(69 days)
The ONLINE TDM Phenytoin - Free Phenytoin application is an in vitro test for the quantitative determination of free phenytoin in human serum and plasma on cobas c systems. The determination of free phenytoin is used in monitoring levels of free phenytoin to ensure appropriate therapy.
The ONLINE TDM Phenytoin - Free Phenytoin application is an in vitro test for the quantitative determination of free phenytoin in human serum and plasma on cobas c systems. The determination of free phenytoin is used in monitoring levels of free phenytoin to ensure appropriate therapy.
Prior to measurement using the ONLINE TDM Phenytoin - Free Phenytoin application, the sample is processed by ultrafiltration to remove the bound phenytoin generating a result for free phenytoin.
The ONLINE TDM Phenytoin - Free Phenytoin application is based on the kinetic interaction of microparticles in a solution (KIMS). Phenytoin antibody is covalently coupled to microparticles and the drug derivative is linked to a macromolecule. The kinetic interaction of microparticles in solutions, photometrically detected by turbidity measurements is induced by binding of drugconjugate to the antibody on the microparticles and is inhibited by the presence of phenytoin in the sample. A competitive reaction takes place between the drug conjugate and phenytoin in the serum sample for binding to the phenytoin antibody on the microparticles. The resulting turbidity is indirectly proportional to the amount of drug present in the sample.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Device Name: ONLINE TDM Phenytoin - Free Phenytoin application
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Characteristic | Acceptance Criteria (Stated or Implied) | Reported Device Performance |
|---|---|---|
| Precision | Implicit: Acceptable repeatability and intermediate precision, likely defined by a maximum allowable Coefficient of Variation (CV%) or Standard Deviation (SD) as per CLSI EP05-A3. (No specific numerical criteria for CV% or SD are explicitly stated as "acceptance criteria" in the text, but the claim "All acceptance criteria were met" implies adherence to predefined thresholds.) | Repeatability (CV%): |
- 2.2% - 2.9% for Control 1, Control 2, and Human Serums 1-5
Intermediate Precision (CV%): - 2.8% - 3.5% for Control 1, Control 2, and Human Serums 1-5 |
| Analytical Sensitivity | Implicit: LoB, LoD, and LoQ determined according to CLSI EP17-A2, and likely within a range consistent with the intended clinical use. (No specific numerical criteria are explicitly stated for these limits as "acceptance criteria"). | LoB: 0.100 µg/mL (0.396 µmol/L)
LoD: 0.200 µg/mL (0.792 µmol/L)
LoQ: 0.400 µg/mL (1.58 µmol/L) |
| Linearity/Reportable Range | Linearity confirmed for the measuring range of 0.400-4.00 µg/mL (1.58-15.8 µmol/L) per CLSI EP06-A-Ed2. | Confirmed for the measuring range of 0.400-4.00 µg/mL (1.58-15.8 µmol/L). |
| Dilution | Automatic rerun function (1:2 dilution) for samples above measuring range should demonstrate acceptable deviation. (Exact % deviation acceptance criteria not stated, but "All acceptance criteria were met" implies compliance). | Demonstrated % deviation results of -7.3% to -11.6% when using the automatic rerun function for samples above the measuring range. |
| Endogenous Interferences | No significant interference at specified concentrations for various endogenous substances (e.g., Hemolysis, Icterus, Triglycerides, Albumin, Total protein, Rheumatoid factors, Immunoglobulin G). (Specific acceptance criteria for "no interference up to" certain levels are explicitly stated in the claims summary, e.g., H index of 1000 for Hemolysis). | All predefined acceptance criteria were met. Specific claims are: - Hemolysis: No interference up to H index of 1000
- Icterus: I index of 60 for conjugated bilirubin
- Triglycerides: 700 mg/dL
- Albumin: 60 g/L
- Total protein: between 2-12 g/dL
- Rheumatoid factors: 1200 IU/mL
- Lipemia: L index of 1000
- Immunoglobulin G: 60 g/L
– No significant phenytoin release for conjugated bilirubin up to 18 mg/dL, unconjugated bilirubin up to 9 mg/dL, triglycerides up to 183 mg/dL, and rheumatoid factors up to 284 IU/mL. |
| Analytical Specificity/Cross-Reactivity | Acceptable cross-reactivity for tested compounds (e.g., Fosphenytoin ≤ 50.0 %, m-HPPH ≤ 10.0 %). (Specific numerical criteria for % Cross Reactivity are explicitly stated in the table). | All acceptance criteria for cross-reactivity were met. Specific values reported: - Fosphenytoin: ≤ 50.0 %
- m-HPPH: ≤ 10.0 %
- p-HPPH: ≤ 5.0 %
- 5(p-methylphenyl)-5-phenylhydantoin: ≤ 5.0 % |
| Exogenous Interferences (Drugs) | No increase in free phenytoin concentrations at tested concentrations for commonly used pharmaceuticals, or expected increases for drugs that compete for albumin binding (e.g., Valproic acid).
