(273 days)
For in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in serum using the ADVIA Centaur, ADVIA Centaur XP and ADVIA Centaur XPT systems. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
The ADVIA Centaur TSH assay is a two-site sandwich immunoassay using direct chemiluminometric technology. It utilizes a ReadyPack Primary Reagent Pack containing both Solid Phase (Polyclonal sheep anti-TSH antibody covalently coupled to paramagnetic particles) and Lite Reagent (Monoclonal mouse anti-TSH antibody labeled with acridinium ester) in separate wells. The assay is performed on the ADVIA Centaur, ADVIA Centaur XP, and ADVIA Centaur XPT systems.
This document is a 510(k) premarket notification for the ADVIA Centaur TSH assay, specifically focusing on its use with the new ADVIA Centaur XPT system. The notification seeks to demonstrate substantial equivalence to the previously cleared ADVIA Centaur TSH assay used with the ADVIA Centaur XP system.
It's important to note that this document does not describe a study proving a device meets acceptance criteria in the traditional sense of a clinical trial for a new diagnostic device. Instead, it focuses on demonstrating that modifications to an existing assay (ADVIA Centaur TSH assay) and a new instrument platform (ADVIA Centaur XPT) do not negatively impact the performance, safety, or effectiveness of the assay, and thus maintain substantial equivalence to the predicate device.
The "acceptance criteria" here are essentially the performance characteristics established for the predicate ADVIA Centaur TSH assay on the ADVIA Centaur XP system. The "study" refers to verification testing done to ensure the modified system (ADVIA Centaur TSH assay on ADVIA Centaur XPT) performs equivalently.
Here's a breakdown of the requested information based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly present a table of acceptance criteria and reported performance in a single section. Instead, it describes changes and states that verification testing met pre-determined acceptance criteria. The key change discussed that directly relates to performance is the Lower Limit of Detection (LoD).
| Performance Metric | Acceptance Criteria (Predicate Device on XP) | Reported Device Performance (Modified Device on XPT) |
|---|---|---|
| Lower Limit of Detection | 0.01 µIU/mL (Based on Analytical Sensitivity) | 0.05 µIU/mL (Based on Limit of Quantitation) |
| Analytical Measuring Range | 0.01-150 µIU/mL | 0.05-150 µIU/mL |
Note: The document states that "All verification testing met pre-determined acceptance criteria." and that the "performance of the ADVIA Centaur TSH assay on the ADVIA Centaur XPT system is substantially equivalent to the ADVIA Centaur TSH assay running on the currently-marketed predicate ADVIA Centaur XP system." This implies that other performance characteristics (e.g., precision, linearity, interference) were evaluated and found to be acceptable, even though specific numerical acceptance criteria and results are not detailed in this summary.
2. Sample Size Used for the Test Set and Data Provenance
The document does not specify the sample size used for the verification testing.
It also does not specify the data provenance (e.g., country of origin, retrospective or prospective). The testing would typically be performed internally by the manufacturer during the development and verification phases of the new instrument and its compatibility with the assay.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
Since this is a submission for an in vitro diagnostic (IVD) device assessing a biomarker (TSH), the "ground truth" for individual sample values is generally established by the device itself or a reference method. It's not a scenario where human experts (like radiologists) establish a ground truth from images. Therefore, this information is not applicable in the context of this document.
4. Adjudication Method for the Test Set
As this is an IVD device measuring a biomarker, the concept of an adjudication method (like 2+1, 3+1 for expert review) for a test set is not applicable. The instrument directly provides quantitative results.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Its Effect Size
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is relevant for medical image analysis where human readers interpret cases, and AI assistance might impact their performance. For an automated in vitro diagnostic assay, this type of study is not applicable.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
The device itself, the ADVIA Centaur TSH assay on the ADVIA Centaur XPT system, operates in a standalone manner. It is an automated in vitro diagnostic test that provides quantitative TSH values. There is no "human-in-the-loop" component in the direct generation of results from the instrument. The results are then used by healthcare professionals for diagnosis.
7. The Type of Ground Truth Used
For a quantitative in vitro diagnostic device like a TSH assay, the "ground truth" for accuracy often refers to:
- Reference methods or highly characterized reference materials for accuracy and calibration.
- Agreement with the predicate device for substantial equivalence demonstrations.
The document implicitly uses agreement with the predicate device (ADVIA Centaur XP system) as the primary "ground truth" for demonstrating substantial equivalence of the modified device (ADVIA Centaur XPT system) performance. The performance of the predicate device itself would have been established against reference methods or clinical outcomes during its initial clearance.
