(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.
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April 7, 2023
Roche Diagnostics Bin Sun Regulatory Affairs Program Manager 9115 Hague Road Indianapolis, IN 46250
Re: K220456
Trade/Device Name: Elecsys FT4 IV Regulation Number: 21 CFR 862.1695 Regulation Name: Free Thyroxine Test System Regulatory Class: Class II Product Code: CEC Dated: December 8, 2022 Received: December 9, 2022
Dear Bin Sun:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Digitally signed by Paula V. Paula V. Caposino -S Caposino -S Date: 2023.04.07
Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K220456
Device Name Elecsys FT4 IV
Indications for Use (Describe)
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.
Type of Use (Select one or both, as applicable):
| Prescription Use (Part 21 CFR 801 Subpart D) |
|---|
| Over-The-Counter Use (21 CFR 801 Subpart C) |
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K220456 Elecsys FT4 IV 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457 |
| Contact | Bin SunPhone: (317) 292-3781Email: bin.sun.bs2@roche.com |
| Date Prepared | April 6, 2023 |
| Proprietary Name | Elecsys FT4 IV |
| Common Name | Free thyroxine |
| Classification Name | Radioimmunoassay, Free thyroxine test system |
| Product Codes,Regulation Numbers | CEC, 21CFR862.1695 |
| Predicate Devices | Elecsys FT4 II (K131244) |
| Establishment Registration | Roche Diagnostics GmbH Mannheim, Germany: 9610126Roche Diagnostics GmbH Penzberg, Germany: 9610529Roche Diagnostics Indianapolis, IN United States: 1823260 |
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1. DEVICE DESCRIPTION
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.
1.1. Reagents
The reagent working solutions include:
Rackpack (kit placed on analyzer)
- M: Streptavidin-coated microparticles .
- . R1: Anti-T4-Ab~Ru(bpy)
- . R2: T4~biotin
INDICATIONS FOR USE 2.
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 immunoassay "ECLIA" is intended for use on the cobas e immunoassay analyzers.
TECHNOLOGICAL CHARACTERISTICS 3.
The following tables compare the Elecsys FT4 IV with its predicate device, Elecsys FT4 II assay (K131244).
| Item | Predicate(Elecsys FT4 II, K131244) | Candidate Device(Elecsys FT4 IV ) |
|---|---|---|
| Proprietary name | Elecsys FT4 II | Elecsys FT4 IV |
| Item | Predicate(Elecsys FT4 II, K131244) | Candidate Device(Elecsys FT4 IV ) |
| Indications for Use | The Elecsys FT4 II assay is for the invitro quantitative determination of freeThyroxine in human serum andplasma. Measurements obtained bythis device are used in the diagnosisand treatment of thyroid diseases.The electrochemiluminescenceimmunoassay "ECLIA" is intendedfor use on Elecsys and cobas eimmunoassay analyzers | The Elecsys FT4 IV assay is for the invitro quantitative determination of freeThyroxine in human serum andplasma. Measurements obtained bythis device are used in the diagnosisand treatment of thyroid disease.The electrochemiluminescenceimmunoassay “ECLIA" is intendedfor use on cobas e immunoassayanalyzers. |
| Test Principle | The Elecsys FT4 II assay is a two-stepcompetitive immunoassay withstreptavidin microparticles andelectrochemiluminescence detectionsystem. | No change |
| Technology | ECLIA | No change |
| Test format | Competitive | No change |
| Test type | Quantitative | No change |