For phenobarbital and mephenytoin, analytical interference starts above specific concentrations (e.g., >90 µg/mL for phenobarbital in ultrafiltrate). | No increase in free phenytoin concentrations observed for a long list of tested drugs.
Increased concentrations observed for Butabarbital, Carbamazepine, Cefoxitin, Ethotoin, p-Hydroxyphenobarbital, Ibuprofen, Oxaprozine, Phenylbutazone, d-Propoxyphene, and Valproic acid when spiked into serum (due to competition for albumin binding). These did not show analytical interference in ultrafiltrate.
Phenobarbital and Mephenytoin showed significant increase above 34.5 µg/mL and 40.0 µg/mL respectively in serum, and analytical interference above 90 µg/mL (phenobarbital) and 60 µg/mL (mephenytoin) in ultrafiltrate. |
| Sample Matrix Comparison | Acceptable correlation/agreement between serum and various plasma types (Li-Heparin, K2-EDTA, K3-EDTA plasma). (No specific numerical criteria for slope, intercept, or correlation coefficient are stated as "acceptance criteria"). | All predefined acceptance criteria were met. - Serum vs. Li-Heparin plasma: Slope 1.018, Intercept -0.0149, r 0.988
- Serum vs. K2-EDTA plasma: Slope 0.923, Intercept -0.0328, r 0.992
- Serum vs. K3-EDTA plasma: Slope 0.950, Intercept -0.0282, r 0.992 |
| Method Comparison | Acceptable agreement with the predicate device (Phenytoin - Free Phenytoin Application on COBAS INTEGRA 400 plus). (No specific numerical criteria for Passing/Bablok or Deming regression parameters are stated as "acceptance criteria"). | Passing/Bablok: y = 1.035x - 0.0165 µg/mL, τ = 0.972
Deming Regression: y = 1.019x + 0.0107 µg/mL, r = 0.998 |
| Stability | Implicit: Data supports Roche Diagnostic's claims as reported in the package labeling. (No specific criteria are detailed in this section.) | Stability data supports claims as reported in package labeling. |
2. Sample Size Used for the Test Set and Data Provenance
- Precision (Repeatability and Intermediate Precision):
- Repeatability: n = 84 (implied total measurements, as 2 aliquots per run, 2 runs per day, 21 days = 84 measurements for intermediate precision, and repeatability likely collected within this structure).
- Intermediate Precision: 2 aliquots per run, 2 runs per day, 21 days.
- Data Provenance: Not explicitly stated, implied to be laboratory-prepared controls and human serum samples.
- Analytical Sensitivity (LoB, LoD, LoQ):
- LoB: One analyte-free sample (ultrafiltrate of human phenytoin-free serum) measured with three reagent lots in 6 runs, each with 10-fold determination (total 180 measurements).
- LoD: 5 serum samples with low analyte concentrations (spiked with phenytoin and ultrafiltrated) measured on three reagent lots with 2-fold determination per run, over 6 runs (total 180 measurements).
- LoQ: 6 serum samples (spiked with phenytoin and ultrafiltrated) measured with three reagent lots, 5 replicates per run, over 5 days (total 450 measurements).
- Data Provenance: Human phenytoin-free serum, spiked human serum samples (ultrafiltrated).
- Linearity/Assay Reportable Range:
- Sample Size: A dilution series ( > 9 levels) prepared from a spiked human ultrafiltrated serum pool and a negative ultrafiltrated serum pool. Tested with 3 reagent lots and 4 replicates per sample. The process was repeated with K3-EDTA plasma.
- Data Provenance: Spiked human ultrafiltrated serum pool and negative ultrafiltrated serum pool, K3-EDTA plasma.
- Dilution:
- Sample Size: Three ultrafiltrates prepared with specific phenytoin concentrations (5.00, 6.00, 7.00 µg/mL).
- Data Provenance: Laboratory-prepared ultrafiltrates with spiked phenytoin.
- Endogenous Interferences:
- Sample Size: Not explicitly stated, but various endogenous substances were evaluated. The description suggests samples were prepared by adding interferents to ultrafiltrate or present in the sample before ultrafiltration.
