(85 days)
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of thyrotropin (TSH) in serum. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of non-protein-bound thyroxine (free T4) in serum and heparinized plasma. Measurements of free thyroxine are used in the diagnosis and treatment of thyroid disease.
Not Found
The provided text describes a 510(k) submission for the IMMULITE 2000 Third Generation TSH and IMMULITE 2000 Free T4 assays. The submission primarily focuses on adding pediatric reference intervals to the device's labeling and asserts that no modifications to the device's design or manufacturing processes are required, thus the predicate devices and subject devices are the same. This means that no new device performance studies were conducted for this specific submission, as the changes are limited to labeling updates based on existing assay capabilities and establishing new reference intervals for a specific population.
Therefore, the requested information regarding acceptance criteria and device performance for a new device study is largely not applicable in the context of this 510(k) summary, as it explicitly states that additional analytical performance data is not needed. The document emphasizes that existing performance characteristics continue to apply.
However, I can extract information related to the establishment of the pediatric reference intervals, which is a form of study performed to define normative values for a specific population for the device.
1. Table of Acceptance Criteria and Reported Device Performance
Since this submission is about establishing new reference intervals for an already approved device and not evaluating the device's analytical performance against new acceptance criteria, the "acceptance criteria" here refer to the statistical methodology used for defining these reference intervals. The "reported device performance" is the established reference interval.
| Parameter | Acceptance Criteria (Methodology for Reference Interval Establishment, per CLSI EP28-A3c) | Reported Device Performance (Established Pediatric Reference Intervals) |
|---|---|---|
| IMMULITE 2000 Free T4 | ||
| Infants (01 – 23 months) | Robust Symmetric (90% CI for Lower/Upper Limit) | 0.80 – 1.27 ng/dL (10.3 – 16.3 pmol/L) |
| Children (02 – 12 years) | Non-Parametric | 0.74 – 1.28 ng/dL (9.5 – 16.5 pmol/L) |
| Adolescents (13 – 20 years) | Non-Parametric | 0.75 – 1.27 ng/dL (9.7 – 16.3 pmol/L) |
| IMMULITE 2000 Third Gen TSH | ||
| Infants (01 – 23 months) | Robust Symmetric after Log Transform (90% CI for Lower/Upper Limit) | 0.83 – 6.5 µIU/mL (mIU/L) |
| Children (02 – 12 years) | Non-Parametric | 0.58 – 4.1 µIU/mL (mIU/L) |
| Adolescents (13 – 20 years) | Non-Parametric | 0.39 – 4.0 µIU/mL (mIU/L) |
Note: The primary "acceptance criteria" for this submission are that the methods used for establishing the reference intervals conform to CLSI EP28-A3c guidance and that the established pediatric reference intervals fall within the existing analytical measuring capability of the assay.
2. Sample size used for the test set and the data provenance
IMMULITE 2000 Free T4:
- Sample Size: A total of 426 patients were analyzed:
- Infants (01 – 23 months): 81
- Children (02 – 12 years): 197
- Adolescents (13 – 20 years): 148
- Data Provenance: The document does not specify the country of origin of the data. It is prospective testing, as it states "Data from a total of [N] patients... tested with the IMMULITE 2000 Free T4 assay were analyzed to establish the reference intervals."
IMMULITE 2000 Third Generation TSH:
- Sample Size: A total of 433 patients were analyzed:
- Infants (01 – 23 months): 90
- Children (02 – 12 years): 195
- Adolescents (13 – 20 years): 148
- Data Provenance: The document does not specify the country of origin of the data. Similar to Free T4, this appears to be prospective testing based on the phrasing "Data from a total of [N] patients... tested with the IMMULITE 2000 Third Generation TSH assay were analyzed to establish the reference intervals."
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
For reference interval studies, the "ground truth" is typically defined by statistical methods applied to a population defined as "healthy" or "normal" for the analyte in question, rather than through expert consensus on individual cases. The document states that the reference intervals were established per the CLSI EP28-A3c guideline: "Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory." This guideline outlines statistical procedures for determining reference intervals. Therefore, independent experts for case-by-case ground truth establishment are not typically involved in this type of study. The expertise lies in the clinical chemists or statisticians who apply the CLSI guideline.
