(158 days)
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.
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 Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) assays were cleared under K081074 and K073604, respectively. The components of the cleared assays were modified to reduce biotin interference.
The modified Assays are comprised of the following components:
Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL): prepackaged liquid reagents in a plastic eight-well cartridge. Wells 1-2 contain Biotinylated TSH antibody (7.5 µg/mL mouse monoclonal), wells 3-4 contain TSH antibody coated Chemibeads (200 µg/mL mouse monoclonal), and wells 5-6 contain Streptavidin Sensibeads (1400 µg/mL recombinant E. coli). Wells 1-6 contain buffers, stabilizers and preservatives. Wells 7-8 are empty.
Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L): prepackaged liquid reagents in a plastic eight-well cartridge. Wells 1-2 contain Streptavidin Sensibeads (225 µg/mL recombinant E. coli), wells 3-4 contain T3 Chemibeads (200 µg/mL), and wells 5-6 contain FT4 Biotinylated antibody (50 ng/mL mouse monoclonal). Wells 1-6 contain buffers, stabilizers and preservatives. Wells 7-8 are empty.
Test Principle: Both devices use a homogeneous chemiluminescent immunoassay based on LOCI® technology.
For TSHL, it's a sandwich immunoassay where sample is incubated with biotinylated antibody and Chemibeads to form bead-TSH-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination at 680 nm generates singlet oxygen from Sensibeads which diffuses into Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of TSH concentration.
For FT4L, it's a sequential immunoassay where sample is incubated with biotinylated antibody. T3 Chemibeads are added and form bead/biotinylated antibody immunocomplexes with the non-saturated fraction of the biotinylated antibody. Sensibeads are then added and bind to the biotin to form bead pair immunocomplexes. Illumination at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is an inverse function of FT4 concentration.
The document provided is a 510(k) clearance letter from the FDA for two in-vitro diagnostic (IVD) devices: Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L). It describes the devices, their intended use, and the performance characteristics tested to demonstrate substantial equivalence to previously cleared predicate devices.
However, it's crucial to understand that this document describes a reagent cartridge, which is a laboratory assay, not an AI/ML-driven device or an imaging device. Therefore, many of the requested criteria (e.g., sample size for training/test sets for AI, data provenance like country of origin for AI, ground truth establishment by experts, adjudication methods, MRMC studies, standalone AI performance) are not applicable to this type of device. The document details the performance of the assay itself in measuring biomarker concentrations, not an AI's ability to interpret images or assist human readers.
I will interpret the request based on the information provided for this specific IVD device, noting where certain requested details are not relevant to the nature of the device.
Acceptance Criteria and Study to Prove Device Meets Criteria (for an IVD Reagent Cartridge)
The device in question, a reagent cartridge for quantitative measurement of TSH and FT4, is a laboratory assay, not an AI/ML or imaging interpretation device. Therefore, the "acceptance criteria" and "study" are focused on analytical performance characteristics (accuracy, precision, linearity, interference, detection limits, etc.) compared to a predicate device, rather than diagnostic accuracy metrics of an AI.
1. Table of Acceptance Criteria and Reported Device Performance
For an IVD reagent cartridge, "acceptance criteria" are typically defined by ranges, limits, or statistical agreementsdemonstrating analytical performance comparable or superior to the predicate device and meeting relevant clinical or analytical standards (e.g., CLSI guidelines). The reported performance demonstrates that the modified devices meet these standards.
