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 411 immunoassay analyzer.

Device Description

The Elecsys FT4 III immunoassay is used for the in vitro quantitative determination of free thyroxine in human serum and plasma. It is intended for use on the cobas e 411 immunoassay analyzer. The cobas e family of analyzers uses electrochemiluminescence immunoassay "ECLIA" technology. The reagent working solutions include: Rackpack (kit placed on analyzer) M: Streptavidin-coated microparticles. R1: Anti-T4-Ab~~biotin. R2: Anti-T4-Ab~~Ru(bpy).

AI/ML Overview

This document describes the premarket notification for the Elecsys FT4 III device, an immunoassay for the quantitative determination of free thyroxine. The submission details the non-clinical performance evaluation of the device as it relates to its substantial equivalence to a predicate device.

Here's an analysis of the provided information regarding acceptance criteria and supporting studies:

1. Table of Acceptance Criteria and Reported Device Performance

The document provides a comparative assay table between the Elecsys FT4 II (predicate device) and Elecsys FT4 III (candidate device), and also presents detailed studies for various performance characteristics. I will synthesize the acceptance criteria (often implied by the "same" or within a stated range compared to the predicate, or by specific criteria in the study descriptions) and the reported performance as presented in the document.

Feature	Acceptance Criteria (Implied/Stated)	Reported Device Performance (Elecsys FT4 III)
Intended Use	Same as predicate.	"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 411 immunoassay analyzer." (Matches predicate, with specified analyzer).
Detection Method	Same as predicate.	Same: Electrochemiluminescent Assay.
Applications/Test Time	Same as predicate.	Same: 18 minute application.
Sample/Reagent Ratio	Same as predicate.	Same: 15 µL.
Sample Type/Matrix	Same as predicate.	Same: Serum and plasma (Li-heparin, K2-EDTA, K3-EDTA).
Calibration Method	Same as predicate.	Same: 2-point calibration.
Calibration Interval	Same as predicate.	Same: Once per reagent lot (renewed after 1 month/28 days when using same lot, after 7 days using same kit, or as required by QC).
Controls	Same as predicate.	Same: PreciControl Universal.
Reagent Stability	Same as predicate: Unopened up to expiration date; After opening at 2-8°C, 84 days (12 weeks); On the analyzers, 28 days (4 weeks); or 56 days (8 weeks) with alternative storage, total onboard not exceeding 120 hours.	Studies executed to support these claims. Study 1: "Reagent stability after first opening at 2-8°C (84 days)"; Study 2: "On board reagent stability (28 days)"; Study 3: "Alternate storage in the refrigerator / on the analyzer (56 days, not exceeding 120 hours onboard)". Real-time stability study ongoing for shelf-life claim. Performance for early time-points supports stability.
Measuring Range	Same as predicate.	Same: 0.101-7.77 ng/dL (1.3-100 pmol/L).
LoB (Limit of Blank)	Values within acceptable limits compared to predicate (predicate: 0.03 ng/dL).	Reported: 0.02 ng/dL (0.3 pmol/L). (Better than predicate).
LoD (Limit of Detection)	Values within acceptable limits compared to predicate (predicate: 0.05 ng/dL).	Reported: 0.04 ng/dL (0.5 pmol/L). (Better than predicate).
LoO (Limit of Quantitation)	Same as predicate.	Same: 0.101 ng/dL (1.3 pmol/L).
Analytical Specificity(Cross-reactivity)	Cross-reactivity percentages for various substances should be comparable to or better than the predicate.	The reported cross-reactivity percentages for Elecsys FT4 III are identical to those of the predicate device for L-T3, D-T3, rT3, 3-iodo-L-tyrosine, 3,5-diiodo-L-tyrosine, 3,3',5-triiodothyracetic acid, and 3,3',5,5'-tetraiodothyroacetic acid, at similar tested concentrations.
Endogenous Interferences	Criterion: Recovery of ≤ ± 0.6 pmol/L of initial value ≤ 6 pmol/L and ± 10 % of initial value > 6 pmol/L for Bilirubin, Hemoglobin, Intralipid, Rheumatoid factors, IgG, IgA, IgM. Biotin interference should be improved compared to the predicate, with a specific threshold.	Bilirubin: ≤ 701 µmol/L or ≤ 41 mg/dL; Hemoglobin: ≤ 0.621 mmol/L or ≤ 1000 mg/dL; Intralipid: ≤ 2000 mg/dL; Rheumatoid factors: ≤ 1200 IU/mL; IgG: ≤ 7 g/dL; IgA: ≤ 1.6 g/dL; IgM: ≤ 1 g/dL. Biotin Interference: Specimens with biotin concentrations up to 104 ng/mL demonstrated ≤ 10% bias. Biotin concentrations > 104 ng/mL can lead to higher positive bias. This is an improvement from predicate's limitation of "> 5 mg/day" and "until at least 8 hours following the last biotin administration". The new device quantifies the effect and states "Do not test samples from patients who take biotin."
