(90 days)
Immunoassay for the in vitro quantitation of autoantibodies to thyroid stimulating hormone (TSH) receptor in human serum using a human thyroid stimulating monoclonal antibody. The anti-TSH receptor determination is used in the assessment of patients suspected of Graves' disease (autoimmune hyperthyroidism).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e 601 immunoassay analyzers.
The Elecsys Anti-TSHR is used for the in vitro quantitative determination of autoantibodies to TSHR receptor in human serum using a human thyroid stimulating monoclonal antibody. It is intended for use on the cobas e 601 immunoassay analyzer. The cobas e family of analyzers uses electrochemiluminescence immunoassay "ECLIA" technology.
Here's an analysis of the provided text to extract the acceptance criteria and study information for the Elecsys Anti-TSHR device:
Acceptance Criteria and Device Performance for Elecsys Anti-TSHR
The Elecsys Anti-TSHR is an immunoassay for the in vitro quantitative determination of autoantibodies to the TSH receptor in human serum, used in the assessment of patients suspected of Graves' disease.
1. Table of Acceptance Criteria and Reported Device Performance:
| Performance Characteristic | Acceptance Criteria (Implicit from study results meeting "predetermined acceptance criterion") | Reported Device Performance |
|---|---|---|
| Precision | All samples to meet predetermined acceptance criteria for repeatability and intermediate imprecision. | Repeatability: Sample 1: 0.105 IU/L SD (7.5% CV); Sample 2: 0.140 IU/L SD (7.5% CV); Sample 3: 0.114 IU/L SD (5.7% CV); Sample 4: 0.252 IU/L SD (1.1% CV); Sample 5: 0.298 IU/L SD (0.8% CV); PC ThyroAB 1: 0.145 IU/L SD (3.3% CV); PC ThyroAB 2: 0.342 IU/L SD (1.9% CV). Intermediate Precision: Sample 1: 0.129 IU/L SD (9.1% CV); Sample 2: 0.161 IU/L SD (8.6% CV); Sample 3: 0.144 IU/L SD (7.2% CV); Sample 4: 0.347 IU/L SD (1.5% CV); Sample 5: 0.505 IU/L SD (1.3% CV); PC ThyroAB 1: 0.178 IU/L SD (4.0% CV); PC ThyroAB 2: 0.397 IU/L SD (2.2% CV). Lot-to-Lot Reproducibility: "Calculated SD´s and CV´s for the multiple lot (reproducibility) study are comparable to those of the single lot (intermediate) precision study (met acceptance)." |
| Analytical Sensitivity | Each lot to meet the predetermined acceptance criterion. | Limit of Blank (LoB): All lots met acceptance. Claim set to 0.5 IU/L. Limit of Detection (LoD): All lots met acceptance. Claim set to 0.8 IU/L. Limit of Quantitation (LoQ): All lots met acceptance. Claim set to 1.1 IU/L. |
| Linearity/Reportable Range | Deviations to be within predetermined acceptance criteria across the entire measuring range. | Linearity confirmed in the range from 0.8 to 40.0 IU/L (all deviations within predetermined acceptance criteria). |
| High Dose Hook Effect | Not applicable. | Not applicable (device is not susceptible). |
| HAMA Interference | Not susceptible to interference from HAMA. | Not susceptible to interference from Human Anti-Mouse Antibodies (HAMA). |
| Endogenous Interference: | Recovery for each sample to meet "predetermined acceptance criterion" (implicit). | Biotin: Claim set to < 600 ng/mL. Hemolysis: Claim set to ≤ 400 mg/dL. Bilirubin: Claim set to ≤ 25 mg/dL. Lipemia: Claim set to ≤ 1500 mg/dL. Rheumatoid Factors (RF): Claim set to ≤ 600 IU/mL. |
| Analytical Specificity/Cross-Reactivity | All cross-reactivities to meet predefined acceptance criterion at specified concentration. | No influence with human autoantibodies to thyroglobulin (< 4000 IU/mL) or anti-TPO (< 600 IU/mL) detectable. Cross-reactants tested and met criteria: Human LH (< 10000 mIU/ML), Human FSH (< 10000 mIU/ML), hCG (< 50000 mIU/ML). |
| Exogenous Interferences (Drugs) | Each compound to be non-interfering at the tested drug concentration. | For all 29 drugs tested (17 common, 13 special), the specification was met. Example drugs and concentrations: Amiodarone (≤ 200 mg/L), Carbimazole (≤ 30 mg/L), Levothyroxine (≤ 0.250 mg/L), etc. |
