectable" or under 1% |
| Analytical Specificity - Endogenous Substances (Interference) | |
| Lipemia (L index) | No significant interference up to an L index of 400 (corresponds to ~600-672 L index reported depending on acetaminophen concentration) |
| Hemolysis (H index) | No significant interference up to an H index of 800 (actual reported values are around 926-1025 H index) |
| Bilirubin (I index) | No significant interference up to an I index of 30 for conjugated and unconjugated bilirubin (actual reported values are around 42-63 I index) |
| Recovery for endogenous interference | Recovery within ± 1 µg/mL for ~5 µg/mL acetaminophen; recovery within ± 10% for ~30 µg/mL acetaminophen |
| Analytical Specificity - Common Drugs (Interference) | |
| Difference in recovery of acetaminophen | ≤ 10 µg/mL: ≤ ± 1 µg/mL; > 10 µg/mL: 100 ± 10 % |
| Matrix Comparison (Anticoagulants) | |
| For samples ≤ 10 µg/mL, deviation from serum recovery | ≤ ± 1 µg/mL |
| For samples > 10 µg/mL, deviation from serum recovery | ≤ ± 10% |
| Serum vs. Li-heparin (Passing/Bablok) | $y = 0.989x + 0.089$, r = 0.998 |
| Serum vs. K2-EDTA (Passing/Bablok) | $y = 1.000x – 0.000$, r = 0.998 |
| Serum vs. K3-EDTA (Passing/Bablok) | $y = 0.992x - 0.163$, r = 0.998 |
2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Precision (Repeatability and Intermediate Precision): The study was conducted according to CLSI EP5-A2 requirements using human samples and controls. "n = 84" is mentioned for repeatability. "2 aliquots per run, 2 runs per day, 21 days" for intermediate precision. The document does not specify the country of origin or whether the data was retrospective or prospective.
- Method Comparison to Predicate: Sample size (n) = 105 human serum samples. The document does not specify the country of origin or whether the data was retrospective or prospective.
- Linearity: One batch of reagent, one run, samples measured in triplicate. Two separate dilution series (serum and Li-Heparin plasma) with thirteen levels each. The document does not specify the country of origin or whether the data was retrospective or prospective.
- Detection Limits (LoB, LoD, LoQ):
- LoB: One analyte-free sample tested in n=5 on two analyzers with three reagent batches for six runs per day across three days.
- LoD: Five low-analyte samples spiked with acetaminophen measured in singlicate on two analyzers with three reagent batches for six runs per day across three days.
- LoQ: A low-level sample set of six measured in two aliquots using three reagent batches on one analyzer over at least six days.
The document does not specify the country of origin or whether the data was retrospective or prospective.
- Analytical Specificity (Cross-Reactivity, Endogenous Substances, Common Drugs): Tested using sample pools (at two target concentrations of acetaminophen) and spiked samples. The specific number of individual samples for each compound/substance is not given, but refers to "two sample pools" or "serum sample pools". The document does not specify the country of origin or whether the data was retrospective or prospective.
- Matrix Comparison: 60 tubes collected per anticoagulant (Lithium-heparin, K2-EDTA, K3-EDTA). This suggests 60 samples for each, so 180 total samples. The document does not specify the country of origin or whether the data was retrospective or prospective.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
This product is an in vitro diagnostic test for the quantitative determination of acetaminophen. The "ground truth" for such assays is typically established by reference methods or spiking known concentrations of analyte into samples. The document does not mention the involvement of medical experts (like radiologists) for ground truth establishment, as it's a quantitative chemical assay, not an image-based diagnostic. It uses USP reference standards for traceability, which represents a highly controlled and recognized standard for chemical concentration.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. Adjudication methods like "2+1" are typically used in studies involving human interpretation (e.g., radiology for diagnostic accuracy) where there might be disagreement among readers, and a third reader is brought in to resolve discrepancies. This document describes the performance of a quantitative chemical assay, where the output is a numerical value.
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
Not applicable. This is not an AI-assisted diagnostic device, nor does it involve human readers interpreting cases. It is a standalone in vitro diagnostic assay.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, this is a standalone device. The entire document describes the performance of the assay itself (cobas c Acetaminophen Gen.2 assay and ACET2 calibrator) on the Roche/Hitachi cobas c 501 analyzer, which processes samples and provides quantitative results without human interpretation or algorithm assistance as part of the primary diagnostic function.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for this chemical assay is primarily based on:
- Known concentrations of analyte: For linearity, detection limits (LoD, LoQ), cross-reactivity, and interference studies, samples were spiked with known concentrations of acetaminophen or interfering substances.
- Reference Methods / Standards: For traceability, the method has been standardized against USP reference standards.
- Comparative Method: The performance was compared to a legally marketed predicate device (Siemens Emit® tox™ Acetaminophen Assay).
8. The sample size for the training set
This document describes the analytical validation of a chemical assay. The concept of a "training set" is typically associated with machine learning or AI models, where data is used to train an algorithm. This document details the performance testing of the device, not the development of a machine learning model. Therefore, a "training set" in the context of an AI algorithm is not applicable here.
9. How the ground truth for the training set was established
As explained above, there is no "training set" in the AI/machine learning sense for this type of in vitro diagnostic device. The analytical characteristics are established through various experiments using samples with known properties or references.
§ 862.3200 Clinical toxicology calibrator.
(a)
Identification. A clinical toxicology calibrator is a device intended for medical purposes for use in a test system to establish points of reference that are used in the determination of values in the measurement of substances in human specimens. A clinical toxicology calibrator can be a mixture of drugs or a specific material for a particular drug (e.g., ethanol, lidocaine, etc.). (See also § 862.2 in this part.)(b)
Classification. Class II (special controls). 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.