Special Thyroid Drugs	No interference with the assay found for specified drugs at given concentrations. Criterion: Recovery within ± 10 % of initial value.	No interference was found for Iodide, Carbimazole, Thiamazole, Propylthiouracil, Perchlorate, Propranolol, Amiodarone, Prednisolone, Hydrocortisone, Flurocortolone, Octreotide at the specified concentrations. (These are the same drugs and concentrations as the predicate, and "no interference" finding is consistent).
Precision	Meeting CLSI guideline EP05-A3 for repeatability and intermediate precision.	Precision was evaluated on a single cobas e 411 analyzer according to CLSI guideline EP05-A3. Results supporting this are expected to be presented in the full study report (not explicitly tabularized here, but stated that it was evaluated).
Sample Matrix Comparison	Acceptable comparison values between serum and various plasma types.	Comparison study performed between Serum, K2-EDTA plasma, and K3-EDTA plasma. Findings indicate acceptable performance, as it is presented as a completed study without issues.
Method Comparison to Predicate	"Assess the bias" between the two assays. Substantial equivalence to predicate expected.	141 serum samples were measured. FT4 values ranged between 2.31 and 91.9 pmol/L for the Reference Method (X). The study aims to support substantial equivalence. (Specific statistics on bias are not provided in this summary, but the study execution implies findings were acceptable).
Lot Calibration Stability	Calibration of a reagent lot is recommended every 28 days (4 weeks), and fresh reagent kits of the same lot can use the Day 0 calibration curve within this period. Recovery of samples within acceptable limits after 36 days using a new kit of the same lot with Day 0 calibration curve.	Elecsys FT4 III was calibrated with a fresh reagent kit on day 0. After 36 days a new reagent kit of the same lot was used and recovery of samples was determined using the calibration curve of day 0. (The study implies acceptable recovery, as "Lot calibration study" is listed as successfully completed).
On-board Cal Stability	Reagent kits can be stored on board for up to 7 days without a new calibration.	Samples measured on Day 0 and Day 8 (on-board condition) using the Day 0 calibration curve. (The study implies acceptable results, as "On-board Calibration Stability" is listed as successfully completed).

2. Sample Size Used for the Test Set and the Data Provenance

Precision (Repeatability and Intermediate Precision):
- Sample Size: Two levels of control (PreciControl Universal) and five human sera (native single donors, native serum pools, spiked serum pools). Tested in 2 replicates per run, 2 runs per day for 21 days.
- Data Provenance: Not explicitly stated, but "human sera" and "single donors" suggest human samples, likely retrospective pools or prospectively collected for the study. No country of origin mentioned.
Endogenous Interferences (Biotin):
- Sample Size: Three human serum samples containing low, mid, and high concentrations of fT4, tested in accordance with CLSI EP07-A2.
- Data Provenance: Human serum samples (single donors, native as well as spiked).
Sample Matrix Comparison:
- Sample Size: 53 serum/plasma pairs per sample material (serum, K2-EDTA plasma, K3-EDTA plasma).
- Data Provenance: Native single donors and pools, as well as spiked samples; human.
Method Comparison to Predicate:
- Sample Size: 141 serum samples (138 native human serum samples and 3 spiked sample pools).
- Data Provenance: Human serum samples.
Reagent Stability (After First Opening, On-board, Alternate Storage):
- Sample Size: Six human serum (HS) samples (native single donor serum, native serum pools, and spiked serum pools) and two controls (PreciControl Universal). Tested in duplicate (for "first opening" and "alternate storage") or two-fold determination (for "on-board").
- Data Provenance: Human serum samples.
Reagent Real-time Stability:
- Sample Size: Three human serum samples.
- Data Provenance: Human serum samples (stored at -20°C).
Calibration Stability (Lot and On-board):
- Sample Size: Five human serum (HS) samples (single donor serum, native serum pools, and spiked serum pools) and two controls (PreciControl Universal). Tested in two-fold determination.
- Data Provenance: Human serum samples.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts

This document describes the performance evaluation of an in vitro diagnostic (IVD) device, specifically an immunoassay for free thyroxine. For such devices, "ground truth" is typically established by reference methods, consensus values for control materials, or by testing against well-characterized clinical samples in comparison to an established predicate device. It is not generally established by a panel of human experts reviewing individual cases in the same way an imaging AI algorithm might be.

Therefore, the concept of "number of experts used to establish the ground truth" as it applies to imaging or clinical decision support AI is not applicable here. The ground truth for these types of studies is based on biochemical measurements and analytical comparisons.

4. Adjudication Method for the Test Set

Again, for an IVD device evaluating a biomarker, traditional "adjudication" by human experts in the context of clinical interpretation of individual cases (e.g., 2+1, 3+1 for discordances in imaging) is not applicable. The performance is adjudicated against analytical measurements and statistical criteria defined in CLSI guidelines and internal validation plans.

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 an in vitro diagnostic device (immunoassay), not an AI-powered clinical decision support or imaging interpretation tool that "assists human readers." Therefore, no MRMC study with human readers improving with AI assistance would be performed.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

The Elecsys FT4 III is an automated immunoassay intended for use on the cobas e 411 analyzer. Its performance is inherently "standalone" in the sense that the analyzer and reagents perform the measurement autonomously. A human laboratory professional loads samples and reagents, and reviews the results. The studies described (precision, interference, method comparison) are all evaluating the standalone analytical performance of this device.

Therefore, yes, the studies described inherently evaluate the "standalone" performance of the algorithm/device system in quantifying free thyroxine in samples.

7. The Type of Ground Truth Used

The ground truth for the various studies is established through:

Reference methods / Predicate Device: For method comparison, the Elecsys FT4 II assay (K131244) served as the reference method ("X").
Known concentrations: For interference studies (e.g., biotin, cross-reactivity), samples were spiked with known concentrations of interfering substances or analytes.
Industry Standards / Guidelines: Adherence to CLSI guidelines (e.g., EP05-A3 for precision, EP07-A2 for interferences) implies that the ground truth for acceptability criteria is based on established laboratory practice and industry consensus for robust analytical performance.
Controls and Calibrators: PreciControl Universal and CalSet FT4 III are used, which have established target values and ranges for quality control and calibration, respectively.

8. The Sample Size for the Training Set

This document describes the performance validation of a commercially manufactured in vitro diagnostic device, not the development of a machine learning algorithm. Therefore, the concept of a "training set" in the context of AI model development is not directly applicable here.

The device's underlying principles are based on established electrochemiluminescence immunoassay (ECLIA) technology and biochemically derived reagent formulations. While there is a development process that optimizes reagents and assay parameters, this is not typically referred to as "training" in the AI sense, nor does the document provide details about such a "training set" if it were analogous.

9. How the Ground Truth for the Training Set Was Established

Given that "training set" as understood in AI/ML model development is not directly applicable to this IVD device's validation data, this question is not applicable in the context of the provided document. The "ground truth" for the device's development (the underlying chemical and physical principles on which it operates) would have been established through extensive biochemical research, assay development, and optimization processes, rather than a discrete "training set" with established ground truth labels in the AI sense.

Summary

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo in blue. Underneath the FDA logo is the text "ADMINISTRATION".