| Performance Characteristic | Acceptance Criteria (Implicit from CLSI Guidelines/Predicate Comparison) | Reported Device Performance (TSHL) | Reported Device Performance (FT4L) |
|---|---|---|---|
| Detection Limits | Meet/Be comparable to predicate; within acceptable analytical ranges. | LoB: 0.003 µIU/LLoD: 0.005 µIU/LLoQ: 0.007 µIU/L | LoB: 0.03 ng/dLLoD: 0.05 ng/dLLoQ: 0.06 ng/dL |
| Linearity / Measuring Interval | Linear across the claimed measuring range with acceptable bias. | 0.007 – 100 µIU/mL | 0.1 – 8.0 ng/dL |
| Method Comparison (vs. Predicate) | High correlation (r close to 1), slope close to 1, small y-intercept. | N=145 Serum samplesy = 0.99x + 0.039 µIU/mL(Correlation (r) implicitly high, as regression equation suggests strong agreement) | N=146 Serum samplesy = 1.02x + 0.03 ng/dL(Correlation (r) implicitly high, as regression equation suggests strong agreement) |
| Precision (Repeatability) | Within-run and total precision (SD/CV) within acceptable clinical laboratory limits. | TSHL: Levels 0.110-88.676 µIU/mLWithin-Run %CV: 2.6-4.4%Total %CV: 1.1-3.0% (Note: Table 5 "Total" %CV for Level 1 is 2.6%, matching within-run %CV, but for others, it's lower. This might be a typo in the table, typically Total CV > Within-Run CV). | FT4L:Levels 0.81-6.41 ng/dLWithin-Run %CV: 2.2-2.6%Total %CV: 0.9-1.1% |
| Precision (Reproducibility) | Total reproducibility (SD/CV) across lots and systems within acceptable clinical laboratory limits. | TSHL:Levels 0.094-81.372 µIU/mLReproducibility %CV: 4.6-7.6% | FT4L:Levels 0.70-6.49 ng/dLReproducibility %CV: 1.8-2.4% |
| Recovery (Dilution) | For TSHL, diluted samples should show recovery close to 100% of the true value. | TSHL:Recovery ranged from 100% to 106% for various samples diluted 5x. | N/A (FT4L not described for dilution recovery) |
| Interference (Biotin) | Modified assay shows significantly reduced interference compared to predicate. | TSHL & FT4L: Specimens with biotin up to 1200 ng/mL demonstrate ≤10% change in results (significant improvement from predicate's 250 ng/mL for TSHL and 100 ng/mL for FT4L). | TSHL & FT4L: Specimens with biotin up to 1200 ng/mL demonstrate ≤10% change in results. |
| Reference Range Verification | Results from healthy samples confirm the established reference intervals. | TSHL: Verified for adults (0.358-3.74 µIU/mL) and pediatric populations. | FT4L: Verified for adults (0.76-1.46 ng/dL) and pediatric populations. |
| Matrix Comparison | Comparable performance across different sample matrices. | Comparable values to serum samples for lithium heparin, sodium heparin, and K2-EDTA plasma. | Same as TSHL. |
| Hook Effect | No significant hook effect within specified range. | No hook effect observed up to 30,000 µIU/mL. | N/A (FT4L not described for hook effect) |
2. Sample Sizes and Data Provenance for the Test Set
The concept of a "test set" in the context of an IVD reagent cartridge refers to the set of samples used for various analytical performance studies. These are not typically split into "training" and "test" sets as in AI/ML.
- Method Comparison:
- TSHL: 145 patient samples (serum)
- FT4L: 146 patient samples (serum)
- Precision (Repeatability): 5 serum samples (TSHL), 3 serum samples (FT4L)
- Precision (Reproducibility): 5 serum samples (TSHL), 3 serum samples (FT4L)
- Linearity: Low and high human serum pools used to create dilution series (TSHL: 12 levels, FT4L: 10 levels)
- Interference (Biotin and HIL): Samples spiked with interferents, specific TSH/FT4 levels tested.
- Dilution Recovery: 7 samples (TSHL)
- Reference Range Verification: "Apparently healthy samples" (specific N not provided, but typically a statistically significant number for verification per CLSI EP28-A3C).
- Matrix Comparison: Samples of various tube types (Serum, lithium heparin, sodium heparin, K2-EDTA plasma)
Data Provenance: The document does not specify the country of origin of the patient samples. The studies are explicitly described as analytical performance studies rather than clinical outcome studies, and they are retrospective (samples tested in the lab, not followed prospectively).
3. Number of Experts and Qualifications for Ground Truth
This is not applicable as the device is a quantitative IVD assay (reagent cartridge), not an AI/ML device requiring expert interpretation of complex clinical data or images. The "ground truth" for this device is the actual concentration of TSH or FT4 in the sample, typically established either by:
- Reference methods (e.g., mass spectrometry, although not explicitly stated as the ground truth method here).
- The predicate device itself (as used in method comparison studies, where the predicate is the "comparison assay").
- Spiking known concentrations into matrices.
4. Adjudication Method for the Test Set
This is not applicable for a quantitative IVD reagent. Adjudication methods (e.g., 2+1, 3+1) are typically used in scenarios where human experts interpret data (like medical images), and their disagreements need to be resolved to establish a definitive ground truth for AI model evaluation.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
This is not applicable. An MRMC study is designed to evaluate the diagnostic performance of human readers, often with and without AI assistance, on a set of cases. This device is a reagent cartridge that provides a quantitative measurement, not an AI that assists human interpretation.