8. The Sample Size for the Training Set
The document does not specify a sample size for a training set. This is because the ADVIA Centaur TSH assay is a reagent-based immunoassay run on an automated instrument, not an AI/ML-based algorithm that typically requires a large training dataset for model development. The "training" for such a system involves calibrating the instrument and assay using specific calibrator materials.
9. How the Ground Truth for the Training Set Was Established
As explained in point 8, there isn't a "training set" in the sense of AI/ML. The "calibration" of the assay utilizes specific calibrator materials. The document states:
- Calibration: "2-point calibration using Calibrator B"
- Calibrators: "Calibrators checked with barcode; Calibrator lot numbers stored and displayed"
The ground truth for these calibrators would have been established by the manufacturer through rigorous testing, potentially against reference methods and with traceability to international standards, to ensure their assigned TSH values are accurate.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
SIEMENS HEALTHCARE DIAGNOSTICS INC. ALEX HSU REGULATORY AND CLINICAL AFFAIRS SPECIALIST 511 BENEDICT AVE. TARRYTOWN NY 10591
April 22, 2015
Re: K141999
Trade/Device Name: ADVIA Centaur TSH Regulation Number: 21 CFR 862.1690 Regulation Name: Thyroid stimulating hormone test system Regulatory Class: II Product Code: JLW Dated: March 25, 2015 Received: March 26, 2015
Dear Alex Hsu:
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 electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
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
510(k) Number (if known) K141999
Device Name ADVIA Centaur TSH
Indications for Use (Describe)
For in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in serum using the ADVIA Centaur, ADVIA Centaur XP and ADVIA Centaur XPT systems. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) | ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
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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: K141999
Date Prepared 1.
April 21, 2015
2. Applicant Information
| Contact: | Alex HsuRegulatory and Clinical Affairs Specialist |
|---|---|
| Address: | Siemens Healthcare Diagnostics Inc.511 Benedict AvenueTarrytown, NY 10591-5097 |
| Phone: | 914-524-3097 |
| Fax: | 914-524-3579 |
| Email: | alex.hsu@siemens.com |
Regulatory Information 3.
Table 1. Regulatory Information for ADVIA Centaur TSH Assay
| Trade Name | ADVIA Centaur ® TSH |
|---|---|
| Model Numbers | 08700387 (5-pack); 04911359 (1-pack) |
| Common Name | Radioimmunoassay, thyroid-stimulating hormone |
| Classification Name | Thyroid stimulating hormone test system |
| FDA Classification | Class II |
| Review Panel | Clinical Chemistry (75) |
| Product Code | JLW |
| Regulation Number | 862.1690 |
Predicate Device Information 4.
The ADVIA Centaur TSH assay was originally cleared by the FDA on 04/30/1991 (K910981) as the ACS TSH Immunoassay.
5. Description of Device Modifications
No changes were made to the ADVIA Centaur TSH assay reagents, calibrators or master curve value assignment in order to run on the ADVIA Centaur XPT.
Previously, the lower limit of detection was based on analytical sensitivity, whereas it is now based on Limit of Quantitation (LoQ). As result, the lower limit of detection has been revised from 0.01 µIU/mL to 0.05 µIU/mL. Accordingly, the analytical measuring range was also modified from 0.01-150 ulU/mL to 0.05-150 µlU/mL.
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| Item | ADVIA Centaur TSH(Unmodified Predicate Device) | ADVIA Centaur TSH(Modified Candidate Device) |
|---|---|---|
| Platforms | ADVIA CentaurADVIA Centaur XP | ADVIA CentaurADVIA Centaur XPADVIA Centaur XPT |
| Intended Use | For in vitro diagnostic use in thequantitative determination ofthyroid-stimulating hormone (TSH,thyrotropin) in serum using theADVIA Centaur and ADVIACentaur XP systems. | For in vitro diagnostic use in thequantitative determination ofthyroid-stimulating hormone (TSH,thyrotropin) in serum using theADVIA Centaur, ADVIA CentaurXP and ADVIA Centaur XPTsystems. Measurements of thyroidstimulating hormone produced bythe anterior pituitary are used in thediagnosis of thyroid or pituitarydisorders. |
| Lower Limit ofDetection | 0.01 µIU/mLBased on Analytical Sensitivity | 0.05 µIU/mLBased on Limit of Quantitation |
| Expected Values | Includes reference ranges for:EuthyroidHyperthyroidHypothyroid | Includes reference ranges for:Euthyroid |
Table 2. List of Assay Modifications
Table 3. List of Instrument Modifications
| Item | ADVIA Centaur XP | ADVIA Centaur XPT |
|---|---|---|