September 18, 2018

Roche Diagnostics Reanna Toney Principal, Regulatory Affairs 9115 Hague Road Indianapolis, IN 46250

Re: K181233

Trade/Device Name: Elecsvs FT4 III Regulation Number: 21 CFR 862.1695 Regulation Name: Free thyroxine test system Regulatory Class: Class II Product Code: CEC Dated: August 2, 2018 Received: August 3, 2018

Dear Reanna Toney:

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/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html; 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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

(http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Kellie B. Kelm -S

for Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K181233

Device Name Elecsys FT4 III

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 411 immunoassay analyzer.

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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K181233 Elecsys FT4 III 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.

In accordance with 21 CFR 807.87. Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).

The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys FT4 III.

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Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457
Contact	Reanna ToneyPhone: (317) 521-4516FAX: (317) 521-2324Email: reanna.toney@roche.comSecondary Contact NameMichael LeutherPhone: (317) 521-3930FAX: (317) 521-2324Email: Michael.leuther@roche.com
Date Prepared	September 18, 2018
Proprietary Name	Elecsys FT4 III
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	For the Elecsys FT4 III, the establishment registration number for RocheDiagnostics GmbH in Mannheim, Germany is 9610126, and for Penzberg,Germany, 9610529. The establishment registration number for RocheDiagnostics in the United States is 1823260

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1. DEVICE DESCRIPTION

1.1. Reagents

The reagent working solutions include:

Rackpack (kit placed on analyzer)

M: Streptavidin-coated microparticles .
R1: Anti-T4-Ab~biotin .
R2: Anti-T4-Ab~Ru(bpy) .

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 411 immunoassay analyzer.

3. TECHNOLOGICAL CHARACTERISTICS

The following tables compare the Elecsys FT4 III with its predicate device, Elecsys FT4 II assay (K131244).

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Feature	Predicate Device:Elecsys FT4 II (K131244)	Candidate Device:Elecsys FT4 III
Intended Use/Indications forUse	Assay for the in vitro quantitativedetermination of free thyroxine in humanserum and plasma. Measurementsobtained by this device are used in thediagnosis and treatment of thyroiddisease.The electrochemiluminescenceimmunoassay "ECLIA” is intended foruse on Elecsys and cobas e immunoassayanalyzers.	Assay for the in vitro quantitative determination offree thyroxine in human serum and plasma.Measurements obtained by this device are used inthe diagnosis and treatment of thyroid disease.The electrochemiluminescence immunoassay"ECLIA" is intended for use on the cobas e 411immunoassay analyzer.
DetectionMethod	Electrochemiluminescent Assay	same
Applications/TestTime	18 minute application	same
InstrumentPlatform	Elecsys and cobas e	cobas e 411
Sample/ReagentRatio	15 µL	same
SampleType/Matrix	Serum and plasma (Li-heparin, K2-EDTA,K3-EDTA	same
Reagents	M: Streptavidin-coated microparticles(transparent cap), 1 bottle, 12 mL:Streptavidin-coated microparticles0.72 mg/mL; preservativeR1: Anti T4-Ab~~Ru(bpy) (gray cap), 1bottle, 18 mL: Polyclonal anti-T4-antibody (sheep) labeled with rutheniumcomplex 75 ng/mL; phosphate buffer 100mmol/L, pH 7.0; preservativeR2: T4~~biotin (black cap), 1 bottle, 18mL: Biotinylated T4 2.5 ng/mL;phosphate buffer 100 mmol/L, pH 7.0;preservative.	M: Streptavidin-coated microparticles (transparentcap), 1 bottle, 12 mL: Streptavidin-coatedmicroparticles 0.72 mg/mL; preservativeR1: Anti T4-Ab~~Ru(bpy) (gray cap), 1 bottle, 18mL: Polyclonal anti-T4-antibody (sheep) labeledwith ruthenium complex 75 ng/mL; phosphatebuffer 100 mmol/L, pH 7.0; preservativeR2: T4~~biotin (black cap), 1 bottle, 18 mL:Biotinylated T4 2.5 ng/mL; free D-biotin 8 ng/mL;phosphate buffer 100 mmol/L, pH 7.0; preservative.
Biotin	D-Biotin concentration in the R2 reagentbuffer: 50 ng/mL	D-Biotin concentration in the R2 reagent buffer:8 ng/mL
Calibrator	FT4 II CalSet	CalSet FT4 III
CalibrationMethod	2-point calibration	same
Feature	Predicate Device:Elecsys FT4 II (K131244)	Candidate Device:Elecsys FT4 III
CalibrationInterval	Calibration must be performed once perreagent lot using fresh reagent (i.e. notmore than 24 hours since the reagent kitwas registered on the analyzer).Calibration interval may be extendedbased on acceptable verification ofcalibration by the laboratory.Renewed calibration is recommended asfollows:after 1 month (28 days) whenusing the same reagent lotafter 7 days (when using the samereagent kit on the analyzer)as required: e.g. quality controlfindings outside the defined limits	same
Controls	PreciControl Universal	same
Traceability/Standardization	This method has been standardizedagainst the Elecsys FT4 method. TheElecsys FT4 assay is traceable to theEnzymun-Test which was standardizedusing equilibrium dialysis.	This method has been standardized against theElecsys FT4 II method. The Elecsys FT4 II assay istraceable to the Enzymun Test which wasstandardized using equilibrium dialysis
Reagent Stability	Store at 2 8 °C.Do not freeze.Store the Elecsys reagent kit upright inorder to ensure complete availability ofthe microparticles during automaticmixing prior to use.Unopened at 2-8 °C. up to statedexpiration dateAfter opening at 2-8 ℃. 84 days (12weeks)On the analyzers. 28 days (4 weeks)onboard or 56 days (8 weeks) when storedalternatively in the refrigerator and on theanalyzer, with the total time onboard onthe analyzer not exceeding 120 hours	same
Measuring Range	0.101-7.77 ng/dL(1.3-100 pmol/L	same
LoB	0.03 ng/dL (0.4 pmol/L)	0.02 ng/dL (0.3 pmol/L)
LoD	0.05 ng/dL (0.6 pmol/L)	0.04 ng/dL (0.5 pmol/L)
LoO	0.101 ng/dL (1.3 pmol/L)	same