6. Standalone Performance (Algorithm Only Without Human-in-the-Loop)
This is not applicable. This device is a reagent cartridge that runs on an automated system, providing a quantitative result. It's inherently "standalone" in providing the measurement, but it's not an "algorithm only" in the sense of an AI interpreting complex data. The performance metrics listed (precision, accuracy relative to predicate, linearity, etc.) are its "standalone" performance.
7. Type of Ground Truth Used
The "ground truth" for this type of quantitative diagnostic test is based on:
- Comparison to a legally marketed predicate device: The current, FDA-cleared versions of the TSHL and FT4L assays (K081074 and K073604) acted as the "gold standard" or comparison method for the method comparison studies.
- Known concentrations: For linearity, recovery, and interference studies, samples were prepared with known concentrations or spiked with known amounts of analytes or interferents.
- Analytically verified samples: Samples used for precision studies have mean values derived from repeated measurements.
8. Sample Size for the Training Set
This is not applicable as the device is a non-AI/ML IVD reagent cartridge. There is no concept of a "training set" for this type of product. The development and optimization of the reagent formulation are internal processes, but they don't involve "training" a model on a dataset in the AI sense.
9. How Ground Truth for the Training Set Was Established
This is not applicable for the same reason as point 8.
U.S. Food & Drug Administration 510(k) Clearance Letter
Page 1
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
www.fda.gov
Doc ID # 04017.07.05
April 25, 2025
Siemens Healthcare Diagnostics Inc.
Yevgenia Sarkisian
Regulatory Affairs Professional
500 GBC Drive
Newark, Delaware 19714
Re: K243570
Trade/Device Name: Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL); Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L)
Regulation Number: 21 CFR 862.1690
Regulation Name: Thyroid Stimulating Hormone Test System
Regulatory Class: Class II
Product Code: JLW, CEC
Dated: March 13, 2025
Received: March 14, 2025
Dear Yevgenia Sarkisian:
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 (the 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 available 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.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
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K243570 - Yevgenia Sarkisian
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Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 801 and Part 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/unique-device-identification-system-udi-system.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-devices/medical-device-safety/medical-device-reporting-mdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-
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K243570 - Yevgenia Sarkisian
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assistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Paula V. Caposino -S
Paula Caposino, Ph.D.
Deputy Director
Division of Chemistry and Toxicology Devices
OHT7: Office of In Vitro Diagnostics
Office of Product Evaluation and Quality
Center for Devices and Radiological Health
Enclosure
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FORM FDA 3881 (8/23)
Page 1 of 1
PSC Publishing Services (301) 443-6740 EF
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Indications for Use
Form Approved: OMB No. 0910-0120
Expiration Date: 07/31/2026
See PRA Statement below.
510(k) Number (if known): K243570
Device Name:
Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL)
Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L)
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.
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.
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)
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:
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"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."
Page 5
510(k) Summary
Siemens Healthcare Diagnostics Inc.
Traditional 510(k) Pre-Market Notification
K243570
Page 1 of 10
This 510(k) summary of safety and effectiveness information is submitted in accordance with the requirements of 21 CFR 807.92 and SMDA 1990.
The assigned 510(k) number is: K243570
I. Applicant Information
Contact Person: Yevgenia Jenny Sarkisian
Address: Siemens Healthcare Diagnostics Inc.
500 GBC Drive, M/S 514
Newark, DE 19714
E-mail: yevgenia.sarkisian@siemens-healthineers.com
Phone: 302-437-5949
Date of Preparation: March 13, 2025
II. Regulatory Information
| Proprietary Name | Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) | Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) |
|---|---|---|
| Common Name | Radioimmunoassay, thyroid-stimulating hormone | Radioimmunoassay, free thyroxine |
| Classification Name | Thyroid-stimulating hormone test system | Free thyroxine test system |
| Regulation Number | 21 CFR 862.1690 | 21 CFR 862.1695 |
| Classification | Class II | Class II |
| Product Code | JLW | CEC |
| Review Panel | Clinical Chemistry | Clinical Chemistry |
III. Predicate Device Information
The predicate devices, Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) are manufactured by Siemens Healthcare Diagnostics Inc., Newark, DE, USA, and were cleared by the FDA under the following K numbers.
| Name | Predicate 510(k) |
|---|---|
| Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) | K081074 |
| Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) | K073604 |
IV. Device Description
The Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) assays were cleared under K081074 and K073604, respectively. The components of the cleared assays were modified to reduce biotin interference.