| Application time | 18 min | No change |
| Assay protocol | 1st Incubation:R1+sample2nd incubation:Addition of R2 + streptavidin-coatedmicroparticles (beads) | No change |
| Sample type | Undiluted human serum and undilutedplasma treated with Li-heparin, K2-EDTA and K3-EDTA | No change |
| Pipetting volumesample | 15 μL | No change |
| Pipetting volume beads | 35 μL | No change |
| Pipetting volume R1 | 75 μL | No change |
| Pipetting volume R2 | 75 μL | No change |
| Handling of R1 and R2 | Liquid, ready to use | No change |
| Buffer composition R1 | phosphate buffer 100 mmol/L | No Change |
| - | Anti-Biotin Antibody; specific forfree, unconjugated biotin ("scavengerantibody"). MAKrK-21E12-IgG | |
| Antibodies used in R1 | Ruthenylated polyclonal T4-specificsheep antibody PABS-Fab-sRu | Ruthenylatedmonoclonal T4-specificrabbit antibody. MABrK-38F8-Fab-sRu |
| Buffer composition R2 | phosphate buffer 100 mmol/L | No Change |
| D-Biotin | N-Biotinylsarcosine (Biotin-derivate) | |
| Item | Predicate(Elecsys FT4 II, K131244) | Candidate Device(Elecsys FT4 IV ) |
| Biotinylated componentin R2 | T4(OSu)-bis-DADOO-Bi | No change |
| Biotin Tolerance | < 20 ng/mL | ≤ 1200 ng/mL |
| SA interferenceelimination | Yes | Improved, addition of Streptavidin rec.Mutein Polymer |
| Measuring range | 0.101-7.77 ng/dL (1.3-100 pmol/L) | No change |
| Analytical Sensitivity | Limit of Blank = 0.03 ng/dL (0.4pmol/L) | Limit of Blank = 0.02 ng/dL (0.3pmol/L) |
| Analytical Sensitivity | Limit of Detection = 0.05 ng/dL (0.6pmol/L) | Limit of Detection = 0.04 ng/dL (0.5pmol/L) |
| Analytical Sensitivity | Limit of Quantitation = 0.101 ng/dL(1.3 pmol/L) | Limit of Quantitation = 0.101 ng/dL(1.3 pmol/L) |
| Calibrators | FT4 II CalSet | CalSet FT4 IV |
| Control material | PreciControl Universal | No Change |
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4. NON-CLINICAL PERFORMANCE EVALUATION
Non-clinical performance evaluation for Elecsys FT4 IV executed with the study briefly summarized.
Precision 4.1.
Repeatability and Intermediate Precision 4.1.1.
Precision measurements were conducted for both 21 days and 5 days with the Elecsys FT4 IV assay to evaluate repeatability (within-run precision) and intermediate precision (withinlaboratory precision) according the CLSI guideline EP05-A3. All predefined acceptance criteria was met for the precision experiments. The results are summarized below:
| Repeatability | Intermediate precision | ||||
|---|---|---|---|---|---|
| Sample | Meanng/dL(pmol/L) | SDng/dL(pmol/L) | CV% | SDng/dL(pmol/L) | CV% |
| Human serum 1 | 0.124(1.59) | 0.003(0.040) | 2.5 | 0.007(0.089) | 5.6 |
| Human serum 2 | 0.515(6.63) | 0.006(0.071) | 1.1 | 0.012(0.153) | 2.3 |
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| Repeatability | Intermediate precision | ||||
|---|---|---|---|---|---|
| Sample | Meanng/dL(pmol/L) | SDng/dL(pmol/L) | CV% | SDng/dL(pmol/L) | CV% |
| Human serum 3 | 0.979(12.6) | 0.010(0.133) | 1.1 | 0.019(0.248) | 2.0 |
| Human serum 4 | 1.82(23.4) | 0.017(0.222) | 1.0 | 0.031(0.402) | 1.7 |
| Human serum 5 | 3.50(45.0) | 0.043(0.558) | 1.2 | 0.074(0.957) | 2.1 |
| Human serum 6 | 6.85(88.2) | 0.117(1.51) | 1.7 | 0.181(2.33) | 2.6 |
| PC) Universal 1 | 1.17(15.1) | 0.010(0.131) | 0.9 | 0.021(0.265) | 1.7 |
| PC Universal 2 | 3.09(39.8) | 0.037(0.482) | 1.2 | 0.064(0.824) | 2.1 |
Lot-to-lot reproducibility 4.1.2.
