DYNOtest Tg-pluS is a immunoradiometric assay (IRMA) for the quantitative determination of thyroglobulin in human serum. It is intended to aid in the monitoring for the presence of local or metastatic thyroid tissue in patients who have had thyroid gland ablation (by surgery with or without radioiodine therapy). DYNOtest Tg-pluS is also indicated for detecting the presence of thyroid tissue in patients with differentiated thyroid cancer when used with radioiodine whole body scans after recombinant thyrotropin (TSH) stimulation or thyroid hormone withdrawal. DYNOtest Tg-pluS includes a recovery test to aid in the detection of interfering anti-thyroglobulin antibodies or other substances.

Device Description

DYNOtest Tg-pluS is a two-step immunoradiometric assay for the quantitative determination of thyroglobulin in human serum using a coated tube technique. Two antigen specific antibodies that recognize different binding sites on the antigen (thyroglobulin) are used in excess. In the first step, thyroglobulin in the sample, standard or control binds to rabbit anti-human Tg polyclonal antibodies attached to the solid phase. Following incubation, unbound thyroglobulin and serum components are washed from the tube. In the second step, the radioactive tracer (mouse antihuman thyroglobulin monoclonal antibody) reacts with the bound antigen forming a sandwich complex fixed to the side of the tube. Following a second incubation, unreacted tracer is washed from the tube and remaining radioactivity in the tubes is measured. The measured radioactivity is directly proportional to the quantity of thyroglobulin in the sample, standard or control. The standard curve is used to derive the thyroglobulin concentration in the patients samples.

Recovery Test: Because non-specific interferents and anti-thyroglobulin antibodies can result in falsely low thyroglobulin values, DYNOtest Tg-pluS includes a recovery test, the purpose of which is to aid in the detection of such interferences. In the recovery test, recovery buffer containing a known quantity of thyroglobulin, is added to the patient sample. In parallel, the recovery buffer is added to a recovery reference sample (thyroglobulin free serum). The patient sample, recovery sample and recovery reference sample are all run using DYNOtest Tg-pluS. The percentage recovery is determined by subtracting the patient Tg value from the patient recovery sample and dividing this result by the recovery reference Tg value:

Recovery Tg - Patient Tg x 100 = % Recovery Recovery reference Tg

Recovery values between 70% and 130% are considered valid. Values <70% and >130% are due to interferences; these patient results should be considered invalid.

AI/ML Overview

Here's an analysis of the provided text, focusing on the acceptance criteria and the study used to evaluate the DYNOtest Tg-pluS device:

Acceptance Criteria and Device Performance for DYNOtest Tg-pluS

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria with specific threshold values for the clinical study. Instead, it presents the results of a clinical performance study and a comparison to a predicate device. The effective acceptance criteria can be inferred from the reported performance characteristics.

Performance Metric	Acceptance Criteria (Inferred)	Reported Device Performance
Comparison to Predicate Device
Concordance (Overall Agreement)	High agreement with predicate device (Nichols Institute Diagnostics Chemiluminescent Thyroglobulin assay)	96.9% (129/133) for results using 1.0 ng/mL (DYNOtest Tg-pluS) vs. 2.0 ng/mL (predicate) as cutoffs.
Clinical Performance (Cut-off > 1.0 ng/mL)
Overall Clinical Sensitivity	Reasonably high sensitivity for diagnostic aid	78.1% (64/82)
Overall Clinical Specificity	Reasonably high specificity for diagnostic aid	90.2% (46/51)
Positive Predictive Value (PPV)	Reasonably high PPV for diagnostic aid	92.8% (64/69)
Negative Predictive Value (NPV)	Reasonably high NPV for diagnostic aid	71.9% (46/64)
Sensitivity (Active Metastatic Disease)	Very high sensitivity expected for detecting active disease	100% (35/35)
Sensitivity (Residual Thyroid/Thyroglossal Duct Remnants)	Moderate sensitivity	61.7% (29/47)
Specificity (Free of Normal/Malignant Tissue)	High specificity expected for healthy individuals	90.2% (46/51)
Analytical Performance
Analytical Sensitivity	< 0.1 ng/mL	0.08 ng/mL
Functional Sensitivity	< 0.5 ng/mL	0.1 ng/mL
Intra-Assay Precision (% CV)	Low % CV (e.g., < 10%)	1.5 - 5.6%
Inter-Assay Precision (% CV)	Low % CV (e.g., < 10%)	2.2 - 6.4%
Recovery from Tg Auto-antibodies	Recovery values between 70% and 130%	9% of samples (7 out of 77) had disturbed recovery (<70% or >130%). Most disturbed samples had Tg < 1 µg/L and autoantibodies > 800 kilounits/L. (This is a specific acceptance criterion mentioned in the text for the recovery test).

2. Sample Size and Data Provenance for the Test Set

Sample Size for Test Set:
- Clinical Performance Study: 133 patients diagnosed with thyroid cancer.
- Predicate Device Comparison: 133 samples from patients diagnosed with thyroid cancer (likely the same cohort as the clinical performance study).
- Interference from Tg auto-antibodies: 77 sera.
Data Provenance: The clinical performance study was prospective in the sense that the device was evaluated on a specific set of categorized patients. The location of the test set is specified as occurring "at a single site," but the country of origin is not explicitly stated. Given the manufacturer is German (BRAHMS AG) and the distributor is US-based (BRAHMS Diagnostica LLC), it's possible the clinical site was in the US or Germany.

