The FT4L method is an in vitro diagnostic test for the quantitative measurement of Free Thyroxine in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of free thyroxine are used in the diagnosis and monitoring of thyroid disease.

The TSH method is an in vitro diagnostic test for the quantitative measurement of Thyroid Stimulating Hormone in human serum and plasma on the Dimension Vista® System. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

Device Description

The submission describes the Dimension® Vista Free Thyroxine Flex® reagent cartridge, FT4 and the Dimension Vista® Thyroid Stimulating Hormone Flex® reagent cartridge, TSH. These are in vitro diagnostic tests for the quantitative measurement of Free Thyroxine and Thyroid Stimulating Hormone in human serum and plasma, respectively, on the Dimension Vista® System. The submission is for the inclusion of pediatric reference intervals to the labeling (Package Inserts) of these assays. No changes were made to the reagents, device design, or manufacturing process.

AI/ML Overview

The document describes the establishment of pediatric reference intervals for the Dimension Vista® Free Thyroxine (FT4) and Thyroid Stimulating Hormone (TSH) Flex® reagent cartridges. It does not contain an acceptance criteria table related to the device's performance against specific metrics of accuracy or precision in the traditional sense, but rather focuses on establishing biological reference intervals. The study's primary goal was to define these pediatric reference intervals.

Here's an analysis of the provided information:

1. Table of Acceptance Criteria and Reported Device Performance

As noted, the document doesn't provide a table of discrete acceptance criteria for device performance (e.g., sensitivity, specificity, accuracy against a gold standard). Instead, the acceptance in this context relates to the establishment and statistical validation of reference intervals for pediatric populations.

The reported "performance" for the Dimension Vista® FT4 and TSH assays, in the context of this submission, is the established pediatric reference intervals. These are compared against adult reference intervals and the assay's analytical measuring range to demonstrate suitability for pediatric use.

Reference Interval Category	Dimension Vista® FT4 (ng/dL)	Dimension Vista® TSH (µIU/mL)
Pediatric Reference Intervals
Infants (01 - 23 months)	0.88 - 1.48	0.816 - 5.91
Children (02 - 12 years)	0.81 - 1.35	0.662 - 3.90
Adolescents (13 – 20 years)	0.78 - 1.33	0.463 - 3.98
Euthyroid Adults (for comparison)	0.76 - 1.46	0.358 - 3.74
Assay Range (for comparison)	0.1 - 8.0	0.005 - 100

Justification of Suitability for Pediatric Use (Acceptance Criteria Implicitly Met):

The document states two key rationales for accepting the pediatric reference intervals, implicitly acting as "acceptance criteria" for the device's application in this population:

1. Alignment with Indications for Use: "Testing of pediatric patients is within the established indications for use in the diagnosis and treatment of thyroid disease..."
2. Analytical Compatibility: "The newly-established pediatric reference intervals are either within or are above the previously-established reference intervals for euthyroid (normal thyroid) adult populations and they are within the analytical measuring ranges of the Dimension Vista® FT4 and TSH assays. Therefore, the Dimension Vista® FT4 and TSH assays have appropriate analytical performance to test pediatric patients."

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

Sample Size: A total of 421 patients were analyzed to establish the pediatric reference intervals:
- Infants (01 - 23 months): 82
- Children (02 - 12 years): 191
- Adolescents (13 – 20 years): 148
Data Provenance: The document does not explicitly state the country of origin or if the data was retrospective or prospective. It implies the samples were collected specifically for this study ("Data from a total of 421 patients... were analyzed to establish..."). Given the context of establishing reference intervals, it is likely prospective collection from healthy individuals within the specified age groups, though this is not explicitly stated.

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

This type of information is not applicable to this study. The "ground truth" here is the biological variation of FT4 and TSH levels in healthy pediatric populations. Reference intervals are established statistically from a cohort of presumably healthy individuals, not through expert consensus on individual cases.