Table 1: Assay Comparison

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Feature	Predicate Device:Elecsys FT4 II (K131244)			Candidate Device:Elecsys FT4 III
AnalyticalSpecificity	The following cross-reactivities werefound, tested with fT4 concentrations ofapproximately 0.974 ng/dL (12.5 pmol/L)and 2.66 ng/dL (34.2 pmol/L):			The following cross-reactivities were found, testedwith fT4 concentrations of approximately1.01 ng/dL (13 pmol/L) and 3.03 ng/dL(39 pmol/L):
	Cross-reactant	Concentration testedng/dL	Cross-reactivity%	Cross-reactant	Concentrationtestedng/dL	Cross-reactivity%
	L-T3	50000	0.005	L-T3	50000	0.005
	D-T3	50000	0.002	D-T3	50000	0.002
	rT3	190000	0.007	rT3	190000	0.007
	3-iodo-L-tyrosine	10000000	0.000	3-iodo-L-tyrosine	10000000	0.000
	3,5-diiodo-L-tyrosine	10000000	0.000	3,5-diiodo-L-tyrosine	10000000	0.000
	3,3',5-triiodothyracetic acid	100000	0.000	3,3',5-triiodothyracetic acid	100000	0.000
	3,3',5,5'-tetraiodothyroacetic acid	100000	0.001	3,3',5,5'-tetraiodothyroaceticacid	100000	0.001