4. Adjudication method for the test set
Not applicable. Reference interval studies do not typically involve adjudication of individual cases in the way diagnostic accuracy studies do. The process involves identifying a healthy reference population and then statistically determining the range of values for that population.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
Not applicable. This submission is for an in-vitro diagnostic (IVD) assay (a lab test), not an AI-based diagnostic imaging or interpretive device that would involve human readers or AI assistance in that context.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Not applicable. This is an IVD assay, which generates quantitative results. The device itself is the "standalone" component in the sense that it performs the measurement. The establishment of reference intervals is for interpreting these quantitative results within a specific population.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The "ground truth" for the pediatric reference interval studies relies on the selection of a "healthy" pediatric population (presumably free from known thyroid or pituitary disorders) from whom samples were collected and tested. The reference intervals are then statistically derived from the measurements of these healthy individuals, following CLSI EP28-A3c guidelines. This is a statistical definition of "normal range" within a defined population rather than a case-specific ground truth like pathology or expert consensus for individual diagnoses. The assumption is that the participants in these groups represented a healthy pediatric population for thyroid function.
8. The sample size for the training set
Not applicable in the typical sense of machine learning. The data described (426 for Free T4, 433 for TSH) is used to establish the reference intervals (similar to a development/validation set in traditional statistics), rather than "training" an algorithm that would then be separately tested. The entire dataset is used to directly calculate the intervals.
9. How the ground truth for the training set was established
Not applicable as a "training set." The "ground truth" for the reference interval establishment relies on the statistical methodology (Robust Symmetric, Non-Parametric) applied to a population described as healthy, as per CLSI EP28-A3c. The selection criteria for this "healthy" pediatric population are implied to be part of the study design to appropriately define the "normal" range.
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May 31, 2016
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
SIEMENS HEALTHCARE DIAGNOSTICS INC. MATTHEW GEE SENIOR MANAGER, REGULATORY AFFAIRS 511 BENEDICT AVENUE TARRYTOWN, NY 10591
Re: K160647
Trade/Device Name: IMMULITE 2000 Third Generation TSH IMMULITE 2000 Free T4 Regulation Number: 21 CFR 862.1690 Regulation Name: Thyroid stimulating hormone test system Regulatory Class: II Product Code: JLW. CEC Dated: March 4, 2016 Received: March 7, 2016
Dear Matthew Gee:
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 regulation (21 CFR Part 801), 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" (21CFR 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 vours.
Katherine Serrano -S
For :
Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.
510(k) Number (if known)
Device Name IMMULITE® 2000 Third Generation TSH IMMULITE® 2000 Free T4
Indications for Use (Describe)
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of thyrotropin (TSH) in serum. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of nonprotein-bound thyroxine (free T4) in serum and heparinized plasma. Measurements of free thyroxine are used in the diagnosis and treatment of thyroid disease.
| Type of Use (Select one or both, as applicable) |
|---|
| ------------------------------------------------- |
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.
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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: K160647
Date Prepared 1.
May 3, 2016
Applicant Information 2.
| Contact: | Matthew Gee, M.Sc.Senior Manager, Regulatory Affairs |
|---|---|
| Address: | Siemens Healthcare Diagnostics Inc.511 Benedict AvenueTarrytown, NY 10591-5097 |
| Phone: | 914-524-2099 |
| Fax: | 914-524-3579 |
| Email: | matthew.gee@siemens.com |
3. Regulatory Information
Table 1. Regulatory Information for IMMULITE 2000 Third Generation TSH and Free T4
| Third Generation TSH | Free T4 | |
|---|---|---|
| Trade Name | IMMULITE® 2000Third Generation TSH | IMMULITE® 2000Free T4 |
| Model Numbers | L2KTS2 (200 tests)L2KTS6 (600 tests) | L2KFT42 (200 tests)L2KFT46 (600 tests) |
| Common Name | Radioimmunoassay, thyroid-stimulating hormone | Radioimmunoassay,free thyroxine |
| Classification Name | Thyroid stimulating hormone testsystem | Free thyroxine test system |
| Product Code | JLW | CEC |
| Regulation Number | 862.1690 | 862.1695 |
| FDA Classification | Class II | Class II |
| Review Panel | Clinical Chemistry | Clinical Chemistry |
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Predicate Device Information 4.
The Predicate Device for the modified IMMULITE 2000 Free T4 assay is the unmodified IMMULITE 2000 Free T4 assay (K083373).
The Predicate Device for the modified IMMULITE 2000 Third Generation TSH assay is the unmodified IMMULITE 2000 Third Generation TSH assay (described in K970227).