4. Adjudication Method for the Test Set

This is not applicable. There was no need for adjudication as the study focused on quantitative measurements and statistical analysis of those measurements to define reference ranges.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

This is not applicable. The device is an in-vitro diagnostic test for quantitative measurement, not an imaging device or a diagnostic aid requiring human interpretation that benefits from AI assistance. Therefore, an MRMC study and effect size for human improvement are not relevant.

6. Standalone Performance

Yes, this study inherently focuses on the standalone performance of the Dimension Vista® FT4 and TSH assays. The goal was to determine the measured analyte levels in a specific population (pediatrics) using the device alone, to establish reference intervals. There is no human-in-the-loop component for the determination of the numeric values.

7. Type of Ground Truth Used

The ground truth used to establish the reference intervals is biological reference data from a population of presumably healthy subjects within specified age groups. This involves statistical methods (non-parametric for children/adolescents, robust symmetric for infants, sometimes after log transformation for skewed data) to determine the central 95% of values.

8. Sample Size for the Training Set

This study is not framed in terms of a "training set" for an algorithm. The samples of 421 pediatric patients (82 infants, 191 children, 148 adolescents) directly served as the dataset from which the reference intervals were derived using statistical methods, which could be considered the "training" for the reference interval definition.

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

The "ground truth" (i.e., the reference intervals) for the pediatric populations was established through statistical analysis of quantitative measurements of FT4 and TSH in serum/plasma samples from the 421 pediatric subjects.

CLSI C28-A3c Guideline: The study followed the "Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -- Third Edition (CLSI C28-A3c)" standard.
Non-parametric approach: Used for children and adolescents, where the 2.5th and 97.5th percentiles of the distribution of values were calculated. This technique is typically used when the sample size is sufficient (usually >120).
Robust symmetrical method (Horn and Pesce, CLSI EP28-A3c): Used for infants due to a sample size of less than 120 (82 patients).
Log transformation: For the TSH assay in infants, the data was highly positively skewed, so a natural log transformation was applied to achieve a normal distribution before applying the robust symmetric method.
Confirmation with Simulated Reference Intervals: Both methods were confirmed with two simulated reference intervals (non-parametric and robust symmetric) estimated as the means of the 95% upper and lower bounds from 1000 data sets.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

November 26, 2014

SIEMENS HEALTHCARE DIAGNOSTICS INC. FRANCES DILLON SR. MANAGER, REGULATORY AFFAIRS PO BOX 6101, M/S 514 NEWARK DE 19714-6101

Re: K140859

Trade/Device Name: Dimension® VISTA Free Thyroxine Flex® Reagent Cartridee, FT4: Dimension® VISTA Thyroid Stimulating Hormone Flex® Reagent Cartridge, TSH Regulation Number: 21 CFR 862.1695 Regulation Name: Free thyroxine test system Regulatory Class: II Product Code: CEC. JLW Dated: November 24, 2014 Received: November 25, 2014

Dear Frances Dillon:

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. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the

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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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 the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Courtney H. Lias -S

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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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

510(k) Number (if known) K140859

Device Name

Dimension® Vista Free Thyroxine Flex® reagent cartridge, FT4

Indications for Use (Describe)

	X Prescription Use (Part 21 CFR 801 Subpart D)Over-The-Counter Use (21 CFR 801 Subpart C)
	CONTINUE ON A SEPARATE PAGE IF NEEDED.
	This section applies only to requirements of the Paperwork Reduction Act of 1995.DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.The burden time for this collection of information is estimated to average 79 hours per response, including thetime to review instructions, search existing data sources, gather and maintain the data needed and completeand review the collection of information. Send comments regarding this burden estimate or any other aspectof this information collection, including suggestions for reducing this burden, to:

	Department of Health and Human ServicesFood and Drug Administration

Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

Type of Use (Select one or both, as applicable)

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

510(k) Number (if known) K140859

Device Name

Dimension Vista® Thyroid Stimulating Hormone Flex® reagent cartridge. TSH

Indications for Use (Describe)