| Method Comparison to Predicate | "Acceptable" agreement and regression results demonstrating substantial equivalence. | Agreement: Positive Percent Agreement (PPA) = 97.37% (95% CI: 93.43 - 98.97); Negative Percent Agreement (NPA) = 95.37% (95% CI: 89.62 - 98.01); Overall Percent Agreement (TPA) = 96.54% (95% CI: 93.55 - 98.17). Regression (Passing/Bablok): y = 1.047x - 0.068 (Slope = 1.029 to 1.064; Intercept = -0.188 to 0.032); r = 0.998. |
| Stability | Stability data to support Roche Diagnostic's claims. | Stability studies reviewed and found acceptable; data supports claims in package inserts. |
2. Sample Size Used for the Test Set and Data Provenance:
- Precision (Repeatability & Intermediate Precision): 5 human serum samples (4 native, 1 spiked) and 2 controls (PC ThyroAB) were tested over 21 days with 2 replicates per run, 2 runs per day. (Total of 84 replicates per sample/control for repeatability and intermediate precision calculations).
- Lot-to-Lot Reproducibility: 5 human serum samples (4 native, 1 spiked) were tested with 2 replicates per run, 2 runs per day, for 3 reagent lots (n = 28 determinations per lot per sample, totaling 3x7x2x2 measurements over 3 lots for each sample).
- Analytical Sensitivity (LoB, LoD, LoQ):
- LoB: Five blank samples with two replicates each per run, for 6 runs on ≥ three days, across three reagent lots. (Total 60 determinations for analyte-free samples).
- LoD: Five low analyte samples with two replicates each per run, for 6 runs on ≥ three days, across three reagent lots. (60 replicates per sample per reagent lot).
- LoQ: Samples tested across three reagent lots for 5 days, one run per day (25 replicates per sample per reagent lot).
- Linearity/Assay Reportable Range: Three high analyte human serum samples (serum pools) were diluted to create 14 concentrations (13 dilutions). Samples were measured in triplicate within a single run.
- Endogenous Interference (Biotin, Hemolysis, Bilirubin, Lipemia, Rheumatoid Factors): Not explicitly stated, but typically involves a few serum samples spiked with interferents and compared to unspiked controls. Each sample was spiked with the interfering substance, another aliquot was spiked with isotonic NaCl solution (dilution pool), and the interfering pool was diluted into the dilution pool (in 10% increments for some).
- Analytical Specificity/Cross-Reactivity: One native human serum sample pool with a low concentration of anti-TSHR was used.
- Exogenous Interferences (Drugs): Two human serum samples (native serum pools) were used.
- Method Comparison to Predicate:
- Agreement: 260 clinical samples from the "intended use population".
- Regression Analysis: A subset of 120 samples, evenly distributed across the measuring range, from the 260 collected samples.
Data Provenance:
- For the "Expected values" (Table 2), an external study used samples from 436 apparently healthy individuals, 210 patients with thyroid diseases without Graves' disease, and 102 patients with untreated Graves' disease.
- For the non-clinical performance evaluation, samples used were primarily "human serum pools" (native and spiked) and controls.
- For the Method Comparison, "clinical samples from the intended use population" were used.
The document does not explicitly state the country of origin or whether the data was retrospective or prospective beyond referring to "clinical samples" and an "external study."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:
This document describes an in vitro diagnostic immunoassay. The concept of "experts establishing ground truth for a test set" as typically understood in AI/imaging studies (e.g., radiologists reviewing images) is not directly applicable here. The "ground truth" for an immunoassay is typically established by reference methods, clinical diagnosis, or by defining specific concentrations for spiked samples or control materials.
For the "Expected Values" in Table 2, an external study was used where an "optimal cutoff of 1.75 IU/L was determined" based on diagnoses of apparently healthy individuals, those with thyroid diseases without Graves', and those with untreated Graves' disease. This implies a clinical diagnostic ground truth, but not direct "expert adjudication" in the sense of multiple experts assigning labels to individual cases for comparison.