The modified Assays are comprised of the following components:
Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL)
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Siemens Healthcare Diagnostics Inc.
Traditional 510(k) Pre-Market Notification
K243570
Page 2 of 10
The modified Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL) consists of prepackaged liquid reagents in a plastic eight-well cartridge. The components of each well are listed in the below table:
| Wells | Form | Ingredient | Concentration | Source |
|---|---|---|---|---|
| 1 – 2 | Liquid | Biotinylated TSH antibody | 7.5 µg/mL | Mouse monoclonal |
| 3 – 4 | Liquid | TSH antibody coated Chemibeads | 200 µg/mL | Mouse monoclonal |
| 5 – 6 | Liquid | Streptavidin Sensibeads | 1400 µg/mL | Recombinant E. coli |
| 7 – 8 | Empty |
a. Wells are numbered consecutively from the wide end of the cartridge.
b. Wells 1 – 6 contain buffers, stabilizers and preservatives.
c. Nominal value per well in a cartridge.
Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L)
The modified Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L) consists of prepackaged liquid reagents in a plastic eight-well cartridge. The components of each well are listed in the below table:
| Wells | Form | Ingredient | Concentration | Source |
|---|---|---|---|---|
| 1 – 2 | Liquid | Streptavidin Sensibeads | 225 µg/mL | Recombinant E. coli |
| 3 – 4 | Liquid | T3 Chemibeads | 200 µg/mL | |
| 5 – 6 | Liquid | FT4 Biotinylated antibody | 50 ng/mL | Mouse monoclonal |
| 7 – 8 | Empty |
a. Wells are numbered consecutively from the wide end of the cartridge.
b. Wells 1 – 6 contain buffers, stabilizers and preservatives.
c. Nominal value per well in a cartridge.
Test Principle
Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL)
The Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge method is a homogeneous, sandwich chemiluminescent immunoassay based on LOCI® technology. The LOCI® reagents include two synthetic bead reagents and a biotinylated anti-TSH monoclonal fragment. The first bead reagent (Sensibeads) is coated with streptavidin and contains a photosensitizer dye. The second bead reagent (Chemibeads) is coated with second anti-TSH monoclonal antibody and contains chemiluminescent dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-TSH-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direction function of the TSH concentration in the sample.
Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L)
The Dimension LOCI Free Thyroxine Flex reagent cartridge method is a homogeneous, sequential, chemiluminescent immunoassay based on LOCI® technology. The LOCI® reagents include two synthetic bead reagents and a biotinylated anti-T4 mouse monoclonal antibody. The first bead reagent (Chemibeads) is coated with triiodothyronine (T3), a naturally occurring, weaker binding analog of T4, and contains chemiluminescent dye. The second bead reagent (Sensibeads) is coated with streptavidin and contains a photosensitizer dye. In a first step, sample is incubated with biotinylated antibody which allows T4 from the sample to saturate a fraction of the biotinylated antibody that is directly related to the free thyroxine (FT4) concentration. In a second step, T3 Chemibeads are added and form bead/biotinylated antibody immunocomplexes with the non-saturated fraction of the biotinylated antibody.
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Siemens Healthcare Diagnostics Inc.
Traditional 510(k) Pre-Market Notification
K243570
Page 3 of 10
Sensibeads are then added and bind to the biotin to form bead pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is an inverse function of the FT4 concentration in the sample.
V. Intended Use / Indications for Use
Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL)
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.
Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L)
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.
VI. Comparison to Predicate Device
Table 1. Comparison Table of Candidate and Predicate Device
| Attribute | Candidate Device | Predicate Device |
|---|---|---|
| Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL), Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) | Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) (K081074) Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) (K073604) | |
| Intended Use / Indications for Use | TSHL: 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. FT4L: 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. | Same |
| Analyte | TSHL: Thyroid Stimulating Hormone FT4L: Free Thyroxine (FT4) | Same |
| Automated | Automated assay | Same |
| Measurement | Quantitative | Same |
| Sample Type | Serum, lithium and sodium heparin, or EDTA plasma | Same |
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Siemens Healthcare Diagnostics Inc.