| User InterfaceCPU | Sun Sparc based CPU runningSolaris (UNIX based ) OS, withadditional Intel based ApplicationPC (APC) for QC, onlinedocumentation running onWindows XP | Single Intel Quad processor basedPC, with a new User Interfaceapplication with integrated APCapplications running on Windows 7 |
| Real Time ControlCPU | Sun Sparc based CPU runningSolaris (UNIX based ) OS forinstrument control and datacollection and analysis; | Real Time application rewritten torun on a RoHS compliant ARM 9based CPU running Nucleus OS; |
| Microcontrollers | Multiple distributed real-timeMicrocontrollers | Same (now RoHS compliant) |
| QC Software | ADVIA QC application providingStored control results, Levy-Jennings plotting, and statistics,integrated on the Application PC(APC) within the product | ADVIA QC application nowintegrated into the UI application |
| Display Monitor | 19" LCD Touch Screen colormonitor with Graphical UserInterface; | 22" LCD Touch Screen Colormonitor supporting a resolution of1680 x 1050 with Graphical UserInterface |
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| Item | ADVIA Centaur XP | ADVIA Centaur XPT |
|---|---|---|
| External Printer | No network capable printer | Support for new high speed andnetworked printers |
| Remote Diagnostics | External Modem for RemoteDiagnostics Interface andapplication Software for remotediagnostics over the Internet viaServer hosted on a separateApplication PC (APC) within theproduct; | Same functionality integrated intothe UI application |
| Barcode Reader | Stationary and handheld barcodescanners for identification of patientsamplesMultiple barcode formats supportedincluding 128, 2 of 5, Code39,Codabar; | Same plus added support for 2Dbarcodes |
| Data Archival | Data Management, instrument datacan be archived to floppy disks orCD | System supports DVDs & memorysticks |
| Cleaning Procedures | Monthly cleaning procedures | Monthly cleaning has beeneliminated |
| Mounting of ReagentCompartmentRefrigerationHardware | Reagent compartment mounted atthe left side of the instrument.Thermo-electric devices forrefrigeration oriented in variousdirections. | Same physical location of reagentcompartment.Thermo-electric devices forrefrigeration oriented in uniformdirection. |
Table 3. List of Instrument Modifications
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Comparison of Similarities and Differences between the 6. Predicate Device and the Candidate Device
| Item | ADVIA Centaur TSH(Unmodified Predicate Device) | ADVIA Centaur TSH(Modified Candidate Device) |
|---|---|---|
| InstrumentPlatforms | ADVIA CentaurADVIA Centaur XP | ADVIA CentaurADVIA Centaur XPADVIA Centaur XPT |
| Intended Use | For in vitro diagnostic use in thequantitative determination of thyroid-stimulating hormone (TSH,thyrotropin) in serum using the ADVIACentaur and ADVIA Centaur XPsystems. | For in vitro diagnostic use in thequantitative determination ofthyroid-stimulating hormone (TSH,thyrotropin) in serum using theADVIA Centaur, ADVIA CentaurXP and ADVIA Centaur XPTsystems. Measurements of thyroidstimulating hormone produced bythe anterior pituitary are used in thediagnosis of thyroid or pituitarydisorders. |
| Methodology | Two-site sandwich immunoassayusing direct chemiluminometrictechnology | Same |
| Reagents | ReadyPack Primary Reagent Packcontains both Solid Phase and LiteReagent in separate wells | Same |
| Lite Reagent | Monoclonal mouse anti-TSH antibodylabeled withacridinium ester | Same |
| Solid Phase | Polyclonal sheep anti-TSH antibodycovalently coupled to paramagneticparticles | Same |
| Specimen Type | Serum | Same |
| Sample Volume | 200 µL | Same |
| Calibration | 2-point calibrationusing Calibrator B | Same |
| Lower Limit ofDetection | 0.01 µIU/mLBased on Analytical Sensitivity | 0.05 µIU/mLBased on Limit of Quantitation |
| Expected Values | Includes reference ranges for:EuthyroidHyperthyroidHypothyroid | Includes reference ranges for:Euthyroid |
| Item | ADVIA Centaur XP | ADVIA Centaur XPT |
| Principles ofOperation | Chemiluminescence using magnetic-particle Solid Phase andchemiluminescent label (acridiniumester) Lite Reagent | Same |
| Optical System | Photo Multiplier Tube (PMT) used inphoton counting mode | Same |
| TemperatureControl | Reactions are controlled at 37°CReagents stored at 4°C to 8°C | Same |
| CleaningProcedures | Monthly cleaning procedures | Monthly cleaning has beeneliminated |
| Mounting ofReagentCompartment | Reagent compartment mounted at theleft side of the instrument. | Same physical location of reagentcompartment. |
| RefrigerationHardware | Thermo-electric devices forrefrigeration oriented in variousdirections. | Thermo-electric devices forrefrigeration oriented in uniformdirection. |
| Test Processing | Random Access and Batch;Cuvettes are incubated in a circular,insulated track (Incubation Ring) thatadvances the cuvette at 15 secondintervals and incubates the cuvette at37°C. The incubation ring moves thecuvettes from the sample probe to theancillary and reagent probes. | Same |