4. Adjudication Method for the Test Set:
Not applicable in the context of an immunoassay performance study as described. Clinical diagnoses or reference assays serve as the "ground truth" rather than expert adjudication of individual test cases.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done:
No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic imaging interpretation devices involving human readers, not for an automated immunoassay such as the Elecsys Anti-TSHR.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was Done:
Yes, the studies described are all standalone performance evaluations of the Elecsys Anti-TSHR device itself. This device is an automated immunoassay system that provides quantitative results without human interpretation in the loop as part of its primary function. Its performance characteristics (precision, sensitivity, linearity, interference, method comparison) are evaluated directly.
7. The Type of Ground Truth Used:
- Clinical Diagnosis/Disease State: For "Expected Values" (Sensitivity and Specificity), the ground truth was based on patient cohorts: apparently healthy individuals, patients with thyroid diseases (without Graves'), and patients with untreated Graves' disease.
- Reference Methods/Known Concentrations: For analytical performance studies (Precision, Analytical Sensitivity, Linearity, Interference, Cross-Reactivity), the ground truth was established by:
- Using predefined control materials with known values.
- Using native human serum pools.
- Spiking samples with known concentrations of analyte or interfering substances.
- Comparison against a predicate device (Elecsys Anti-TSHR Immunoassay K080092) for method comparison.
8. The Sample Size for the Training Set:
The document describes performance evaluation studies, not the development or training of an AI algorithm. Therefore, there is no "training set" in the context of artificial intelligence or machine learning. The studies described are for validation and verification of the device's performance characteristics.
9. How the Ground Truth for the Training Set Was Established:
As there is no "training set" for an AI model mentioned in the context of this immunoassay, this question is not applicable. The device's underlying principles are based on electrochemiluminescence immunoassay (ECLIA) technology, not machine learning that requires a training set.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
February 27, 2020
Roche Diagnostics Reanna Toney Principal, Regulatory Affairs 9115 Hague Road Indianapolis, Indiana 46250
Re: K193313
Trade/Device Name: Elecsys Anti-TSHR Regulation Number: 21 CFR 866.5870 Regulation Name: Thyroid autoantibody immunological test system Regulatory Class: Class II Product Code: JZO Dated: November 26, 2019 Received: November 29, 2019
Dear Reanna Toney:
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. 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 located 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.
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 Part
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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-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 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-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/medicaldevices/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-device-advice-comprehensive-regulatoryassistance/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,
Carolina Kagan, M.Sc. Acting Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K193313
Device Name Elecsys Anti-TSHR
Indications for Use (Describe)
Immunoassay for the in vitro quantitation of autoantibodies to thyroid stimulating hormone (TSH) receptor in human serum using a human thyroid stimulating monoclonal antibody. The anti-TSH receptor determination is used in the assessment of patients suspected of Graves' disease (autoimmune hyperthyroidism).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e 601 immunoassay analyzers.
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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Elecsys Anti-TSHR 510(k) Summary K193313
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys Anti-TSHR.
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| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457 |
| Contact | Reanna ToneyPhone: (317) 521-4516FAX: (317) 521-2324Email: reanna.toney@roche.comSecondary Contact: Tammy DeanPhone: (317) 521-3978FAX: (317) 521-2324Email: tammy.dean@roche.com |
| Date Prepared | February 26, 2020 |
| Proprietary Name | Elecsys Anti-TSHRCalSet Anti-TSHRPreciControl ThyroAB |
| Common Name | anti-TSHR |
| Classification Name | System, Test, Thyroid AutoantibodyCalibrator, SecondarySingle (specified) analyte controls (assayed and unassayed) |
| Product Codes,Regulation Numbers | JZO, 21 CFR 866.5870JIT, 21CFR862.1150, EXEMPTJJX, 21CFR862.1660, EXEMPT |
| Predicate Devices | Elecsys Anti-TSHR Immunoassay (K080092) |
| Establishment Registration | For the Elecsys Anti-TSHR, the establishment registration number for RocheDiagnostics GmbH in Mannheim, Germany is 9610126, and for Penzberg,Germany, 9610529. The establishment registration number for RocheDiagnostics in the United States is 1823260 |
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1. DEVICE DESCRIPTION
The Elecsys Anti-TSHR is used for the in vitro quantitative determination of autoantibodies to TSHR receptor in human serum using a human thyroid stimulating monoclonal antibody. It is intended for use on the cobas e 601 immunoassay analyzer. The cobas e family of analyzers uses electrochemiluminescence immunoassay "ECLIA" technology.