Traditional 510(k) Pre-Market Notification
K243570
Page 4 of 10
| Detection Limit | TSHL: Limit of Blank (LoB) = 0.003 µIU/mL (0.003 mIU/L) Limit of Detection (LoD) = 0.005 µIU/mL (0.005 mIU/L) Limit of Quantitation (LoQ) = 0.007 µIU/mL (0.007 mIU/L) FT4L: Limit of Blank (LoB) = 0.03 ng/dL (0.4 pmol/L) Limit of Detection (LoD) = 0.05 ng/dL (0.6 pmol/L) Limit of Quantitation (LoQ) = 0.06 ng/dL (0.8 pmol.L) | TSHL: Limit of Blank (LoB) = 0.0025 µIU/mL [mIU/L] Limit of Detection (LoD) = 0.004 µIU/mL [mIU/L] FT4L: Limit of Blank (LoB) = 0.03 ng/dL (0.39 pmol/L) Limit of Detection (LoD) = 0.06 ng/dL (0.77 pmol/L) |
| Assay Measuring Interval | TSHL: 0.007 – 100 µIU/mL (mIU/L) FT4L: 0.1 – 8.0 ng/dL (1.3 – 103 pmol/L) | Same |
| Operating Principle | Immunologic sandwich | Same |
| Technology | Direct chemiluminescent | Same |
| Instrument | Dimension® EXL™ integrated chemistry system with LOCI® Module | Same |
| Sample Volume | TSHL: 12 µL FT4L: 10 µL | Same |
| Calibrator | LOCI Thyroid Calibrator | Same |
| Controls | Commercially available | Same |
| Interfering Substances - Biotin | TSHL and FT4L: Specimens that contain biotin at a concentration of 1200 ng/mL demonstrate a less than or equal to 10% change in results. Biotin concentrations greater than this may lead to falsely elevated results for patient samples. | TSHL: Biotin concentration of 250 ng/mL demonstrate a less than or equal to 10% change in results. FT4L: Biotin concentration of 100 ng/mL demonstrate a less than or equal to 10% change in results. |
| Non-Interfering Substances - Biotin | TSHL and FT4L: Substance Test Concentration SI Units Biotin 1200 ng/mL 4908 mmol/L | N/A |
VII. Summary of Performance Testing
Substantial equivalence of the modified Dimension® LOCI® Thyroid Stimulating Hormone Flex® reagent cartridge (TSHL) and Dimension® LOCI® Free Thyroxine Flex® reagent cartridge (FT4L) assays was demonstrated by testing performance characteristics including detection capability, linearity, method comparison, precision, recovery, interference, hook effect, reference range and matrix comparison.
The following performance data are provided in support of a substantial equivalence determination.
i. Detection Limits
Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) were determined in
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accordance with CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – Second Edition. The LoB, LoD, and LoQ estimates are summarized in the table below:
Table 2. Detection Capability
| Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L) | Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL) | |
|---|---|---|
| LoB | 0.03 ng/dL (0.4 pmol/L) | 0.003 µIU/L (0.003 mIU/L) |
| LoD | 0.05 ng/dL (0.6 pmol/L) | 0.005 µIU/L (0.005 mIU/L) |
| LoQ | 0.06 ng/dL (0.8 pmol.L) | 0.007 µIU/L (0.007 mIU/L) |
ii. Measuring Interval / Linearity
Linearity studies were conducted with one (1) reagent lot consistent with the governing standard CLSI EP06-ED2: Evaluation of the Linearity of Quantitative Measurement Procedures.
Low and high human serum pools were used for the linearity study. A dilution series composed of 12 levels for Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge and 10 levels for Dimension LOCI Free Thyroxine Flex reagent cartridge was prepared by mixing the low and high pools. Measurements were made with N=5 replicates per level. Expected low and high sample values were assigned as the mean of the 5 replicates from one reagent lot. The expected values for the middle levels were calculated from high and low pool values and the dilution factors. Bias was calculated for each sample as the difference between the mean observed value and the value predicted by the linear regression model. These were converted into % Bias values, with respect to the predicted value for each sample, as appropriate and compared to the acceptance criteria.
Linearity was confirmed across the assay range by acceptable ADL at each individual level and supports the measuring interval of:
- Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL): 0.007 – 100 µIU/mL (mIU/L)
- Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L): 0.1 – 8.0 ng/dL (1.3 – 103 pmol/L)
iii. Method Comparison: Quantitative Assay
The method comparison study was run according to the guidance from CLSI EP09c, 3rd ed Measurement Procedure Comparison and Bias Estimation Using Patient Samples.
