DIMENSION LOCI FREE THYROXINE FLEX REAGENT CARTRIDGE, FT4L, DIMENSION LOCI THYROID STIMULATING HORMONE FLEX REAGENT CART

K140842 · Siemens Healthcare Diagnostics, Inc. · CEC · Nov 26, 2014 · Clinical Chemistry

Device Facts

• Record ID: K140842
• Device Name: DIMENSION LOCI FREE THYROXINE FLEX REAGENT CARTRIDGE, FT4L, DIMENSION LOCI THYROID STIMULATING HORMONE FLEX REAGENT CART
• Applicant: Siemens Healthcare Diagnostics, Inc.
• Product Code: CEC · Clinical Chemistry
• Decision Date: Nov 26, 2014
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1695
• Device Class: Class 2
• Attributes: Pediatric

Intended Use

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 TSHL method is an in vitro diagnostic test for the quantitative measurement of Thyroid Stimulating Hormone (TSH, thyrotropin) in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of TSH are used in the diagnosis and monitoring of thyroid disease.

Device Story

In vitro diagnostic reagents for Dimension® EXL™ integrated chemistry system with LOCI® Module; used for quantitative measurement of TSH and Free Thyroxine in human serum/plasma. TSHL uses sandwich chemiluminescent immunoassay; FT4L uses sequential chemiluminescent immunoassay. Both utilize LOCI® technology: latex beads (Sensibeads/Chemibeads) and biotinylated antibodies. Illumination at 680 nm generates singlet oxygen from Sensibeads, triggering chemiluminescence in Chemibeads measured at 612 nm. Signal intensity correlates with analyte concentration. Used in clinical laboratories by trained personnel to assist physicians in diagnosing and monitoring thyroid disease.

Clinical Evidence

No new clinical performance data was required. Pediatric reference intervals were established by analyzing data from 411 patients (FT4L) and 407 patients (TSHL) using a non-parametric approach and robust symmetrical methods in accordance with CLSI EP28-A3c. Analytical performance data from previous 510(k) submissions (K130276 and K081074) remains applicable.

Technological Characteristics

LOCI® (Luminescent Oxygen Channeling Immunoassay) technology; reagent cartridges for use on Dimension® EXL™ integrated chemistry system. No changes to materials, energy source, or software. Pediatric reference intervals established via statistical analysis of patient data.

Indications for Use

Indicated for quantitative measurement of TSH and Free Thyroxine in human serum and plasma for diagnosis and monitoring of thyroid disease in pediatric populations (infants 1-23 months, children 2-12 years, adolescents 13-20 years).

Regulatory Classification

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.

Predicate Devices

• Dimension® LOCI Thyroid Stimulating Hormone Flex® reagent cartridge (k081074)
• Dimension® LOCI Free Thyroxine Flex® reagent cartridge (k130276)

Submission Summary (Full Text)

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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" around the perimeter. Inside the circle is an abstract symbol resembling an eagle or a stylized human profile, composed of three overlapping shapes.

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: K140842

Trade/Device Name: Dimension® LOCI Free Thyroxine Flex® Reagent Cartridge, FT4L: Dimension® LOCI Thyroid Stimulating Hormone Flex® Reagent Cartridge. TSHL Regulation Number: 21 CFR 862.1695 Regulation Name: Free thyroxine test system Regulatory Class: II Product Code: CEC. JLW Dated: November 21, 2014 Received: November 24, 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 [phone] or [phone] 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 [phone] or [phone] or at its Internet address

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

Sincerely yours,

Courtney

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) K140842

### Device Name

Dimension® LOCI Free Thyroxine Flex® reagent cartridge, FT4L

Indications for Use (Describe)

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.

| <span> <span style="font-size: 14px;">☑</span> Prescription Use (Part 21 CFR 801 Subpart D) </span> | <span>☐ Over-The-Counter Use (21 CFR 801 Subpart C)</span> |
|-----------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|
|-----------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|

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

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

## Indications for Use

510(k) Number (if known) K140842

### Device Name

Dimension® LOCI Thyroid Stimulating Hormone Flex® reagent cartridge. TSHL

Indications for Use (Describe)

The TSHL method is an in vitro diagnostic test for the quantitative measurement of Thyroid Stimulating Hormone (TSH, thyrotropin) in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of TSH are used in the diagnosis and monitoring of thyroid disease.

| <span> <span style="font-size: 12px;"> <span style="text-decoration: underline;"> <span style="font-weight: bold;"></span> </span> </span> </span> | <span> <span style="font-size: 12px;"> <span style="text-decoration: underline;"> <span style="font-weight: bold;"></span> </span> </span> </span> |
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| <span> <span> <div style="display: inline-block;"> <img alt="checkbox" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAEAAAABCAQAAAC1HAwCAAAAC0lEQVR42mNkYAAAAAYAAjCB0C8AAAAASUVORK5CYII=" style="width: 10px; height: 10px;"/> </div> Prescription Use (Part 21 CFR 801 Subpart D) </span> </span> | <span> <span> <div style="display: inline-block;"> <img alt="checkbox" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAEAAAABCAQAAAC1HAwCAAAAC0lEQVR42mNkYAAAAAYAAjCB0C8AAAAASUVORK5CYII=" style="width: 10px; height: 10px;"/> </div> Over-The-Counter Use (21 CFR 801 Subpart C) </span> </span> |
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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