1.1. Reagents
The reagent working solutions include:
Reagent rackpack (kit placed on the analyzer)
- . Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: M Streptavidin-coated microparticles 0.72 mg/mL; preservative.
- . Buffer solution (gray cap), 1 bottle, 7 mL: Phosphate buffer 20 mmol/L, pH 7.4; R1 stabilizers, preservative.
- . Anti TSHR~Ru(bpy) (black cap), 1 bottle, 7 mL: Monoclonal anti TSHR R2 antibody M22 (human) labeled with ruthenium complex approximately 0.3 mg/L; phosphate buffer 20 mmol/L, pH 7.4; stabilizers, preservative.
Pretreatment rackpack
- . PT1 Pretreatment buffer solution (black cap), 1 bottle, 4 mL: Phosphate buffer 20 mmol/L, pH 7.4; stabilizers, preservative.
- PT2 Empty bottle (white cap) for pretreatment reagent (PTR) reconstituted with . pretreatment buffer (PTB).k Pack
- Pretreatment reagent, pTSHR-anti-pTSHR-Ab~biotin complex (white cap), ● PTR 1 bottle for 4 mL of PTB: Phosphate buffer 40 mmol/L, pH 7.2; stabilizers.
- . Pretreatment buffer (white cap), 1 bottle, 5 mL:Reconstitution medium for PTR; PTB phosphate buffer 10 mmol/L, pH 7.2; stabilizer.
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2. INDICATIONS FOR USE
Immunoassay for the in vitro quantitative determination of autoantibodies to thyroid stimulating hormone (TSH) receptor in human serum using a human thyroid stimulating monoclonal antibody. The anti-TSH receptor determination is used in the assessment of patients suspected of Graves' disease (autoimmune hyperthyroidism).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 601 immunoassay analyzers.
3. TECHNOLOGICAL CHARACTERISTICS
The following table lists the technical characteristics from the Elecsys Anti-TSHR method sheet.
| Table 1: Elecsys Anti-TSHR Technical Characteristics | ||
|---|---|---|
| Feature | Elecsys Anti-TSHR |
|---|---|
| Technology | ECLIA |
| Application/test time | 18 minutes |
| Instrument platform | cobas e 601 immunoassay analyzers |
| Test format | Competition |
| Test type | Quantitative |
| Assay protocol | Sample+PT1+PT2, incubation, +R1, incubation, + R2 |
| Handling of R1 and R2 | Liquid, Ready for use |
| Sample Type/Matrix | serum |
| Measuring Range | 0.8 - 40 IU/L |
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Table 2: Substantial Equivalency
| Item | Elecsys Anti-TSHR(K080092) | Elecsys Anti-TSHR(K193313) |
|---|---|---|
| Proprietary name | Elecsys Anti-TSHR Immunoassay | Elecsys Anti-TSHR |
| Catalog number | 04388780 160 | 08496609 190 |
| Intended use | Immunoassay for the in vitroquantitative determination ofautoantibodies to TSH receptor inhuman serum using a human thyroidstimulating monoclonal antibody. Theanti-TSH receptor determination isused in the assessment of patients withsuspect Graves' disease (autoimmunehyperthyroidism).The electrochemiluminescenceimmunoassay "ECLIA" is intended foruse on Elecsys and cobas eimmunoassay analyzers. | Immunoassay for the in vitro quantitativedetermination of autoantibodies tothyroid stimulating hormone (TSH)receptor in human serum using a humanthyroid stimulating monoclonal antibody.The anti-TSH receptor determination isused in the assessment of patientssuspected of Graves' disease(autoimmune hyperthyroidism).The electrochemiluminescenceimmunoassay “ECLIA" is intended foruse on the cobas e 601 immunoassayanalyzer. |
| Technology | ECLIA | Same |
| Test format | Competitive | Same |
| Test type | Quantitative | Same |
| Assay protocol | sample+PT1+PT2, incubation, +R1,incubation, +beads+R2, incubation | Same |