☑ Prescription Use (Part 21 CFR 801 Subpart D)	☐ Over-The-Counter Use (21 CFR 801 Subpart C)
------------------------------------------------------------------------------------------------	-----------------------------------------------------------------------------------------------

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the
time to review instructions, search existing data sources, gather and maintain the data needed and complete
and review the collection of information. Send comments regarding this burden estimate or any other aspect
of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services

Food and Drug Administration

Office of Chief Information Officer

Paperwork Reduction Act (PRA) Staff

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

PRAStaff@fda.hhs.gov

Type of Use (Select one or both, as applicable)

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Image /page/4/Picture/0 description: The image contains the word "SIEMENS" in a sans-serif font. The text is a teal color. The letters are evenly spaced and the word is horizontally oriented.

Section 6. 510(k) Summary of Safety and Effectiveness

This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.

The assigned 510(k) Number is: K140859

1. Date Prepared

November 25, 2014

Applicant Information 2.

Contact:	Frances A. Dillon.Senior Manager, Regulatory Affairs
Address:	Siemens Healthcare Diagnostics Inc.P.O. Box 6101, M/S 514Newark, DE 19714
Phone:	302-631-6951
Fax:	302-631-6299
Email:	frances.a.dillon@siemens.com

3. Regulatory Information

	FT4	TSH
Trade Name	Dimension Vista® Free ThyroxineFlex® reagent cartridge, FT4	Dimension Vista® Thyroid StimulatingHormone Flex® reagent cartridge, TSH
Model Numbers	K6410	K6412
Common Name	Radioimmunoassay,free thyroxine	Radioimmunoassay, thyroid stimulatinghormone
Classification Name	Free thyroxine test system	Thyroid stimulating hormone testsystem
FDA Classification	Class II	Class II
Review Panel	Clinical Chemistry	Clinical Chemistry
Product Code	CEC	JLW
Regulation Number	862.1695	862.1690

Table 1. Regulatory Information for Dimension Vista® FT4 and TSH Assays

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Predicate Device Information 4.

The inclusion of pediatric reference intervals to the labeling (Package Inserts) of the Dimension Vista® FT4 and TSH assays does not require any other device modifications (i.e. no change to design or manufacturing process). No changes were made to the reagents. Therefore, as shown in the table below, the predicate and subject devices are the same.

	FT4	TSH
Predicate Device	Dimension Vista® Free ThyroxineFlex® reagent cartridge, FT4	Dimension Vista® Thyroid StimulatingHormone Flex® reagent cartridge, TSH
Subject Device	Same (As above)	Same (As above)
Predicate 510(k)	K053531	K060090

Table 2. Summary of Predicate Devices for Dimension Vista® FT4 and TSH Assays

Substantial Equivalence Information 5.

The following table demonstrates substantial equivalence between the predicate Dimension Vista® thyroid assays (with unmodified labeling) and Dimension Vista® thyroid assays which have modified Instructions for Use (Package Inserts) including pediatric reference intervals.