The method comparison study was performed comparing the modified device to the currently marketed device. A single replicate was processed for each sample. Two replicates were processed for each sample and the first replicate was analyzed. Slope and Y-intercept and Correlation (r) results were generated using Deming regression.
Table 3. Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL): A total of 145 patient samples covering the full range of the assay were analyzed and included in the final analysis.
| Lot | Specimen Type | Comparison Assay (x) | N | Regression Equation |
|---|---|---|---|---|
| 1 | Serum | TSHL commercial formulation | 145 | y = 0.99x + 0.039 µIU/mL |
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Table 4. Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L): A total of 146 patient samples covering the full range of the assay were analyzed and included in the final analysis.
| Lot | Specimen Type | Comparison Assay (x) | N | Regression Equation |
|---|---|---|---|---|
| 1 | Serum | FT4L commercial formulation | 146 | y = 1.02x + 0.03 ng/dL |
iv. Verification of Assay Precision
Repeatability studies were conducted on three (3) reagent lots on one (1) Dimension EXL analyzer in accordance with CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures.
Testing was performed on five (5) serum samples for Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge and three (3) serum samples for Dimension LOCI Free Thyroxine Flex reagent cartridge, spanning the range of the assay. Each sample was tested in duplicate over a period of 20 days, two runs per day.
Table 5. Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL): Repeatability
| Level | Mean (µIU/mL) | Within-Run | Total | ||
|---|---|---|---|---|---|
| SD (µIU/mL) | %CV | SD (µIU/mL) | %CV | ||
| 1 | 0.110 | 0.0040 | 3.6% | 0.0029 | 2.6% |
| 2 | 0.372 | 0.0116 | 3.1% | 0.0069 | 1.9% |
| 3 | 3.765 | 0.1209 | 3.2% | 0.0802 | 2.1% |
| 4 | 15.208 | 0.3936 | 2.6% | 0.3108 | 2.0% |
| 5 | 88.676 | 3.9406 | 4.4% | 2.6218 | 3.0% |
Table 6. Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L): Repeatability
| Level | Mean (ng/dL) | Within-Run | Total | ||
|---|---|---|---|---|---|
| SD (ng/dL) | %CV | SD (ng/dL) | %CV | ||
| 1 | 0.81 | 0.021 | 2.6% | 0.009 | 1.1% |
| 2 | 1.50 | 0.033 | 2.2% | 0.014 | 0.9% |
| 3 | 6.41 | 0.168 | 2.6% | 0.055 | 0.9% |
Reproducibility studies were conducted on three (3) reagent lots on three Dimension EXL analyzers in accordance with CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures.
Testing was performed on five (5) serum samples for Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL) and three (3) serum samples for Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L), spanning the range of the assay. Each sample was tested over a period of five (5) days, five (5) replicates per day.
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Table 7. Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL): Reproducibility
| Level | Mean (µIU/mL) | Repeatability | Between-Day | Between-Lot | Between-System | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SD (µIU/mL) | CV (%) | SD (µIU/mL) | CV (%) | SD (µIU/mL) | CV (%) | SD (µIU/mL) | CV (%) | SD (µIU/mL) | CV (%) | ||
| 1 | 0.094 | 0.0025 | 2.7% | 0.0049 | 5.2% | 0.0022 | 2.3% | 0.0040 | 4.3% | 0.0071 | 7.6% |
| 2 | 0.358 | 0.0088 | 2.5% | 0.0089 | 2.5% | 0.0051 | 1.4% | 0.0163 | 4.6% | 0.0211 | 5.9% |
| 3 | 3.855 | 0.1082 | 2.8% | 0.1193 | 3.1% | 0.0000 | 0.0% | 0.0755 | 2.0% | 0.1778 | 4.6% |
| 4 | 14.425 | 0.3358 | 2.3% | 0.4980 | 3.5% | 0.0117 | 0.1% | 0.3037 | 2.1% | 0.6732 | 4.7% |
| 5 | 81.372 | 2.4293 | 3.0% | 2.8811 | 3.5% | 1.1456 | 1.4% | 0.0000 | 0.0% | 3.9389 | 4.8% |
Table 8. Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L): Reproducibility
| Level | Mean (ng/dL) | Repeatability | Between-Day | Between-Lot | Between-System | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SD (ng/dL) | CV (%) | SD (ng/dL) | CV (%) | SD (ng/dL) | CV (%) | SD (ng/dL) | CV (%) | SD (ng/dL) | CV (%) | ||
| 1 | 0.70 | 0.008 | 1.1% | 0.013 | 1.9% | 0.002 | 0.3% | 0.008 | 1.1% | 0.017 | 2.4% |
| 2 | 1.49 | 0.014 | 0.9% | 0.019 | 1.3% | 0.005 | 0.3% | 0.028 | 1.9% | 0.036 | 2.4% |
| 3 | 6.49 | 0.058 | 0.9% | 0.103 | 1.6% | 0.000 | 0.0% | 0.009 | 0.1% | 0.119 | 1.8% |
v. Recovery
Dilution recovery was conducted with 1 reagent lot consistent with CLSI EP34-ED1:2018 Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking for Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge. Manual dilution of 5x increases the upper end of the measuring interval from 100.000 µIU/mL to 500.000 µIU/mL.