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Feature	Predicate Device:Elecsys FT4 II (K131244)	Candidate Device:Elecsys FT4 III
Limitations	The assay is unaffected by icterus(bilirubin < 701 µmol/L or < 41 mg/dL),hemolysis (Hb < 0.621 mmol/L or < 1.0g/dL), lipemia (Intralipid < 2000 mg/dL),biotin (< 81.8 nmol/L or < 20 ng/mL),albumin < 6.3 g/dL, IgG < 7 g/dL, IgA <1.6 g/dL and IgM < 1 g/dL.Criterion: Recovery within ± 10 % ofinitial value.Samples should not be taken from patientsreceiving therapy with high biotin doses(i.e. > 5 mg/day) until at least 8 hoursfollowing the last biotin administration.No interference was observed fromrheumatoid factors up to a concentrationof 1200 IU/mL and samples from dialysispatients.Any influence that might affect thebinding behavior of the binding proteinscan alter the result of the fT4 tests (e.g.drugs, NTIs (Non Thyroid Illness) orpatients suffering from FDH (FamilialDysalbuminemic Hyperthyroxinemia) orincreased TBG in pregnancy).The test cannot be used in patientsreceiving treatment with lipid-loweringagents containing D T4. If the thyroidfunction is to be checked in such patients,the therapy should first be discontinuedfor 4-6 weeks to allow the physiologicalstate to become re-established.Autoantibodies to thyroid hormones caninterfere with the assay.In vitro tests were performed on 17commonly used pharmaceuticals. Nointerference with the assay was found.	Bilirubin ≤ 701 µmol/L or ≤ 41 mg/dLHemoglobin ≤ 0.621 mmol/L or ≤ 1000 mg/dLIntralipid ≤ 2000 mg/dLRheumatoid factors ≤ 1200 IU/mLIgG ≤ 7 g/dLIgA ≤ 1.6 g/dLIgM ≤ 1 g/dLCriterion: Recovery of ≤ ± 0.6 pmol/L of initialvalue ≤ 6 pmol/L and ± 10 % of initial value > 6pmol/L.Any influence that might affect the binding behaviorof the binding proteins can alter the result of the fT4tests (e.g. drugs, NTIs (Non Thyroid Illness) orpatients suffering from FDH (FamilialDysalbuminemic Hyperthyroxinemia)).The test cannot be used in patients receivingtreatment with lipid-lowering agents containing DT4. If the thyroid function is to be checked in suchpatients, the therapy should first be discontinued for4-6 weeks to allow the physiological state tobecome re-establishedAutoantibodies to thyroid hormones can interferewith the assay.Pharmaceutical substances In vitro tests wereperformed on 16 commonly used pharmaceuticals.No interference with the assay was found.
Feature	Predicate Device:Elecsys FT4 II (K131244)	Candidate Device:Elecsys FT4 III
Special thyroiddrugs	The following special thyroid drugs were tested with concentrations shown in the table below. No interference with the assay was found.Criterion: Recovery within ± 10 % of initial value.	In addition, the following special thyroid drugs were tested. No interference with the assay was found.
	Drug	Concentration(µg/mL)
	Iodide	0.200
	Carbimazole	6
	Thiamazole	80
	Propylthiouracil	300
	Perchlorate	2000
	Propranolol	240
	Amiodarone	200
	Prednisolone	100
	Hydrocortisone	200
	Flurocortolone	100
	Octreotide	0.300

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Feature	Predicate Device:Elecsys FT4 II (K131244)	Candidate Device:Elecsys FT4 III
Biotin	Samples should not be taken from patients receiving therapy with high biotin doses (i.e. > 5 mg/day) until at least 8 hours following the last biotin administration.	Biotin interference% Bias for samples containing various concentrations of Biotin
		Sample ng/dL (pmol/L) 52 65 78 91 104 117 150 300 600 1200 0.96 (12.4) 1.2 2.1 3.6 5.7 8.5 10.9 17.6 57.1 256 * 1.66 (21.4) -1.8 -1.4 1.3 3.0 7.3 7.6 16.1 53.7 291 * 2.61 (33.6) -0.5 0.6 2.3 4.7 7.5 9.7 15.9 56.5 * * * = Values above the measuring range. % Bias can not be calculated.** Specimens with biotin concentrations up to 104 ng/mL demonstrated ≤ 10% bias in results. Biotin concentrations greater than 104 ng/mL can lead to higher positive bias for fT4 results.Some studies have shown that serum concentrations of biotin can reach 355 ng/mL within the first hour after biotin ingestion for subjects consuming supplements of 20 mg biotin per day and up to 1160 ng/mL for subjects after a single dose of 300 mg biotin.Do not test samples from patients who take biotin.