- Data Provenance: Laboratory-prepared samples with added endogenous substances or naturally occurring levels.
- Analytical Specificity/Cross-Reactivity:
- Sample Size: Two ultrafiltrated human serum pools spiked with phenytoin (1.00 and 2.50 µg/mL) for each potential cross-reacting compound. Phenytoin concentration determined in at least 5-fold determination.
- Data Provenance: Ultrafiltrated human serum pools spiked with phenytoin and cross-reactants.
- Exogenous Interferences - Drugs:
- Sample Size: Not explicitly stated, but drugs were tested individually at specified concentrations. Some drugs were tested by spiking into serum, others into ultrafiltrate.
- Data Provenance: Laboratory-prepared samples with added drugs.
- Sample Matrix Comparison:
- Sample Size: ≥ 50 samples comparing serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma.
- Data Provenance: Native human samples collected in different tube types, spiked and ultrafiltrated.
- Method Comparison:
- Sample Size: 138 native human ultrafiltrated serum samples (≤10% spiked).
- Data Provenance: Native human ultrafiltrated serum samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
This device is an in vitro diagnostic (IVD) test system for the quantitative determination of free phenytoin. The "ground truth" for such a device is typically established by reference methods or established analytical techniques, often involving highly skilled laboratory personnel operating calibrated equipment, rather than clinical experts (like radiologists).
The text does not mention the use of clinical experts (e.g., radiologists) or their qualifications to establish ground truth. The methodologies like CLSI guidelines (EP05-A3, EP17-A2, EP06-A-Ed2) imply adherence to established laboratory standards and practices for analytical validation, often performed by trained laboratory scientists or technicians.
4. Adjudication Method for the Test Set
This type of analytical device validation does not typically involve an "adjudication method" in the way it's understood for image-based diagnostics (e.g., 2+1, 3+1 consensus among radiologists). Results are quantitative and are compared directly to expected values, reference methods, or statistical acceptance criteria.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done. MRMC studies are relevant for AI-powered diagnostic devices where human readers interpret images or data, and the study assesses how AI assistance impacts their performance. This submission is for an in vitro diagnostic (IVD) laboratory test system, not an image-interpretation AI device.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
This device is a standalone in vitro diagnostic test system. Its performance characteristics (precision, sensitivity, linearity, interference, etc.) are evaluated directly as the device itself operates. There isn't a separate "human-in-the-loop performance" concept for this type of quantitative assay, as the device provides a direct numerical result. The reported performance is the standalone performance of the ONLINE TDM Phenytoin - Free Phenytoin application on cobas c systems.
7. The Type of Ground Truth Used
The ground truth for the analytical performance studies primarily relied on:
- Reference Materials: Calibrators (Preciset TDM I), Controls (TDM Control Set), and laboratory-prepared samples with known concentrations of phenytoin and/or interferents (e.g., spiked serum, ultrafiltrates).
- Established Methods: Comparison to a predicate device (Phenytoin - Free Phenytoin Application on COBAS INTEGRA 400 plus) in the method comparison study.
- Theoretical Standards: Adherence to CLSI (Clinical and Laboratory Standards Institute) guidelines (EP05-A3, EP17-A2, EP06-A-Ed2) for defining analytical limits and linearity.
There is no mention of pathology, outcomes data, or expert consensus in the clinical sense for establishing ground truth for this analytical performance.
8. The Sample Size for the Training Set
The document does not describe a "training set" as would be relevant for a machine learning or AI-based device. This device is a chemical assay (Kinetic Interaction of Microparticles in a Solution - KIMS). The development of the assay itself would involve optimization and calibration phases, but these are not referred to as statistical "training sets" in the context of general device validation.
9. How the Ground Truth for the Training Set Was Established
Since there is no "training set" described in the context of an AI/ML algorithm, this question is not applicable. The assay's performance is driven by its chemical and optical principles, not by learning from a labeled dataset. The "ground truth" during assay development would be established through careful analytical chemistry techniques to ensure the reagents and measurement system accurately quantify free phenytoin.
§ 862.3350 Diphenylhydantoin test system.
(a)
Identification. A diphenylhydantoin test system is a device intended to measure diphenylhydantoin, an antiepileptic drug, in human specimens. Measurements obtained by this device are used in the diagnosis and treatment of diphenylhydantoin overdose and in monitoring levels of diphenylhydantoin to ensure appropriate therapy.(b)
Classification. Class II.