See Table 9 below.
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Table 9. Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL) Dilution Recovery
| Operator | Dilution | Replicate | Sample value (µIU/mL) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | |||
| 1 | 1 | 1 | 28.952 | 92.725 | 35.653 | 34.008 | 24.694 | 38.264 | 31.634 |
| 2 | 28.922 | 90.896 | 36.832 | 34.361 | 22.559 | 37.912 | 30.315 | ||
| 3 | 29.980 | 95.951 | 36.287 | 34.746 | 24.076 | 38.750 | 31.700 | ||
| 2 | 1 | 28.041 | 95.940 | 35.531 | 35.037 | 25.489 | 37.942 | 30.767 | |
| 2 | 28.853 | 96.417 | 32.648 | 34.582 | 24.532 | 38.484 | 32.629 | ||
| 3 | 29.072 | 95.794 | 34.895 | 34.712 | 24.176 | 37.376 | 31.437 | ||
| 2 | 1 | 1 | 27.513 | 98.611 | 35.685 | 35.336 | 23.533 | 36.042 | 29.336 |
| 2 | 28.388 | 99.592 | 34.653 | 35.052 | 23.346 | 35.748 | 28.785 | ||
| 3 | 28.791 | 92.230 | 34.932 | 34.754 | 23.692 | 35.552 | 26.989 | ||
| 2 | 1 | 26.165 | 88.588 | 35.973 | 34.436 | 23.747 | 34.676 | 29.743 | |
| 2 | 28.224 | 92.116 | 35.585 | 34.959 | 22.339 | 33.752 | 28.819 | ||
| 3 | 28.639 | 93.167 | 35.373 | 35.248 | 23.823 | 35.097 | 28.220 |
| Average Value (µIU/mL) | 28.462 | 94.336 | 35.337 | 34.769 | 23.834 | 36.633 | 30.031 |
| Dilution Factor | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
| Estimated Value (µIU/mL) | 142.308 | 471.678 | 176.686 | 173.846 | 119.169 | 183.165 | 150.156 |
| Dimension LOCI TSHL Reagent Cartridge (Predicate Device) Value (µIU/mL) | 137.211 | 470.077 | 167.028 | 165.169 | 119.141 | 174.674 | 147.087 |
| %Recovery | 104% | 100% | 106% | 105% | 100% | 105% | 102% |
vi. Interferences
Hemolysis, Icterus, and Lipemia (HIL) – Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL)
Interference testing for the Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL) method was performed in accordance with CLSI EP07-ED3: Interference Testing in Clinical Chemistry, third edition.
The following substances tested were determined to have no significant interference:
Table 10. Interference HIL Claims – Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL):
| Compound | Interferent test Concentration | TSH Level |
|---|---|---|
| Hemolysis (Hemoglobin) | 500 mg/dL | 0.300 µIU/mL |
| Hemolysis (Hemoglobin) | 750 mg/dL | 8.000 µIU/mL |
| Icterus, Bilirubin (unconjugated) | 60 mg/dL | 0.300 µIU/mL 8.000 µIU/mL |
| Icterus, Bilirubin (conjugated) | 40 mg/dL | 0.300 µIU/mL |
| Icterus, Bilirubin (conjugated) | 60 mg/dL | 8.000 µIU/mL |
| Lipemia (Intralipid®) | 3000 mg/dL | 8.000 µIU/mL |
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Interfering Substances – Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL)
Interference testing was performed in accordance with CLSI EP07-ED3: Interference Testing in Clinical Chemistry, third edition. Specimens that contain biotin at a concentration of 1200 ng/mL demonstrate a less than or equal to 10% change in results. Biotin concentrations greater than this may lead to falsely depressed results for patient samples.