| Pipetting volume sample | 50 µL | Same |
| Pretreatment buffer solution (PT1) | 10 µL | Same |
| Pretreatment reagent buffer (PT2) | 20 µL | Same |
| Pipetting volume M (beads) | 30 µL | Same |
| Pipetting volume R1 | 40 µL | Same |
| Pipetting volume R2 | 50 µL | Same |
| Handling of PT1 | Liquid, ready to use | Same |
| Handling of PT2 | Mix pretreatment reagent (PTR) +4 mL of pretreatment buffer (PTB) | Same |
| Handling of R1 and R2 | Liquid, ready to use | Same |
| Measuring range | 0.800 - 40.0 IU/L | Same |
| Biotin tolerance | Up to 10 ng/mL | Up to 600 ng/mL |
| Expected values | In an external study using the ElecsysAnti-TSHR assay on samples from436 apparently healthy individuals,210 patients with thyroid diseases*without diagnosis of Graves' disease,and 102 patients with untreatedGraves' disease an optimal cutoff of1.75 IU/L was determined. At thiscutoff the sensitivity was calculated at96 % and the specificity at 99 %. | In an external study using the ElecsysAnti-TSHR assay on samples from436 apparently healthy individuals, 210patients with thyroid diseases*without diagnosis of Graves' disease,and 102 patients with untreatedGraves' disease an optimal cutoff of 1.75IU/L was determined. Assay values lessthan or equal to the cut-off, 1.75 IU/L,are considered negative. Values greaterthan the cut-off are considered positive.At this cutoff the sensitivity wascalculated at 96 % and the specificity at99 %. |
| Buffer composition R1 | Phosphate buffer 20 mmol/L | |
| Biotinylated antibody | MAKM-4E31-IgG-Bi(DDS* mono) | |
| Buffer composition R2 | Phosphate buffer 20 mmol/L | |
| - |
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4. NON-CLINICAL PERFORMANCE EVALUATION
The non-clinical performance studies for Elecsys Anti-TSHR are summarized below.
Precision 4.1.
Repeatability and Intermediate Precision 4.1.1.
Precision of the Elecsys Anti-TSHR assay was evaluated on one cobas e 601 immunoassay analyzer with one reagent lot. The protocol consisted of testing 2 replicates of each control level and human sera (HS) per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Human serum samples used were native human serum pools (human serum 1-4) and spiked human serum (human serum 5). Repeatability and Intermediate imprecision were calculated according to EP05-A3. All samples met the predetermined acceptance criterion.
| Repeatability | Intermediate Precision | ||||
|---|---|---|---|---|---|
| Mean | SD | CV | SD | CV | |
| Sample | IU/L | IU/L | % | IU/L | % |
| Sample 1 | 1.41 | 0.105 | 7.5 | 0.129 | 9.1 |
| Sample 2 | 1.87 | 0.140 | 7.5 | 0.161 | 8.6 |
| Sample 3 | 1.99 | 0.114 | 5.7 | 0.144 | 7.2 |
| Sample 4 | 22.7 | 0.252 | 1.1 | 0.347 | 1.5 |
| Sample 5 | 37.5 | 0.298 | 0.8 | 0.505 | 1.3 |
| PC ThyroAB 1 | 4.42 | 0.145 | 3.3 | 0.178 | 4.0 |
| PC ThyroAB 2 | 18.1 | 0.342 | 1.9 | 0.397 | 2.2 |
The following table summarizes the precision data for Elecsys Anti-TSHR.
4.1.2. FDA requested Lot-to-Lot Reproducibility
Lot-to-lot reproducibility of the Elecsys Anti-TSHR assay was evaluated on one cobas e 601 analyzer using three reagent lots. A precision study was performed with 2 replicates of each human sera (HS) per run, 2 runs per day (n = 28 determinations per lot, 3x7x2x2 measurements for each sample). The samples were run in randomized order on the analyzer. Human serum samples used were human serum pools (human serum 1-4) as well as spiked human serum (human serum 5).