Lot-to-lot reproducibility was performed for the Elecsys FT4 IV assay using three reagent lots according the CLSI guideline EP05-A3. All predefined acceptance criteria was met for the lot-tolot reproducibility experiment.
Analytical Sensitivity 4.2.
4.2.1. Limit of Blank (LoB)
Experimental Design included three reagent lots evaluated on one cobas e 411 analyzer, six runs over three or more days with one blank sample with ten replicates per run. The zero-level (blank) sample used was fT4 depleted human serum sample pool. In total, 60 determinations for analyte free samples have been obtained. The LoB was calculated according to CLSI EP17-A2. The LoB claim in the labeling will be set to 0.02 ng/dL (0.3 pmol/L).
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Limit of Detection (LoD) 4.2.2.
Experimental Design included three reagent lots evaluated on one cobas e 411 analyzer, six runs over three or more days with five samples with two replicates/sample/run. The five samples were low-level human serum sample pools (diluted). A pooled estimate of the precision (SD total) for the 5 low-level samples was calculated. The LoD was calculated according to CLSI EP17-A2. The LoD claim in the labeling will be set to 0.04 ng/dL (0.5 pmol/L).
Limit of Quantitation (LoQ) 4.2.3.
The LoO is defined as the lowest concentration of analyte that can be reproducibly measured with an intermediate precision CV of no more than 20%. Experimental Design included three reagent lots evaluated on one cobas e 411 analyzer, one run per day over five days. Five replicates per each sample per run with at least five low level samples of serum and 25 replicates/sample/reagent lot. The LoQ was calculated according to CLSI EP17-A2. The LoQ claim in the labeling will be set to 0.101 ng/dL (1.3 pmol/L).
Linearity/Assay Reportable Range 4.3.
Linearity of the Elecsys FT4 IV assay was assessed using human serum samples on the cobas e 411 Immunoassay Analyzer according to CLSI EP6-Ed2.
The serum samples spiked by T4 (sample High) and diluted by fT4 depleted human serum (sample Blank) are used to prepare dilutions series. Three individual human serum samples with an analyte concentration above the upper limit of the measuring range and sample Blank with known of zero are mixed to prepare the dilution series. 13 concentrations (levels) cover the measuring range were prepared. The concentration ranges of the samples cover the entire measuring range of the assay. Samples were assayed in 4-fold determination within a single run. SD and CV were calculated for each 4-fold determination on 1 lot of reagent. The linearity data is analyzed using first-order Weight Least Squares regression (WLS) without intercept according to CLSI EP06-Ed2.
Linearity was confirmed in the range of 0.098-8.13 ng/dL (1.26-105 pmol/L), and a measuring range of 0.101-7.77 ng/dL (1.3-100 pmol/L) will be claimed in the labeling.
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4.4. Human Anti-Mouse Antibodies (HAMA)
Not Applicable (no mouse antibodies used)
Endogenous Interferences 4.5.
Nine endogenous substances were evaluated for potential interference with the Elecsys FT4 IV assay on the cobas e 411 analyzer according the CLSI guideline EP07-A3. All predefined acceptance criteria was met, and the proposed labeling claims for each endogenous substance can be found below:
| Compound | Concentration tested |
|---|---|
| Bilirubin | ≤ 701 µmol/L or ≤ 41 mg/dL |
| Hemoglobin | ≤ 0.621 mmol/L or ≤ 1000 mg/dL |
| Intralipid | ≤ 2000 mg/dL |
| Biotin | ≤ 4912 nmol/L or ≤ 1200 ng/mL |
| Rheumatoid factors | ≤ 1200 IU/mL |
| IgG | ≤ 7 g/dL |
| IgA | ≤ 1.6 g/dL |
| IgM | ≤ 1 g/dL |
| Albumin | ≤ 6.3 g/dL |
Analytical Specificity/Cross-Reactivity 4.6.