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4. NON-CLINICAL PERFORMANCE EVALUATION

Non-clinical performance evaluation for Elecsys FT4 III executed with the study briefly summarized.

4.1. Precision

Repeatability and Intermediate Precision 4.1.1. -

Precision was evaluated on a single cobas e 411 analyzer according to CLSI guideline EP05-A3 using one reagent lot for evaluation. The protocol consisted of testing 2 replicates of each of two levels of control, PreciControl Universal and five human sera per run, 2 runs per day for 21 days. The samples were run in randomized order on the cobas e 411 analyzer. Serum samples used were native single donors, native serum pools, and spiked serum pools.

Human Anti-Mouse Antibodies (HAMA) 4.2.

Not Applicable (no mouse antibodies used)

Endogenous Interferences 4.3.

Biotin 4.3.1.

The purpose of this study was to evaluate endogenous substances for potential interference with the parameters measured with the Elecsys FT4 III on the cobas e 411 immunoassay analyzer using human serum samples (single donors, native as well as spiked).

For each interfering substance three human serum samples containing low, mid and high concentrations of fT4 were tested in accordance with CLSI EP07-A2.

4.4. Sample Matrix Comparison

The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys FT4 III immunoassay was determined by comparing values obtained from samples (native single donors and pools as well as spiked samples) drawn into Serum, K2-and K3-EDTA plasma primary tubes. 53 serum/plasma pairs per sample material were tested in singleton with one reagent lot on one cobas e 411 immunoassay analyzer.

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4.5. Method Comparison to Predicate

A method comparison was performed using the Elecsys FT4 III assay (candidate device, Y) and the Elecsys FT4 II assay (predicate device, X) to assess the bias between the two assays.

A total of 141 serum samples (138 native human serum samples and 3 spiked sample pools) were measured in singleton on the cobas e 411 analyzer in one run covering the entire measuring range. FT4 values ranged between 2.31 and 91.9 pmol/L for the Reference Method (X).

Reagent Stability 4.6.

To test reagent stability, four studies were executed with 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) .
Study 3: Alternate storage in the refrigerator / on the analyzer (56 days, not exceeding . 120 hours onboard)
Study 4: A real-time stability study is ongoing to support shelf-life stability claim. •

Reagent Stability After First Opening 4.6.1.

Elecsys FT4 III reagent kits can be used after first opening for up to 84 days when stored at 2-8°C. Reagent stability after first opening for the Elecsys FT4 III assay was tested on one cobas e 411 immunoassay analyzer.

A fresh reagent rackpack was placed on the analyzer and calibrated. Reference values for the samples tested were determined. After initial measurement the kit was removed from the analyzer and kept at 2-8 °C for 36, 63 and 85 days. After 36, 63 and 85 days the kit was placed on the analyzer again, calibrated and the test samples were determined.

Samples tested in duplicate include six human serum (HS) samples and two controls (PreciControl Universal) for run qualification. The human samples used were native single donor serum, native serum pools, and spiked serum pools.

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Reagent On-board stability (28 days) 4.6.2.

Elecsys FT4 III reagent kits can be stored on board of the analyzers for up to 28 days. A new calibration of the kit kept on-board is recommended every 7 days.

Reagent On-board Stability for the Elecsys FT4 III assay was tested on one cobas e 411 immunoassay analyzer.

A fresh reagent rackpack was placed on the analyzer and calibrated. All samples were measured on day 0. On day 8, 15, 22 and 29, the same samples were measured with the same reagent kit kept at 20°C ± 3°C (on-board condition) using the calibration curves established on day 0, 8, 15, 22 and 29, respectively.

Samples tested include five human serum (HS) samples and two controls (PreciControl Universal) for run qualification. Each sample was tested in two-fold determination. Human serum samples used were native single donor serum, native serum pools, and spiked serum pools.