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Repeatability, Between-Run, Between-Day, Between-Lot and Total imprecision were calculated according to EP05-A3. Calculated SD´s and CV´s for the multiple lot (reproducibility) study are comparable to those of the single lot (intermediate) precision study over 21 days using only one reagent lot indicating that the updated assay performs consistently from lot to lot.
4.2. Analytical Sensitivity
4.2.1. Limit of Blank (LoB)
LoB of the Elecsys Anti-TSHR was determined according to CLSI EP17-A2. The experimental design included three reagent lots evaluated on one cobas e 601 analyzer, six runs on ≥ three days, with five blank samples with two replicates each per run. In total, 60 determinations for analyte free samples have been obtained. All lots met the predetermined acceptance criterion. The LoB claim in the labeling will be set to 0.5 IU/L.
4.2.2. Limit of Detection (LoD)
LoD of the Elecsys Anti-TSHR was determined according to CLSI EP17-A2. The experimental design included three reagent lots evaluated on one cobas e 601 analyzer, six runs on ≥ three days, with five low analyte samples with two replicates each per run. Sixty (60) replicates per sample per reagent lot were run. All lots met the predetermined acceptance criterion. The LoD claim in the labeling will be set to 0.8 IU/L.
Limit of Quantitation (LoQ) 4.2.3.
LoQ of the Elecsys Anti-TSHR was determined according to CLSI EP17-A2. The experimental design included three reagent lots evaluated on one cobas e 601 analyzer for 5 days, one run per day. There were 25 replicates per sample per reagent lot. All lots met the predetermined acceptance criterion. The LoQ claim in the labeling will be set to 1.1 IU/L.
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4.3. Linearity/Assay Reportable Range
The linearity study was conducted to demonstrate that there exists a mathematically verified linear relationship between the determined values and the true concentrations across the claimed measuring range. The study was performed according to CLSI guideline EP06-A.
Three high analyte human serum samples (serum pools) were diluted with anti-TSHR free serum. 14 concentrations (13 dilutions) throughout the measuring range were prepared. Samples were measured in triplicate within a single run.
The linearity data were analyzed with regards to linear, quadratic and cubic polynomials according to CLSI EP6-A. In a first step, a linearity check was performed with a first order (linear) regression and then with higher order models (quadratic and cubic). If a first order polynomial gives the best fit, the tested measuring range is linear. If a better fit is obtained with a 2nd or 3rd order polynomial, the difference between this polynomial and the 1st order polynomial is calculated. The difference must be within specification across the entire measuring range.
All deviations were within predetermined acceptance criteria. Linearity was confirmed in the range from 0.8 to 40.0 IU/L.
4.4. High Dose Hook Effect
Not Applicable
4.5. Human Anti-Mouse Antibodies (HAMA)
The Elecsys Anti-TSHR is not susceptible to interference from Human Anti-Mouse Antibodies (HAMA).
4.6. Endogenous Interference
The purpose of this study was to evaluate endogenous substances for potential interference with the parameters measured with the Elecsys Anti-TSHR on the cobas e 601 analyzer.
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4.6.1. Biotin
One aliquot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. The claim of package insert has been set to < 600 ng/mL.
Hemolysis 4.6.2.
One aliguot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. The claim of package insert has been set to ≤ 400 mg/dL.
4.6.3. Bilirubin
One aliquot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. The claim of package insert has been set to ≤ 25 mg/dL.
4.6.4. Lipemia
One aliguot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. The claim of package insert has been set to ≤ 1500 mg/dL.
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4.6.5. Rheumatoid Factors (RF) Interference
One aliquot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. The claim of package insert has been set to ≤ 600 IU/mL.
Summary 4.6.6.
| Potential Interferent | Concentration |
|---|---|
| Hemolysis | 400 mg/dL |
| Bilirubin | 25.0 mg/dL |
| Lipemia | 1500 mg/dL |
| Biotin | 600 ng/mL |
| Rheumatic Factor | 600 IU/mL |
Table 3: Summary of Endogenous Interference Results
Analytical Specificity/Cross-Reactivity 4.7.