A cross-reactivity study was conducted with Elecsys FT4 IV on the cobas e 411 analyzer to evaluate the potential cross-reacting compounds using human serum samples (native human single donor sera). For each potential cross-reacting compound two human serum samples with a low (approximately 1.5 ng/dL or 19.4 pmol/L) and slightly elevated (approximately 5 ng/dL or 64.5 pmol/L) concentration level of FT4 were tested. The results are summarized below:
| Cross-reactant | Concentration testedng/dL | Cross-reactivity% |
|---|---|---|
| L-T3 | 50000 | 0.005 |
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| Cross-reactant | Concentration testedng/dL | Cross-reactivity% |
|---|---|---|
| D-T3 | 50000 | 0.003 |
| rT3 | 190000 | 0.002 |
| 3-iodo-L-tyrosine | 10000000 | 0.000 |
| 3,5-diiodo-L-tyrosine | 10000000 | 0.000 |
| 3,3',5-triiodothyroacetic acid | 100000 | 0.000 |
| 3,3',5,5'-tetraiodothyroacetic acid | 100000 | 0.003 |
Exogenous Interferences – Drugs 4.7.
An exogenous interference study was conducted to evaluate 17 commonly and 15 specially used pharmaceutical compounds for potential interference with the Elecsys FT4 IV assay on the cobas e 411 analyzer. No significant interference was found with the highest concentration tested listed in the table below:
| Common therapeutic drugs | Concentration tested |
|---|---|
| ug/mL | |
| Acetylcysteine | 150.0 |
| Ampicillin | 75.0 |
| Ascorbic Acid | 52.5 |
| Cyclosporine | 1.80 |
| Cefoxitin | 750 |
| Heparin | 3300 IU/L |
| ltraconazole | 15.0 |
| Levodopa | 7.50 |
| Methyldopa | 22.5 |
| Metronidazole | 123.0 |
| Phenylbutazone | 80.0 |
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| Common therapeutic drugs | Concentration testedμg/mL |
|---|---|
| Doxycycline | 18.0 |
| Acetylsalicylic Acid | 30.0 |
| Rifampicin | 48.0 |
| Acetaminophen | 156.0 |
| Ibuprofen | 109.0 |
| Theophylline | 60.0 |
The drugs Furosemide, Carbamazepine, Phenytoin and Levothyroxine Sodium (L-T4, synthetic levothyroxine) caused elevated FT4 findings at the daily therapeutic dosage level. For all other special thyroid drugs tested the specification was met as each compound was found to be noninterfering at the stated drug concentrations.
The results are summarized below:
| Drug | Concentration testedµg/mL |
|---|---|
| Carbimazole | 18 |
| Thiamazole | 80 |
| Propylthiouracil | 300 |
| Perchlorate | 600 |
| Propranolol | 120 |
| Amiodarone | 200 |
| Prednisolone | 100 |
| Hydrocortisone | 200 |
| Octreotide | 0.3 |
| Furosemide | 3.5 |
| Liothyronine | 0.02 |
| Potassium iodide (SSKI) | 150 |
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| Drug | Concentration testedμg/mL |
|---|---|
| Lithium | 540 |
| Phenytoin | 13.5 |
| Carbamazepine | 9 |
Sample Matrix Comparison 4.8.
The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys FT4 IV immunoassay was determined by comparing values obtained from samples (native single donors and pools as well as spiked or diluted samples) drawn into Serum, Li-Heparin, K2-and K3-EDTA plasma primary tubes. All predefined acceptance criteria was met, supporting the labeling claim that serum, Li-Heparin, K2-EDTA and K3-EDTA plasma are acceptable sample types.
Method Comparison to Predicate 4.9.