Item	Predicate Device(Unmodified Labeling)	Subject Device(With Pediatric Reference Intervals)
Analytes	Dimension Vista® FT4Free Thyroxine (FT4)	Dimension Vista® FT4Same
	Dimension Vista® TSHThyroid Stimulating Hormone	Dimension Vista® TSHSame
Reagents	Dimension Vista® FT4Dimension Vista® Free ThyroxineFlex® reagent cartridge, FT4	Dimension Vista® FT4Same
	Dimension Vista® TSHDimension Vista® Thyroid StimulatingHormone Flex® reagent cartridge, TSH	Dimension Vista® TSHSame
Instruments	Dimension Vista® 500, 1000T, 1500and 3000T systems	Same
Intended UseStatements	Dimension Vista® FT4The FT4 method is an in vitrodiagnostic test for the quantitativemeasurement of Free Thyroxine inhuman serum and plasma on theDimension Vista® System.	Dimension Vista® FT4The FT4 method is an in vitrodiagnostic test for the quantitativemeasurement of Free Thyroxine inhuman serum and plasma on theDimension Vista® System.Measurements obtained by this deviceare used in the diagnosis andtreatment of thyroid diseases.*
Item	Predicate Device(Unmodified Labeling)	Subject Device(With Pediatric Reference Intervals)
	Dimension Vista® TSHThe TSH method is an in vitrodiagnostic test for the quantitativemeasurement of Thyroid StimulatingHormone in human serum and plasmaon the Dimension Vista® System.	Dimension Vista® TSHThe TSH method is an in vitrodiagnostic test for the quantitativemeasurement of Thyroid StimulatingHormone in human serum and plasmaon the Dimension Vista® System.Measurements of thyroid stimulatinghormone produced by the anteriorpituitary are used in the diagnosis ofthyroid or pituitary disorders.*
	AnalyticalMeasuring Range(Assay Range)	Dimension Vista® FT40.1-8.0 ng/dL [1.3-103 pmol/L]
	Dimension Vista® TSH0.005–100 µIU/mL [mIU/L]	Dimension Vista® TSHSame
	AdultReference Intervals	Dimension Vista® FT40.76-1.46 ng/dL [9.8-18.8 pmol/L]calculated non-parametrically andrepresents the central 95% of resultsdetermined from a population of 199apparently healthy adults (140 malesand 59 females, 18 - 59 years of age)
	Dimension Vista® TSH0.358-3.74 µIU/mL [mIU/L] calculatednon-parametrically and represents thecentral 95% of results determined froma population of 297 apparently healthyadults (187 males and 110 females, 8-65 years of age).	Dimension Vista® TSHSame
	PediatricReference Intervals	Dimension Vista® FT4None
	Dimension Vista® TSHNone	Dimension Vista® TSHInfants (01 - 23 months)0.816 - 5.91 µIU/mLChildren (02 - 12 years)0.662 - 3.90 µIU/mLAdolescents (13 – 20 years0.463 - 3.98 µIU/mL)

Table 3. Summary of Substantial Equivalence for Dimension Vista® FT4 and TSH Assays

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Table 3. Summary of Substantial Equivalence for Dimension Vista® FT4 and TSH Assays

*Additional text regarding indications added as FDA requested for 510(k) K132249.

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Standard/Guidance Document Reference 6.

Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -- Third Edition (CLSI C28-A3c).

7. Pediatric Reference Intervals

Data from a total of 421 patients (82 infants, 191 children, 148 adolescents) were analyzed to establish the Dimension Vista® FT4 and TSH assay reference intervals for the studied pediatric population. Testing was performed on a Dimension Vista® 1500 system. These pediatric reference intervals, as well as the previously-established euthyroid adult reference intervals and analytical measuring ranges, are presented below.

	Dimension Vista® FT4	Dimension Vista® TSH
Infants (01 - 23M)	0.88 - 1.48 ng/dL	0.816 - 5.91 µIU/mL
Children (02 – 12Y)	0.81 - 1.35 ng/dL	0.662 - 3.90 µIU/mL
Adolescents (13 – 20Y)	0.78 - 1.33 ng/dL	0.463 - 3.98 µIU/mL
Euthyroid Adults*	0.76 - 1.46 ng/dL	0.358 - 3.74 µIU/mL
Assay Range*	0.1 - 8.0 ng/dL	0.005 - 100 µIU/mL

Table 4. Comparison of Pediatric and Adult 95% Reference Intervals

Information taken from existing Instructions for Use (Package Inserts)

A non-parametric approach was used to establish the reference intervals for children and adolescents where the 2.5th and 97.5th percentiles of the distribution of values were calculated. Because fewer than 120 patient samples were included for the infant age group, the reference intervals were calculated by using a robust measure of location and spread, as developed by Horn and Pesce and recommended in CLSI EP28-A3c: Defining, Establishing, and Verifying Reference Intervals.