The modifications to the IMMULITE 2000 Free T4 and Third Generation TSH assays to add pediatric reference intervals to the Package Inserts are limited to changes in labeling. The update of reference intervals does not require modifications to the design or manufacturing processes of the devices. Therefore, the predicate devices and subject devices are the same.
5. Substantial Equivalence Information
The following table demonstrates substantial equivalence between the predicate IMMULITE 2000 Free T4 (K083373) and the IMMULITE 2000 Free T4 which has modified Instructions for Use (Package Inserts) with added pediatric reference intervals.
| Item | Predicate Device (K083373)with Unmodified Labeling | Subject Devicewith Updated Reference Intervals |
|---|---|---|
| Analytes | free thyroxine (T4) | Same |
| Instruments | IMMULITE 2000 systems | Same |
| Intended UseStatements | For in vitro diagnostic use with theIMMULITE® 2000 SystemsAnalyzers — for the quantitativemeasurement of non-protein-boundthyroxine (free T4) in serum andheparinized plasma, as an aid in theclinical assessment of thyroidstatus. | For in vitro diagnostic use with theIMMULITE® 2000 SystemsAnalyzers — for the quantitativemeasurement of non-protein-boundthyroxine (free T4) in serum andheparinized plasma. Measurementsof free thyroxine are used in thediagnosis and treatment of thyroiddisease. |
| AnalyticalMeasuring Range(Assay Range) | 0.30 - 6.00 ng/dL(3.9 - 77.2 pmol/L) | Same |
| AdultReference Ranges | EuthyroidHypothyroidHyperthyroid | Same |
| PediatricReference Intervals | None | Infants: 01 – 23 monthsChildren: 02 – 12 yearsAdolescents: 13 – 20 years |
Table 2. Summary of Substantial Equivalence for IMMULITE 2000 Free T4
The following table demonstrates substantial equivalence between the predicate IMMULITE 2000 Third Generation TSH (described in K970227) and the IMMULITE 2000 Third Generation TSH which has modified Instructions for Use (Package Inserts) with updated pediatric reference intervals.
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| Item | Predicate Device (K970227)with Unmodified Labeling | Subject Devicewith Updated Reference Intervals |
|---|---|---|
| Analytes | thyroid stimulating hormone (TSH) | Same |
| Instruments | IMMULITE 2000 systems | Same |
| Intended UseStatements | For in vitro diagnostic use with theIMMULITE® 2000 SystemsAnalyzers — for the quantitativemeasurement of thyrotropin (TSH)in serum, as an aid in the clinicalassessment of thyroid status. | For in vitro diagnostic use with theIMMULITE® 2000 SystemsAnalyzers — for the quantitativemeasurement of thyrotropin (TSH)in serum. Measurements of thyroidstimulating hormone produced bythe anterior pituitary are used in thediagnosis of thyroid or pituitarydisorders. |
| AnalyticalMeasuring Range(Assay Range) | 0.004 – 75 μIU/mL (mIU/L) | Same |
| AdultReference Ranges | EuthyroidHyperthyroid | Same |
| PediatricReference Intervals | Groupings by age (in years) from1 year to 12 years | Infants: 01 – 23 monthsChildren: 02 – 12 yearsAdolescents: 13 – 20 years |
Table 3. Summary of Substantial Equivalence for IMMULITE 2000 Third Generation TSH
Standard/Guidance Document Reference 6.
Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -- Third Edition (CLSI EP28-A3c); FDA Recognition Number 7-224.
7. Pediatric Reference Intervals
Free T4
Data from a total of 426 patients (81 infants, 197 children, 148 adolescents) tested with the IMMULITE 2000 Free T4 assay were analyzed to establish the reference intervals for the studied pediatric population. Results are described in the following table.
| Group | N | 95% ReferenceInterval | ReferenceIntervalMethodology | 90% ConfidenceInterval for LowerLimit of ReferenceInterval | 90% ConfidenceInterval for UpperLimit of ReferenceInterval |
|---|---|---|---|---|---|
| Infants(01 – 23 months) | 81 | 0.80 – 1.27 ng/dL(10.3 – 16.3 pmol/L) | RobustSymmetric | 0.76 – 0.84 ng/dL(9.8 – 10.8 pmol/L) | 1.23 – 1.32 ng/dL(15.8 – 17.0 pmol/L) |
| Children(02 – 12 years) | 197 | 0.74 – 1.28 ng/dL(9.5 – 16.5 pmol/L) | Non-Parametric | --- | --- |
| Adolescents(13 – 20 years) | 148 | 0.75 – 1.27 ng/dL(9.7 – 16.3 pmol/L) | Non-Parametric | --- | --- |
Table 4. Pediatric 95% Reference Intervals (Free T4)
As taken from information in the existing Instructions for Use (Package Insert), the claim for the euthyroid adult reference range is 0.89 - 1.76 ng/dL (11.5 - 22.7 pmol/L), and the
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current claim for the assay range is 0.30 – 6.00 ng/dL (3.9 – 77.2 pmol/L). This demonstrates that the new pediatric reference intervals are within the analytical measuring capability of the assay.
