(414 days)
Assay for the in vitro quantitative determination of free thyroxine in human serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of thyroid disease.
The electrochemiluminescence immunoasay "ECLIA" is intended for use on the cobas e immunoassay analyzers.
The Elecsys FT4 IV immunoassay a fourth generation FT4 assay by Roche Diagnostics for the for the in vitro quantitative determination of free thyroxine in human serum and plasma. It is intended for use on the cobas e immunoassay analyzers. The cobas e family of analyzers uses electrochemiluminescence immunoassay "ECLIA" technology. The assay is an 18 minute assay utilizing a competition principle using a monoclonal antibody which is specifically directed against free thyroxine. Results are determined via a calibration curve which is instrument specifically generated by 2-point calibration against the master curve for that reagent lot.
Here's a breakdown of the acceptance criteria and the study information for the Elecsys FT4 IV device, based on the provided text:
Device: Elecsys FT4 IV (Free Thyroxine Test System)
Predicate Device: Elecsys FT4 II (K131244)
Intended Use: In vitro quantitative determination of free thyroxine in human serum and plasma for the diagnosis and treatment of thyroid disease, intended for use on cobas e immunoassay analyzers.
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state acceptance criteria in a dedicated section with specific numerical targets for each performance characteristic. Instead, it generally states that "All predefined acceptance criteria was met" for various studies. The reported device performance is presented as the results obtained from these studies.
| Performance Characteristic | Reported Device Performance (Elecsys FT4 IV) | Acceptance Criteria (Implicitly Met) |
|---|---|---|
| Precision | "All predefined acceptance criteria was met" (CLSI guideline EP05-A3) | |
| - Repeatability (CV%) | Ranges from 0.9% to 2.5% | Implicitly met for various sample levels |
| - Intermediate Precision (CV%) | Ranges from 1.7% to 5.6% | Implicitly met for various sample levels |
| Lot-to-lot Reproducibility | Not explicitly stated, but "All predefined acceptance criteria was met" | Implicitly met (CLSI guideline EP05-A3) |
| Analytical Sensitivity | "All predefined acceptance criteria was met" (CLSI EP17-A2) | |
| - Limit of Blank (LoB) | 0.02 ng/dL (0.3 pmol/L) | Implicitly met, this is the derived claim |
| - Limit of Detection (LoD) | 0.04 ng/dL (0.5 pmol/L) | Implicitly met, this is the derived claim |
| - Limit of Quantitation (LoQ) | 0.101 ng/dL (1.3 pmol/L) at ≤ 20% intermediate precision CV | Implicitly met, this is the derived claim |
| Linearity/Assay Reportable Range | Linear in range 0.098-8.13 ng/dL (1.26-105 pmol/L) | Implicitly met (CLSI EP6-Ed2) |
| - Measuring Range Claim | 0.101-7.77 ng/dL (1.3-100 pmol/L) | Implicitly met based on linearity study |
| Human Anti-Mouse Antibodies (HAMA) | Not Applicable (No mouse antibodies used) | N/A |
| Endogenous Interferences | No significant interference for tested compounds (e.g., Bilirubin ≤ 701 µmol/L, Biotin ≤ 1200 ng/mL) | "All predefined acceptance criteria was met" (CLSI guideline EP07-A3) |
| Analytical Specificity/Cross-Reactivity | Low cross-reactivity for tested compounds (e.g., L-T3 0.005%, D-T3 0.003%, rT3 0.002%) | Implicitly met |
| Exogenous Interferences (Drugs) | No significant interference for most common therapeutic drugs, specific drugs like Furosemide, Carbamazepine, Phenytoin, and Levothyroxine Sodium (L-T4) caused elevated FT4 findings at daily therapeutic dosage levels. | Implicitly met for non-interfering drugs; specific findings reported for interfering drugs. |
| Sample Matrix Comparison | Serum, Li-Heparin, K2-EDTA, K3-EDTA plasma are acceptable sample types | "All predefined acceptance criteria was met" |
| Method Comparison to Predicate | Passing Bablok: y = 1.03x - 0.025, τ = 0.967; Linear Regression: y = 1.04x - 0.034, r = 0.999 | Implicitly demonstrates substantial equivalence to predicate |
| Reagent Stability After First Opening | Up to 84 days when stored at 2-8°C | Implicitly met |
| Reagent On-board Stability | Up to 28 days | Implicitly met |
| Lot Calibration Stability | Recommended every 28 days | Implicitly met |
| On-board Calibration Stability | Up to 7 days without new calibration | Implicitly met |
| Expected Values/Reference Range | 0.92 – 1.68 ng/dL (11.9 – 21.6 pmol/L) (95% CI of 2.5th: 0.81-0.96 ng/dL; 95% CI of 97.5th: 1.51-2.00 ng/dL) | Established from 150 healthy subjects in the United States |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision (Repeatability and Intermediate Precision): Not explicitly stated how many individual samples were used, but multiple human serum samples (6 levels) and PreciControl Universal (2 levels) were tested. Repeatability involved measurements over 21 days and 5 days, and intermediate precision over the same periods.
- Analytical Sensitivity (LoB, LoD, LoQ):
- LoB: One blank sample (fT4 depleted human serum pool) with ten replicates per run, across six runs over three or more days, evaluated on three reagent lots. Total 60 determinations.
- LoD: Five low-level human serum sample pools (diluted) with two replicates/sample/run, across six runs over three or more days, evaluated on three reagent lots.
- LoQ: At least five low-level samples of serum, with five replicates per sample per run, over five days (total 25 replicates/sample/reagent lot), evaluated on three reagent lots.