The robust symmetrical method was used for the Dimension Vista FT4 analysis because the data was normally distributed. The reference interval calculated from the actual data using the robust symmetrical method was confirmed with two simulated reference intervals (nonparametric and robust symmetric). Each simulated reference interval was estimated as the means of the 95% upper and lower bounds from 1000 data sets. In each case, a normal distribution was fitted to the actual results, with either n=120 for the non-parametric analysis, or n=82 for the robust symmetric analysis.

For the Dimension Vista TSH assay, the sample distribution for infant subjects was highly positively skewed. As permitted by CLSI EP28-A3, the actual results were natural log transformed to produce a well-fitted normal distribution. The infant reference intervals were then calculated using the robust symmetric method on the log transformed data. The reference interval was confirmed with two simulated reference intervals (nonparametric and robust symmetric). Each simulated reference interval was estimated as the means of the 95% upper and lower bounds from 1000 data sets. In each case, a normal distribution was fitted to the actual results, with either n=120 for the non-parametric analysis, or n=82 for the robust symmetric analysis.

The 90% confidence intervals for the Infant 95% Reference Intervals are listed below.

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Infants (01 - 23M)	Dimension® Vista FT4	Dimension® Vista TSH
Calculation Method	Robust Symmetric	Robust Symmetric After LogTransformed
Reference Interval	0.88 - 1.48 ng/dL	0.816 - 5.91 µlU/mL
90% Confidence Intervalof Lower Limit	0.82 - 0.95 ng/dL	0.683 - 0.962 µIU/mL
90% Confidence Intervalof Upper Limit	1.42 - 1.53 ng/dL	5.06 - 7.09 µlU/mL

Table 5. Infant Reference Interval - 90% Confidence Intervals for Upper and Lower Limits

Performance Characteristics 8.

The inclusion of pediatric reference intervals in the Instructions for Use (Package Inserts) does not necessitate the collection of additional analytical performance data as no changes were made to the reagents. Therefore, all analytical performance data previously reviewed for the Dimension Vista® FT4 and TSH assays continue to apply to these assays. All performance data is cross-referenced to the predicate 510(k) submissions for the FT4 and TSH assays (K053531 and K060090).

Specifically, the following studies are not needed for the purpose of this submission:

. Precision/Reproducibility
l Linearity
. Calibrator/Assay Traceability
l Calibrator/Assay Stability
Assay Cut-off
. Method Comparison
. Matrix Comparison
Sensitivity (Detection Limits, LoB, LoD, LoQ) .
Analytical Specificity I

9. Shelf-Life

The inclusion of pediatric reference intervals in the Instructions for Use (Package Inserts) does not necessitate the collection of additional stability data as no changes were made to the reagents. Therefore, all stability methods, acceptance criteria and data previously reviewed for the Dimension Vista® FT4 and TSH assays continue to apply to these assays.

Specifically, the following stability studies are not needed for the purpose of this submission:

I Shelf Life Stability
. Onboard Stabilitv
I Open Vial Stability

10. Conclusions

The Dimension Vista® FT4 and TSH assays with pediatric reference intervals are substantially equivalent to the currently marketed Dimension Vista® FT4 and TSH assays.

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No changes were made to the reagents. The inclusion of pediatric reference intervals in the Instructions for Use (Package Inserts) does not require a change in the device design or a change in the manufacturing process.

The addition of pediatric reference intervals for the Dimension Vista® FT4 and TSH assays is further supported by the following rationale:

1. Testing of pediatric patients is within the established indications for use in the diagnosis and treatment of thyroid disease), as described in 21 CFR §862.1695 and 21 CFR §862.1690.
1. The newly-established pediatric reference intervals are either within or are above the previously-established reference intervals for euthyroid (normal thyroid) adult populations and they are within the analytical measuring ranges of the Dimension Vista® FT4 and TSH assays. Therefore, the Dimension Vista® FT4 and TSH assays have appropriate analytical performance to test pediatric patients.

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.