The effect on quantitation of analyte in the presence of potential cross-reacting compounds using the Elecsys Anti-TSHR was determined on the cobas e 601 analyzer using a native human serum sample pool. For each potential cross-reacting compound a human serum sample with a low concentration level of anti-TSHR was tested. Results from these spiked serum samples were matched against the unspiked references and the % cross-reactivity was calculated. All cross-reactivities met the predefined acceptance criterion at the specified concentration level of the corresponding cross reactant.
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No influence with human autoantibodies to thyroglobulin (< 4000 IU/mL) or anti-TPO (< 600 IU/mL) was detectable.
| Cross-reactant | Concentration tested |
|---|---|
| mIU/ML | |
| Human LH | < 10000 |
| Human FSH | < 10000 |
| hCG | < 50000 |
4.8. Exogenous Interferences - Drugs
The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 17 commonly and 13 specially used pharmaceutical compounds with the reference sample (unspiked). Two human serum samples (native serum pools) were used and tested on the cobas e 601 analyzer. The drug concentrations tested correspond at least to the three times maximum daily doses (or the one-time maximum daily dose, respectively). Drug interferences are measured based on recommendations given in CLSI guidelines EP7-ED3 and EP37-ED1 and other published literature. For all drugs tested, the specification was met as each compound was found to be non-interfering at the drug concentration as listed. The method sheet will include an interference claim for Heparin.
| Drug | Concentration testedmg/L |
|---|---|
| Amiodarone | ≤ 200 |
| Carbimazole | ≤ 30 |
| Fluocortolone | ≤ 20 |
| Hydrocortisone | ≤ 200 |
| Iodide | ≤ 0.040 |
| Levothyroxine | ≤ 0.250 |
| Liothyronine | ≤ 0.015 |
| Thiamazole | ≤ 16 |
| Octreotide | ≤ 0.300 |
| Perchlorate | ≤ 400 |
| Prednisolone | ≤ 20 |
| Propranolol | ≤ 240 |
| Propylthiouracil | ≤ 60 |
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4.9. Method Comparison to Predicate
A method comparison was performed using the Elecsys Anti-TSHR updated assay (candidate device) and the current Elecsys Anti-TSHR immunoassay (predicate device) to assess the bias between the two assays. A total of 260 clinical samples from the intended use population were measured with both assays in singleton on the cobas e 601 analyzer covering the entire measuring range. From these measurements, positive percent agreement, negative percent agreement, and total percent agreement were calculated.
Table 4: Agreement between Elecsys Anti-TSHR and Predicate
| % Agreement | 95% Confidence Interval | |
|---|---|---|
| Positive Percent Agreement (PPA) | 97.37 | 93.43 - 98.97 |
| Negative Percent Agreement (NPA) | 95.37 | 89.62 - 98.01 |
| Overall Percent Agreement (TPA) | 96.54 | 93.55 - 98.17 |
An additional method comparison study was performed using the Elecsys Anti-TSHR updated assay (candidate device, Y) and the current Elecsys Anti-TSHR immunoassay (predicate device, X) to assess the bias between the two assays. From the 260 samples collected and analyzed, a subset of 120 samples, evenly distributed across the measuring range, were used for regression analysis (Passing/Bablock method).
| N = 120 | |
|---|---|
| Passing/Bablok | 95% CI |
| y = 1.047x-0.068 | Slope = 1.029 to 1.064 |
| r = 0.998 | Intercept = -0.188 to 0.032 |
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Stability 4.10.
The stability studies and acceptance criteria have been reviewed and found to be acceptable. The stability data supports Roche Diagnostic's claims as reported in the package inserts.
5. CONCLUSION
The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys Anti-TSHR. The data from the nonclinical tests demonstrate that the device is as safe, as effective, and performs as well as or better than the predicate device.
§ 866.5870 Thyroid autoantibody immunological test system.
(a)
Identification. A thyroid autoantibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the thyroid autoantibodies (antibodies produced against the body's own tissues). Measurement of thyroid autoantibodies may aid in the diagnosis of certain thyroid disorders, such as Hashimoto's disease (chronic lymphocytic thyroiditis), nontoxic goiter (enlargement of thyroid gland), Grave's disease (enlargement of the thyroid gland with protrusion of the eyeballs), and cancer of the thyroid.(b)
Classification. Class II (performance standards).