| Assay Protocols | Assay specific parameters contained inTest Definitions (TDefs) for eachassay.7.5 min incubation, single step; or20 min incubation, single step;or7.5 min / 20 min incubation, 2-step; or20 min / 20 min incubation, 2-step | Same |
| Specimens | Serum or plasma;Sample cups or primary tubes;Dilutions allowed on a per-assay basis;Capability of diluting samples requiringpretreatment | Same |
| Disposables | Reaction cuvettes;Sample Pipette Tips | Same |
| Calibration | 2 point user run calibration;6 to 10 point stored calibration for eachreagent;Calibrators checked with barcode;Calibrator lot numbers stored anddisplayed | Same |
Table 4. Similarities/Differences: Unmodified and Modified ADVIA Centaur TSH Assays
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| ltem | ADVIA Centaur XP | ADVIA Centaur XPT |
|---|---|---|
| Throughput | 120 to 240 tests/hr | Same |
| Time to FirstResult | 15 min, 30 min, 60 min dependingupon assay protocol | Same |
| Dimensions | Floor Model, 60H x 42D x 58L1200 lbs | Same |
| User InterfaceCPU | Sun Sparc based CPU running Solaris(UNIX based ) OS, with additional Intelbased Application PC (APC) for QC,online documentation running onWindows XP | Single Intel Quad processor basedPC, with a new User Interfaceapplication with integrated APCapplications running on Windows 7 |
| Real Time ControlCPU | Sun Sparc based CPU running Solaris(UNIX based ) OS for instrumentcontrol and data collection andanalysis; | Real Time application rewritten torun on a RoHS compliant ARM 9based CPU running Nucleus OS; |
| Microcontrollers | Multiple distributed real-timeMicrocontrollers | Same (now RoHS compliant) |
| QC Software | ADVIA QC application providingStored control results, Levy-Jenningsplotting, and statistics, integrated onthe Application PC (APC) within theproduct | ADVIA QC application nowintegrated into the UI application |
| Display Monitor | 19" LCD Touch Screen color monitorwith Graphical User Interface; | 22" LCD Touch Screen Colormonitor supporting a resolution of1680 x 1050 with Graphical UserInterface |
| External Printer | No network capable printer | Support for new high speed andnetworked printers |
| RemoteDiagnostics | External Modem for RemoteDiagnostics Interface and applicationSoftware for remote diagnostics overthe Internet via Server hosted on aseparate Application PC (APC) withinthe product; | Same functionality integrated intothe UI application |
| Barcode Reader | Stationary and handheld barcodescanners for identification of patientsamplesMultiple barcode formats supportedincluding 128, 2 of 5, Code39,Codabar; | Same plus added support for 2Dbarcodes |
| Data Archival | Data Management, instrument datacan be archived to floppy disks or CD | System supports DVDs & memorysticks |
Table 5. Similarities/Differences: ADVIA Centaur XP and ADVIA Centaur XPT Instruments
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7. Summary of Design Control Activities
Design control activities, as outlined in 21CFR 820.30, were completed for the ADVIA Centaur XPT system.
A risk analysis (Failure Modes and Event Analysis) was undertaken to assess risks of using the device. This evaluation followed the Siemens Healthcare Diagnostics procedure for risk analysis, which is based on ISO 14971:2007, Medical devices - Application of risk management to medical devices. The risk analysis concluded that all identified risks were properly mitigated and no unacceptable risks are present.
The performance of the ADVIA Centaur TSH assay using the ADVIA Centaur XPT system was verified to ensure equivalent performance when used on the predicate ADVIA Centaur XP system. All verification testing met pre-determined acceptance criteria. Therefore, the introduction of the ADVIA Centaur XPT system does not negatively impact the performance, safety or effectiveness of the ADVIA Centaur TSH assay.
Conclusions 8.
The performance of the ADVIA Centaur TSH assay on the ADVIA Centaur XPT system is substantially equivalent to the ADVIA Centaur TSH assay running on the currently-marketed predicate ADVIA Centaur XP system.
The ADVIA Centaur XPT system has the same operating principles, assay performance characteristics and intended use as the predicate device, the ADVIA Centaur XP system. The results of performance testing and verification activities demonstrate that the design modifications to the ADVIA Centaur XPT do not impact its safety or effectiveness and do not alter its performance claims.
Furthermore, there have been no changes to the intended use of the ADVIA Centaur TSH assay, other than to include the ADVIA Centaur XPT, as described in the labeling, or the fundamental scientific technology of the device.
§ 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.