Third Generation TSH
Data from a total of 433 patients (90 infants, 195 children, 148 adolescents) tested with the IMMULITE 2000 Third Generation TSH assay were analyzed to establish the reference intervals for the studied pediatic population. These pediatric reference intervals, as well as the previously-established euthyroid adult reference intervals and analytical measuring ranges, are presented below.
| Group | N | 95% Reference Interval | Reference Interval Methodology | 90% Confidence Interval for Lower Limit of Reference Interval | 90% Confidence Interval for Upper Limit of Reference Interval |
|---|---|---|---|---|---|
| Infants(01 – 23 months) | 90 | 0.83 – 6.5 µIU/mL(mIU/L) | RobustSymmetric afterLog Transform | 0.70 – 0.99 µIU/mL(mIU/L) | 5.58 – 7.65 µIU/mL(mIU/L) |
| Children(02 – 12 years) | 195 | 0.58 – 4.1 µIU/mL(mIU/L) | Non-Parametric | --- | --- |
| Adolescents(13 – 20 years) | 148 | 0.39 – 4.0 µIU/mL(mIU/L) | Non-Parametric | --- | --- |
Table 5. Pediatric 95% Reference Intervals (Third Generation TSH)
As taken from information in the existing Instructions for Use (Package Insert), the claim for the euthyroid adult reference range is 0.40 - 4.0 µIU/mL (mIU/L), and the current claim for the assay range is 0.004 – 75 µIU/mL (mIU/L). This demonstrates that the new pediatric reference intervals are within the analytical measuring capability of the assay.
Performance Characteristics 8.
The inclusion of pediatric reference intervals in the Instructions for Use (Package Insert) does not necessitate the collection of additional analytical performance data. Therefore, all analytical performance data currently claimed for the IMMULITE Free T4 and Third Generation TSH assays continue to apply to these devices.
Specifically, the following studies are not needed for the purpose of this submission:
- l Precision/Reproducibility
- I Linearity
- l Calibrator/Assay Traceability
- Calibrator/Assay Stability
- l Assay Cut-off
- I Method Comparison
- I Matrix Comparison
- l Sensitivity (Detection Limits, LoB, LoD, LoQ)
- Analytical Specificity
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9. Shelf-Life
The inclusion of pediatric reference intervals in the Instructions for Use (Package Insert) does not necessitate the collection of additional stability data. Therefore, all stability methods, acceptance criteria and data currently claimed for the IMMULITE Free T4 and Third Generation TSH assays continue to apply to these devices.
Specifically, the following stability studies are not needed for the purpose of this submission:
- . Shelf Life Stability
- Onboard Stability
- Open Vial Stability
10. Conclusions
The IMMULITE Free T4 and Third Generation TSH assays with updated pediatric reference intervals are substantially equivalent to the currently marketed IMMULITE Free T4 and Third Generation TSH assays.
The modification of the Instructions for Use (Package Insert) to add/update pediatric reference intervals does not require a change in the device design or a change in the manufacturing process.
All analytical data currently claimed for the IMMULITE Free T4 and Third Generation TSH assays continue to apply to these devices.
The modification of pediatric reference intervals for the IMMULITE Free T4 and Third Generation TSH assays is further supported by the following rationale:
-
- Testing of pediatric patients is within the established indications for use (i.e. for use in the diagnosis of thyroid or pituitary disorders), as described in 21 CFR §862.1695 and 21 CFR §862.1690.
-
- The newly-established pediatric reference intervals are at comparable levels or above the existing reference ranges for euthyroid (normal thyroid) adult populations. In addition, the pediatric reference intervals are well within the analytical measuring ranges of the IMMULITE Free T4 and Third Generation TSH assays. Therefore, the IMMULITE Free T4 and Third Generation TSH assays have appropriate analytical performance to test pediatric patients.
§ 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.