Table 11. Non-Interfering Substances Claims – Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL):
| Compound | Interferent test Concentration | TSH Level |
|---|---|---|
| Biotin | 1200 ng/mL | 0.300 µIU/mL |
Non-Interfering Substances – Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL)
The modifications to the assay to reduce biotin interference does not impact the specificity of the assay to the analyte or to the interferents other than biotin. All non-interfering substances referenced in the Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge Instructions for Use were previously verified and cleared under K081074.
Hemolysis, Icterus, and Lipemia (HIL) – Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L)
Interference testing for the Dimension LOCI Free Thyroxine Flex reagent cartridge method was performed in accordance with CLSI EP07-ED3: Interference Testing in Clinical Chemistry, third edition.
The following substances tested were determined to have no significant interference:
Table 12. Interference HIL Claims – Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L):
| Compound | Interferent test Concentration | FT4 Level |
|---|---|---|
| Hemolysis (Hemoglobin) | 750 mg/dL | 1.10 ng/dL 3.00 ng/dL |
| Icterus, Bilirubin (unconjugated) | 30 mg/dL | 1.10 ng/dL 3.00 ng/dL |
| Icterus, Bilirubin (conjugated) | 26 mg/dL | 1.10 ng/dL 3.00 ng/dL |
| Lipemia (Intralipid®) | 3000 mg/dL | 1.10 ng/dL 3.00 ng/dL |
Interfering Substances – Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L)
Interference testing was performed in accordance with CLSI EP07-ED3: Interference Testing in Clinical Chemistry, third edition. Specimens that contain biotin at a concentration of 1200 ng/mL demonstrate a less than or equal to 10% change in results. Biotin concentrations greater than this may lead to falsely depressed results for patient samples.
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Table 13. Non-Interfering Substances Claims – Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L):
| Compound | Interferent test Concentration | FT4 Level |
|---|---|---|
| Biotin | 1200 ng/mL | 1.10 ng/dL 3.00 ng/dL |
Non-Interfering Substances – Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L)
The modifications to the assay to reduce biotin interference does not impact the specificity of the assay to the analyte or to the interferents other than biotin. All non-interfering substances referenced in the Dimension LOCI Free Thyroxine Flex reagent cartridge Instructions for Use were previously verified and cleared under K073604.
vii. Hook Effect
No hook effect was observed up to 30,000 µIU/mL for Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge.
viii. Verification of Reference Range
The reference range was verified by assaying apparently healthy samples according to CLSI EP28- A3C: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory. The existing reference ranges were verified:
Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (TSHL):
- Adults (age 21-65): 0.358 - 3.74 µIU/mL
- Pediatric populations:
- Infants (01-23 months): 0.867 - 6.43 µIU/mL
- Children (02-12 years): 0.704 - 4.01 µIU/mL
- Adolescents (13-20 years): 0.516 - 4.13 µIU/mL
Dimension LOCI Free Thyroxine Flex reagent cartridge (FT4L):
- Adults (age 21-65): 0.76 – 1.46 ng/dL
- Pediatric populations:
- Infants (01-23 months): 0.93 – 1.45 ng/dL
- Children (02-12 years): 0.82 – 1.40 ng/dL
- Adolescents (13-20 years): 0.78 – 1.34 ng/dL
Siemens provides this information for reference. As with all in vitro diagnostic assays, each laboratory should determine its own reference ranges for the diagnostic evaluation of patient results. Consider these values as a guideline only.
ix. Matrix Comparison
The matrix comparison/specimen equivalence study was performed to evaluate the performance using different tube types (Serum, lithium heparin, sodium heparin and K2-EDTA) comparing plasma to serum. The study demonstrated comparable values to serum samples.
VIII. Conclusion
These performance studies support that the modified Candidate Devices, Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge and Dimension LOCI Free Thyroxine Flex reagent cartridge are substantially equivalent to the currently marketed Predicate Devices, Dimension LOCI Thyroid Stimulating Hormone Flex reagent cartridge (K081074) and Dimension LOCI Free Thyroxine Flex reagent cartridge (K073604).
§ 862.1690 Thyroid stimulating hormone test system.
(a)
Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known as thyrotrophin and thyrotrophic hormone, in serum and plasma. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.(b)
Classification. Class II.