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[e-mail]

"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)

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# SIEMENS

# 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: K140842

#### 1. Date Prepared

November 25, 2014

#### 2. Applicant Information

| Contact: | Frances A. Dillon<br>Senior Manager, Regulatory Affairs |
|----------|-----------------------------------------------------------------------------------|
| Address: | Siemens Healthcare Diagnostics Inc.<br>P.O. Box 6101, M/S 514<br>Newark, DE 19714 |
| Phone: | 302-631-6951 |
| Fax: | 302-631-6299 |
| Email: | [e-mail] |

#### Regulatory Information 3.

### Table 1. Regulatory Information for Dimension® FT4L and TSHL Assays

| | FT4L | TSHL |
|---------------------|-----------------------------------------------------------------|---------------------------------------------------------------------------------|
| Trade Name | Dimension® LOCI Free Thyroxine<br>Flex® reagent cartridge, FT4L | Dimension® LOCI Thyroid Stimulating<br>Hormone Flex® reagent cartridge,<br>TSHL |
| Model Numbers | RF610 | RF612 |
| Common Name | Radioimmunoassay,<br>free thyroxine | Radioimmunoassay, thyroid stimulating<br>hormone |
| Classification Name | Free thyroxine test system | Thyroid stimulating hormone test<br>system |
| FDA Classification | Class II | Class II |
| Review Panel | Clinical Chemistry | Clinical Chemistry |
| Product Code | CEC | JLW |
| Regulation Number | 862.1695 | 862.1690 |

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### Predicate Device Information 4.

The inclusion of pediatric reference intervals to the labeling (Package Inserts) of the Dimension® FT4L and TSHL 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.

| | FT4L | TSHL |
|------------------|-----------------------------------------------------------------|---------------------------------------------------------------------------------|
| Predicate Device | Dimension® LOCI Free Thyroxine<br>Flex® reagent cartridge, FT4L | Dimension® LOCI Thyroid Stimulating<br>Hormone Flex® reagent cartridge,<br>TSHL |
| Subject Device | Same (As above) | Same (As above) |
| Predicate 510(k) | K130276 | K081074 |

| | | Table 2. Summary of Predicate Devices for Dimension® FT4L and TSHL Assays |
|--|--|---------------------------------------------------------------------------|
|--|--|---------------------------------------------------------------------------|

### Substantial Equivalence Information 5.

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

| Item | Predicate Device<br>(Unmodified Labeling) | Subject Device<br>(With Pediatric Reference Intervals) |
|----------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|
| Analytes | Dimension® FT4L | Dimension® FT4L |
| | Free Thyroxine (FT4) | Same |
| | Dimension® TSHL | Dimension® TSHL |
| | Thyroid Stimulating Hormone | Same |
| Reagents | Dimension® FT4L | Dimension® FT4L |
| | Dimension® LOCI Free Thyroxine<br>Flex® reagent cartridge, FT4L | Same |
| | Dimension® TSHL | Dimension® TSHL |
| | Dimension® LOCI Thyroid Stimulating<br>Hormone Flex® reagent cartridge,<br>TSHL | Same |
| Instruments | Dimension® EXL™ with LOCI®<br>Module and Dimension® EXL™ 200 | Same |
| Intended Use<br>Statements | Dimension® FT4L<br>The FT4L method is an in vitro<br>diagnostic test for the quantitative<br>measurement of Free Thyroxine in<br>human serum and plasma on the<br>Dimension® EXL™ integrated<br>chemistry system with LOCI® Module.<br>Measurements of free thyroxine are<br>used in the diagnosis and monitoring of | Dimension ® FT4L<br>Same |