A method comparison was performed with the Elecsys FT4 II assay (predicate device) and the Elecsys FT4 IV assay, using a total of 121serum samples on the cobas e 411 analyzer using one lot of the Elecsys FT4 II assay and one lot of the FT4 IV assay covering the entire measuring range. The sample concentrations were between 0.13 and 7.68 ng/dL (1.65 and 98.8 pmol/L) for the reference method. The results can be found below (ng/dL):
Passing Bablok
y = 1.03x - 0.025
τ = 0.967
Linear regression
y = 1.04x - 0.034
r = 0.999
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4.10. Reagent Stability
To test reagent stability, two studies completed, including:
- Study 1: Reagent stability after first opening at 2-8°C (84 days) .
- Study 2: On board reagent stability (28 days) .
4.10.1. Reagent Stability After First Opening
Reagent stability after first opening for the Elecsys FT4 IV assay was tested on one cobas e 411 analyzer. Elecsys FT4 IV reagent kits can be used after first opening for up to 84 days when stored at 2-8°C.
4.10.2. Reagent On-board stability (28 days)
On-board reagent stability for the Elecsys FT4 IV assay was tested on one cobas e 411 analyzer. Elecsys FT4 IV reagent kits can be stored on-board the analyzers for up to 28 days (4 weeks).
4.11. Calibration Stability
To test calibration stability, two studies were completed, including:
- . Study 1. Lot calibration stability
- Study 2. On-board calibration stability .
4.11.1. Lot calibration study
Lot calibration frequency for the Elecsys FT4 IV assay was tested on one cobas e 411 analyzer. Calibrations of an Elecsys FT4 IV reagent lot is recommended every 28 days (1 month) when using the same reagent lot.
4.11.2. On-board Calibration Stability
Reagent on-board calibration frequency for Elecsys FT4 IV assay was tested on one cobas e 411 analyzer. Elecsys FT4 IV reagent kits can be stored on board of the analyzers for up to 7 days without a new calibration.
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EXTERNAL (CLINICAL) TESTING 5.
Not Applicable
CLINICAL PERFORMANCE EVALUATION 6.
Not Applicable
7. EXPECTED VALUES/REFERENCE RANGE
A Reference Range study was performed in order to determine the specific reference intervals for Elecsys FT4 IV on the cobas e 411 immunoassay analyzer from health donors in the United States under routine laboratory conditions according to CLSI EP28-A3c. Serum samples from apparently healthy donors in the United States were obtained from a commercial vendor according to the inclusion and exclusion criteria. One clinical laboratory was contracted to measure samples with Elecsys FT4 IV assay on the cobas e 411 analyzer.
The calculated 95% reference range corresponds to the 2.5th and 97.5th percentiles of results obtained from 150 apparently healthy subjects is 0.92 – 1.68 ng/dL (11.9 – 21.6 pmol/L). The results are summarized below:
| 2.5th percentile | 95 % Cl of the 2.5thpercentile | 97.5th percentile | 95 % Cl of the 97.5thpercentile | Unit |
|---|---|---|---|---|
| 0.92 | 0.81-0.96 | 1.68 | 1.51-2.00 | ng/dL |
| 11.9 | 10.4-12.3 | 21.6 | 19.4-25.8 | pmol/L |
ADDITIONAL INFORMATION 8.
The Elecsys FT4 IV is intended to be used with the following calibrators and controls:
- . FT4 IV CalSet
- PreciControl Universal ●
FT4 IV CalSet, product code JIS, is a Class II 510(k) Exempt device and therefore, is not included with this submission.
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PreciControl Universal, product code JJY, is a Class I 510(k) Exempt device and therefore, is not included with this submission.
9. CONCLUSIONS
The information provided in this 510(k) Premarket Notification supports the determination that the Elecsys FT4 IV assay is substantially equivalent to the predicate device, Elecsys FT4 II (K131244).
§ 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.