(28 days)
COBAS INTEGRA Bilirubin Direct: The cassette COBAS INTEGRA Bilirubin Direct (BIL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA systems for the quantitative determination of the direct (conjugated) bilirubin concentration in serum and plasma (test BIL-D, 0-049).
COBAS INTEGRA Total Bilirubin Special: The COBAS INTEGRA Total Bilirubin Special (BILTS) cassette contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA systems for the quantitative determination of total bilirubin in serum and plasma of adults and neonates (test BILTS, 0-985).
Roche Hitachi Total Bilirubin Special: For the quantitative determination of total bilirubin in serum and plasma of adults and neonates on Roche/Hitachi automated clinical chemistry analyzers.
Measurement of the levels of bilirubin and organic compound formed during the normal and abnormal distruction of red cells, if used in the diagnosis of liver, hemolytic hemoatological, and metabolic disorders, including hepatitis and gall bladder block
The COBAS INTEGRA and Roche/Hitachi total or direct reagent is intended for use on the COBAS INTEGRA and Roche/Hitachi systems for the quantitative determination of total or direct bilirubin in serum and plasma.
The provided text describes modifications to existing Bilirubin test systems (COBAS INTEGRA Bilirubin Direct, COBAS INTEGRA Total Bilirubin Special, and Roche/Hitachi Total Bilirubin) and seeks substantial equivalence to their predicate devices. The document highlights changes in traceability, quantification of interference, reagent handling, pH values, lower detection limits, and recommended calibrators. It compares the modified devices to the predicate devices, showing similarities in intended use, specimen type, test principle, and some performance characteristics, while noting differences in reagent composition, traceability, and endogenous interferences.
Here's an analysis of the acceptance criteria and the study information, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" but rather presents a comparison of performance characteristics between the predicate and modified devices, implying that the modified device's performance aligns with or improves upon the predicate.
| Feature | Predicate Device Performance | Modified Device Performance |
|---|---|---|
| COBAS INTEGRA Bilirubin Direct | ||
| Lower detection limit | 3.1 x 10^-3^ $ΛA$ per mg/dL of direct bilirubin | 0.10 mg/dL (Note: The text states a change in stated lower detection limit from 0.81 umol/L to 1.7 umol/L previously, then lists 0.10 mg/dL here. This might be a unit conversion or a specific claim for the modified device based on new methodology rather than a direct comparison to the predicate's stated limit in the same unit.) |
| Measuring range | 0-20 mg/dL | 0.10-25 mg/dL |
| Traceability | Standardized against the manual test performance using the Jendrassic Grof method | Standardized against the Doumas reference method |
| Endogenous Interferences (Hemolysis) | Even slight hemolysis interferes with the test | No significant interference up to an H index of 10 |
| Endogenous Interferences (Lipemia) | Even slight lipemia interferes with the test | No significant interference up to an L index of 270 |
| Reagent R1 pH | 1.1 | 1.2 |
| COBAS INTEGRA Total Bilirubin Special & Roche/Hitachi Total Bilirubin | ||
| Precision (Device 3) | Within run: 0.4% @ 18.53 mg/dL, 2.8% @ 0.91mg/dL | |
| Between day: 2.5% @ 18.08 mg/dL, 4.9% @ 0.89 mg/dL | Within run: 0.81% @ 18.81 mg/dL, 3.1% @ 0.87 mg/dL | |
| Between day: 0.83% @ 15.41 mg/dL, 2.2% @ 0.86 mg/dL | ||
| Measuring range | Device 2: 0-25 mg/dL, 0-250 mg/dL (with post-dilution) | |
| Device 3: 0.1-35.0 mg/dL | Device 2: 0-25 mg/dL, 0-100 mg/dL (with post-dilution) | |
| Device 3: Same (0.1-35.0 mg/dL) | ||
| Endogenous Interferences (Lipemia - Device 2) | No significant interference up to 1800 mg/dL as Intralipid | No significant interference up to 1400 mg/dL as Intralipid |
2. Sample size used for the test set and the data provenance:
The document mentions "internal investigation and customer feedback" for the total bilirubin re-evaluation and "communicated to the customers via Reagent Bulletins" regarding shifts in direct bilirubin values. For the stated performance characteristics (e.g., precision, measuring range, interference), it lists numerical values, implying that experiments were conducted. However, the exact sample size used for the test set, or the data provenance (e.g., country of origin, retrospective or prospective nature of the data), is not explicitly stated within the provided text.
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 information is not provided in the document. The context is for in vitro diagnostic reagents, not image-based AI, so clinical expert review in the traditional sense might not apply. Instead, "ground truth" would relate to reference methods or comparative assays as described below.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:
This information is not provided in the document. Again, for a chemical assay, this type of adjudication process for a test set is not typically relevant.
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:
This is not applicable to the described device. The device is a bilirubin test system (chemical reagent), not an AI-assisted diagnostic tool for human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
This is not applicable to the described device. This device is a chemical assay, not an algorithm, and does not involve human-in-the-loop performance in the context of an AI-driven diagnosis.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The "ground truth" for the performance characteristics seems to be established through:
- Reference Methods:
- For COBAS INTEGRA Bilirubin Direct, traceability was changed to the Doumas reference method. The predicate was standardized against the Jendrassic Grof method.
- For COBAS INTEGRA Total Bilirubin Special and Roche/Hitachi Total Bilirubin, they are standardized against the Doumas reference method.
- Comparative Assays: Performance characteristics like precision, measuring range, and interference levels are determined by running the assay and comparing the results against established analytical methods and specifications.
- Internal Investigation and Re-evaluation: As stated for the Total Bilirubin, "Roche Diagnostics has re-evaluated the assignments for the Total Bilirubin assays and has adjusted the C.f.a.s calibrator setpoints for both methods... The results were verified by using US reference laboratory."
8. The sample size for the training set:
This information is not provided. As these are chemical reagents and not machine learning models in the usual sense, the concept of a "training set" with specific sample sizes for algorithm development is not directly applicable. The development and optimization of the reagents involve analytical studies and calibrations, not 'training' on a dataset in the AI context.
9. How the ground truth for the training set was established:
This information is not provided and is largely not applicable in the context of chemical reagent development as described. The "ground truth" for calibration and validation of the reagent system centers around established reference methods (like the Doumas method) and analytical performance testing, rather than a "training set" with independently established ground truth as would be used for AI/ML models. For the calibrators, "Roche Diagnostics has re-evaluated the assignments... and has adjusted the C.f.a.s calibrator setpoints for both methods... The results were verified by using US reference laboratory." This suggests reference laboratory analysis for calibrator value assignment.
§ 862.1110 Bilirubin (total or direct) test system.
(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.