- Linearity/Assay Reportable Range: Three individual human serum samples (spiked and diluted) to prepare dilution series. 13 concentrations (levels) prepared. Samples assayed in 4-fold determination within a single run.
- Endogenous Interferences: Nine endogenous substances evaluated. The number of samples for each is not specified, but typically involves spiked samples.
- Analytical Specificity/Cross-Reactivity: For each potential cross-reacting compound, two human serum samples (low and slightly elevated FT4 levels) were tested.
- Exogenous Interferences (Drugs): 17 commonly and 15 specially used pharmaceutical compounds evaluated.
- Sample Matrix Comparison: Samples (native single donors and pools, spiked or diluted) drawn into Serum, Li-Heparin, K2-and K3-EDTA plasma primary tubes. Number of samples not specified.
- Method Comparison to Predicate: 121 serum samples.
- Expected Values/Reference Range: 150 apparently healthy subjects.
Data Provenance:
- For the Expected Values/Reference Range study, serum samples were obtained from a "commercial vendor" and collected from "health donors in the United States."
- Other studies generally refer to "human serum" or "human serum samples," implying samples of human origin, but specific countries or retrospective/prospective nature are not typically detailed for non-clinical analytical performance studies unless relevant regulations require it. However, given the context of an IVD, these are typically laboratory-based studies using banked or ethically sourced human samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document describes the analytical performance of an in vitro diagnostic (IVD) device. For IVDs measuring biomarkers, "ground truth" is typically established by existing reference methods, certified reference materials, or by the analytical properties of the substance itself (e.g., purified analytes for spiking studies).
- No human experts are explicitly mentioned for establishing ground truth in the context of diagnostic accuracy for the Elecsys FT4 IV performance studies.
- The ground truth for FT4 concentration in samples used for studies like linearity or precision is based on the expected concentration determined by established laboratory practices, dilutions, spiking with known amounts of analyte, or values obtained from a reference method (in the case of method comparison).
- For the Reference Range study, classification as "apparently healthy subjects" serves as a form of ground truth for establishing normal ranges, likely based on medical history or screening criteria provided by the commercial vendor.
4. Adjudication Method for the Test Set
Not applicable. This is an IVD device measuring a quantitative biomarker (free thyroxine). The performance evaluation involves analytical studies (precision, sensitivity, linearity, interference, method comparison) against established analytical standards or a predicate device, not subjective interpretation requiring adjudication by multiple readers or experts.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No. MRMC studies are typically performed for imaging devices or devices that involve human interpretation of results. This is an IVD that quantitatively measures a biomarker on an automated analyzer. The device produces a numerical result, and there is no "human reader" in the loop for interpreting device output in a way that would necessitate an MRMC study for comparative effectiveness.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, this is implicitly a standalone study for the device. The entire non-clinical performance evaluation (Sections 4.1 to 4.11) describes the performance of the Elecsys FT4 IV assay itself, as an automated system on the cobas e immunoassay analyzers. It evaluates the device's accuracy, precision, sensitivity, and resistance to interference independently of human interpretation of the final numerical result. The output (a quantitative FT4 value) is what clinicians interpret in the context of a patient's condition.
7. The Type of Ground Truth Used
The ground truth used for these analytical studies primarily consists of:
- Reference Standards/Known Concentrations: For studies like linearity, analytical sensitivity (LoB, LoD, LoQ), and interference, samples are often prepared with known concentrations of the analyte or interfering substances.
- Comparative Reference Method: For the method comparison study, the predicate device (Elecsys FT4 II) served as the reference for comparison.
- Absence of Analyte: For LoB determination, "fT4 depleted human serum sample pool" was used.
- Clinically Defined Status: For the reference range study, samples from "apparently healthy donors" were used to establish normal values, which serves as a clinical ground truth for a non-diseased population.
8. The Sample Size for the Training Set
The document describes an analytical device and its performance verification, not a machine learning or AI algorithm in the traditional sense that requires a "training set" for model development.
- The Elecsys FT4 IV assay is an ECLIA (Electrochemiluminescence Immunoassay), which is a chemical reaction-based detection system, not a software algorithm that learns from data like an AI model.
- Therefore, the concept of a "training set" in the context of AI/ML is not directly applicable here. The device's calibration curve is generated using calibrators ("CalSet FT4 IV") against a master curve for each reagent lot, which is a standard procedure for IVDs, not an AI training process.
9. How the Ground Truth for the Training Set Was Established
As explained in point 8, the concept of a "training set" for an AI/ML model is not applicable to an immunoassay device like the Elecsys FT4 IV.
The "ground truth" for the device's operational parameters (like its calibration curve) is established through:
- Reference materials/calibrators: The device uses specific "CalSet FT4 IV" calibrators. These calibrators have assigned values traceable to reference methods or primary standards, which serve as the "ground truth" for calibrating the device for quantitative measurements.
- Master curve: The instrument-specific calibration curve is generated by 2-point calibration against a master curve for that reagent lot. The master curve itself is derived from extensive characterization of a reagent lot using precisely known reference materials across the measuring range.
§ 862.1695 Free thyroxine test system.
(a)
Identification. A free thyroxine test system is a device intended to measure free (not protein bound) thyroxine (thyroid hormone) in serum or plasma. Levels of free thyroxine in plasma are thought to reflect the amount of thyroxine hormone available to the cells and may therefore determine the clinical metabolic status of thyroxine. Measurements obtained by this device are used in the diagnosis and treatment of thyroid diseases.(b)
Classification. Class II.