Alternate storage in the refrigerator / on the analyzer (56 days, not exceeding 4.6.3. 120 hours onboard)

Elecsys FT4 III reagent kits can be stored in total for 56 days when stored alternatively in the refrigerator and on the analyzer, with a total time onboard the analyzer not exceeding 120 hours. Reagent refrigerator / on-board Stability for the Elecsys FT4 III assay was tested on one cobas e 411 immunoassay analyzer.

A fresh reagent rackpack was placed on the analyzer and calibrated. All samples were measured on day 0. On day 24, 29, 36, 43, 50 and 57, the same samples were measured with the same reagent kit kept in the refrigerator at 2-8°C and at 20°C ± 3°C (on-board condition) for 57 days not exceeding 120 hours under on-board condition using the calibration curves established on day 24, 29, 36, 43, 50 and 57, respectively.

Samples tested include five human serum (HS) samples and two controls (PreciControl Universal) for run qualification. Each sample was tested in two-fold determination. Human

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serum samples used were native single donor serum, native serum pools, and spiked serum pools.

Reagent Real-time Stability 4.6.4.

In the ongoing real-time stability study, the Elecsys FT4 III reagent is stored at 2-8°C. The stored assay reagents are tested at time point T=0 (after manufacturing) and at specified intervals over the shelf life of the device up to the planned shelf life plus one month. Testing will be performed using three human serum samples (stored at -20°C).

Data for the time-points at 0, 7, 10 and 13 months tested in duplicate are available. The average on-test recovery value will be calculated as absolute deviation / percent recovery compared to the reference value measured at T=0 for the human serum samples.

4.7. Calibration Stability

To test calibration stability, two studies were completed, including:

Study 1. Lot calibration stability .
Study 2. On-board calibration stability .
Lot calibration study 4.7.1.

Calibration of an Elecsys FT4 III reagent lot is recommended every 28 days (4 weeks). During that time period fresh reagent kits of the same lot can be used without calibration using the calibration curve of the day 0 reagent kit.

Elecsys FT4 III was calibrated with a fresh reagent kit on day 0 using a cobas e 411 immunoassay analyzer. After 36 days (5 weeks) a new reagent kit of the same lot was used and recovery of samples was determined using the calibration curve of day 0.

Five human serum (HS) samples and two controls (PreciControl Universal) for run qualification were tested; each sample was tested with two-fold determination. Human serum samples used were single donor serum, native serum pools, and spiked serum pools.

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On-board Calibration Stability 4.7.2.

Elecsys FT4 III reagent kits can be stored on board of the analyzers for up to 7 days without a new calibration.

Reagent On-board Calibration stability for the Elecsys FT4 III assay was tested on one cobas e 411 immunoassay analyzer.

A fresh reagent rackpack was placed on the analyzer and calibrated. All samples were measured on day 0. On day 8 the same samples were measured with the same reagent kit kept at 20°C ± 3°C (on-board condition) using the calibration curve established on day 0.

Samples tested include five human serum (HS) samples and two controls (PreciControl Universal) for run qualification. Each sample was tested in two-fold determination. Human serum samples used were single donor serum. native serum pools, and spiked serum pools.

Biotin 4.8.

The Elecsys FT4 II was cleared under K131244; Elecsys FT4 III is a modification of this assay with only minor changes in the assay buffer composition to increase the Biotin resistance. For this purpose the D-Biotin concentration in the R2 reagent buffer was reduced.

EXTERNAL (CLINICAL) TESTING 5.

Not Applicable

CLINICAL PERFORMANCE EVALUATION 6.

Not Applicable

ADDITIONAL INFORMATION 7.

The Elecsys FT4 III is intended to be used with the following calibrators and controls:

FT4 III CalSet .
Elecsys FT4 CalCheck •
PreciControl Universal .

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FT4 III CalSet, product code JIS, is a Class II 510(k) Exempt device and therefore, is not included with this submission.

The Elecsys FT4 CalCheck, product code JJX, is a Class I 510(k) Exempt device and therefore, is not included with this submission.

PreciControl Universal, product code JJY, is a Class I 510(k) Exempt device and therefore, is not included with this submission.

8. CONCLUSIONS

The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys FT4 III. The data supports a safe, effective device which performs as well as or better than the predicate device.

Regulation Number and Section

§ 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.