| Table 3. Summary of Substantial Equivalence for Dimension® FT4L and TSHL Assays | | | |
|---------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|
| | | | |
| Item | Predicate Device<br>(Unmodified Labeling) | Subject Device<br>(With Pediatric Reference Intervals) | |
| | thyroid disease. | | |
| | Dimension® TSHL | Dimension® TSHL | |
| | The TSHL method is an in vitro<br>diagnostic test for the quantitative<br>measurement of Thyroid Stimulating<br>Hormone (TSH, thyrotropin) in human<br>serum and plasma on the Dimension®<br>EXL™ integrated chemistry system<br>with LOCI® Module. Measurements of<br>TSH are used in the diagnosis and<br>monitoring of thyroid disease. | same | |
| Analytical<br>Measuring Range<br>(Assay Range) | Dimension® FT4L<br>0.1 – 8.0 ng/dL [1.3 – 103 pmol/L] | Dimension® FT4L<br>Same | |
| | Dimension® TSHL | Dimension® TSHL | |
| | 0.007 – 100 μIU/mL [mIU/L] | Same | |
| Adult<br>Reference Intervals | Dimension® FT4L<br>0.76 – 1.46 ng/dL [9.8 – 18.8 pmol/L]<br>The reference interval was transferred<br>from that previously determined for the<br>FT4 method on the Dimension Vista®<br>System. It represents the central 95%<br>of results determined non-<br>parametrically from a population of 199<br>healthy adults (140 males and 59<br>females, 18 - 59 years of age). The<br>original determination and transference<br>to the FT4L method was done in<br>accordance with CLSI/NCCLS C28-A2. | Same | |
| | Dimension® TSHL<br>0.358 - 3.74 µIU/mL [mIU/L]<br>The reference interval was transferred<br>from that previously determined for the<br>TSH method on the Dimension Vista®<br>System. It represents the central 95%<br>of results determined non-<br>parametrically from a population of 297<br>apparently healthy adults (187 males<br>and 110 females, 18 - 65 years of<br>age). The original determination and<br>transference to the TSHL method was<br>done in accordance with CLSI/NCCLS<br>C28-A2. | Same | |
| Item | Predicate Device<br>(Unmodified Labeling) | Subject Device<br>(With Pediatric Reference Intervals) | |
| Pediatric<br>Reference Intervals | Dimension® FT4L<br>None | Dimension® FT4L<br>Infants (01 – 23 months)<br>0.93 - 1.45 ng/dL<br>Children (02 – 12 years)<br>0.82 - 1.40 ng/dL<br>Adolescents (13 – 20 years)<br>0.78 - 1.34 ng/dL | |
| | Dimension® TSHL | Dimension® TSHL<br>Infants (01 – 23 months)<br>0.867 – 6.43 µIU/mL<br>Children (02 – 12 years)<br>0.704 - 4.01 µIU/mL<br>Adolescents (13 – 20 years)<br>0.516 - 4.13 µIU/mL | |

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### Table 3. Summary of Substantial Equivalence for Dimension® FT4L and TSHL Assays

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Table 3. Summary of Substantial Equivalence for Dimension® FT4L and TSHL Assays

### 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 411 patients (77 infants, 187 children, 147 adolescents) were analyzed to establish the Dimension® FT4L assay reference intervals for the studied pediatric population. Data from a total of 407 patients (75 infants, 185 children, 147 adolescents) were analyzed to establish the Dimension® TSHL assay reference intervals for the studied pediatric population. Testing was performed on a Dimension® EXL™ with LM system. These pediatric reference intervals, as well as the previously-established euthyroid adult reference intervals and analytical measuring ranges, are presented below.

| | Dimension® FT4L | Dimension® TSHL |
|------------------------|-------------------|----------------------|
| Infants (01 - 23M) | 0.93 - 1.45 ng/dL | 0.867 – 6.43 µIU/mL |
| Children (02 - 12Y) | 0.82 - 1.40 ng/dL | 0.704 - 4.01 µIU/mL |
| Adolescents (13 - 20Y) | 0.78 - 1.34 ng/dL | 0.516 - 4.13 µIU/mL |
| Euthyroid Adults* | 0.76 - 1.46 ng/dL | 0.358 - 3.74 µIU/mL |
| Assay Range* | 0.1 - 8.0 ng/dL | 0.007 - 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 2.5" and 97.5" 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,

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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 FT4L 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=77 for the robust symmetric analysis.

For the Dimension TSHL 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=75 for the robust symmetric analysis.

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

| Infants (01 - 23M) | Dimension® FT4L | Dimension® TSHL |
|-------------------------------------------|-------------------|-------------------------------------------|
| Calculation Method | Robust Symmetric | Robust Symmetric After Log<br>Transformed |
| Reference Interval | 0.93 - 1.45 ng/dL | 0.867 - 6.43 µIU/mL |
| 90% Confidence Interval<br>of Lower Limit | 0.89 - 0.97 ng/dL | 0.710 - 1.04 µIU/mL |
| 90% Confidence Interval<br>of Upper Limit | 1.41 - 1.50 ng/dL | 5.40 - 7.54 µIU/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® FT4L and TSHL assays continue to apply to these assays. All performance data is cross-referenced to the predicate 510(k) submissions for the FT4L and TSHL assays (K130276 and K081074).

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

- Precision/Reproducibility ■
- . Linearity
- l Calibrator/Assay Traceability
- . Calibrator/Assay Stability
- l Assay Cut-off
- " Method Comparison
- l Matrix Comparison

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- י Sensitivity (Detection Limits, LoB, LoD, LoQ)
- l Analytical Specificity

### Shelf-Life 9.

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® FT4L and TSHL assays continues to apply to these assays.

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

- י Shelf Life Stability
- l Onboard Stability
- l Open Vial Stability

### 10. Conclusions

The Dimension® FT4L and TSHL assays with pediatric reference intervals are substantially equivalent to the currently marketed Dimension® FT4L and TSHL assays.

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® FT4L and TSHL 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.
- 2. 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® FT4L and TSHL assays. Therefore, the Dimension® FT4L and TSHL assays have appropriate analytical performance to test pediatric patients.