3. Number of Experts and Qualifications for Ground Truth

The document does not mention the number or qualifications of experts used to establish the ground truth for the test set.

4. Adjudication Method for the Test Set

The document does not describe a specific adjudication method (like 2+1 or 3+1). The "ground truth" (reference methodology) was established based on a combination of existing diagnostic results.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study focuses on the performance of the in-vitro diagnostic (IVD) device itself, not on how human readers' performance might change with or without AI assistance. The device is an assay, not an AI imaging interpretation tool.

6. Standalone Performance Study

Yes, the studies reported are for the standalone performance of the DYNOtest Tg-pluS device. The clinical performance section, including sensitivity, specificity, PPV, and NPV, directly evaluates the algorithm/assay without human-in-the-loop performance modifications.

7. Type of Ground Truth Used

The ground truth for the clinical performance study was established using a combination of existing clinical diagnostic results and reference methods:

"Tg results from a reference method (immunochemiluminescent method)"
"results from radioiodine whole body scans following TSH stimulation by administration of recombinant TSH or withdrawal of thyroid hormone therapy."
Patients were categorized into three groups: (1) free of thyroid tissue, (2) active metastatic disease, and (3) residual thyroid/thyroglossal duct remnants.

For the auto-antibody interference study, the ground truth was based on samples that "tested positive for Tg auto antibodies using a radioimmunometric assay (DYNOtest anti-TGn)."

8. Sample Size for the Training Set

The document does not specify a separate training set or its sample size. This type of in-vitro diagnostic assay (IRMA) typically relies on extensive analytical validation and calibration to established standards (like CRM 457, in this case) rather than a "training set" in the machine learning sense. The "standards" and "controls" mentioned in the device description are used for calibration and quality control, not for training a predictive algorithm in the same way an AI model would be trained.

9. How Ground Truth for the Training Set Was Established

Since a distinct "training set" in the context of machine learning is not mentioned or applicable to this type of assay, the concept of establishing ground truth for it is also not applicable here. The assay is calibrated against a standard (CRM 457), which serves as a known reference for target values.

Summary

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SUMMARY OF SAFETY AND EFFECTIVENESS

KO21057

This summary of safety and effectiveness is being submitted in accordance with the requirements of The Safe Medical Devices Act of 1990 (SMDA 1990) and 21 CFR 807.92.

GENERAL INFORMATION I.

Date of Summary Preparation:	August 28, 2002
Distributor:	BRAHMS Diagnostica LLC35 B South Peachtree StreetNorcross, Georgia 30071
Manufacturer:	BRAHMS AGNeuendorfstrasse 2516761 Hennigsdorf/BerlinGermany
Contact Person:	William G. FrankBRAHMS Diagnostica LLC35 B South Peachtree StreetNorcross, Georgia 30071
Device Name:	DYNOtest Tg-pluS
Common or Usual Name:	Immunoradiometric assay for thequantitative determination ofthyroglobulin in human serum
Classification:Regulation Number:Product Code:	ClassII866.601MSW, Immunology
Substantial Equivalence To:	Nichols Institute DiagnosticsChemiluminescence Thyroglobulin

II. INTENDED USE

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withdrawal. DYNOtest Tg pluS includes a recovery test to aid in the detection of interfering anti-thyroglobulin antibodies or other substances.

III. DEVICE DESCRIPTION

Recovery Tg - Patient Tg x 100 = % Recovery Recovery reference Tg

Recovery values between 70% and 130% are considered valid. Values <70% and >130% are due to interferences; these patient results should be considered invalid.

IV. COMPARISON TO PREDICATE DEVICE

Comparison to predicate device: DYNOtest Tg-pluS is substantially equivalent to the Nichols Institute Diagnostics Chemiluminescent Thyroglobulin assay (K994140). The following method comparison study included 133 samples from patients diagnosed with thyroid cancer. Concordance testing yielded the following results:

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DYNOtest Tg-pluS	≤ 2.0ng/mL	2.1-4.9ng/mL	5.0-9.9ng/mL	10.0-29.9ng/mL	30.0-59.9ng/mL	≥ 60.0ng/mL
≤ 1.0 ng/mL	61	3	0	0	0	0
1.1-2.4 ng/mL	1	13	4	0	0	0
2.5-4.9 ng/mL	0	3	7	0	0	0
5.0-14.9 ng/mL	0	0	1	19	2	0
15.0-29.9ng/mL	0	0	0	1	3	1
> 30.0 ng/mL	0	0	0	0	0	14

NID Chemiluminescent Thyroglobulin

Note: DYNOtest Tg-pluS is calibrated against CRM 457 at a ratio of 0.5:1 whereas the comparison method is calibrated against CRM 457 at a 1:1 ratio

Agreement for results using 1.0 ng/mL determined with DYNOtest Tg-pluS as the cutoff compared to 2.0 ng/mL Tg as the cutoff for the comparison method = 96.9% (129/133).

The following tables outline the similarities and differences between the BRAHMS DYNOtest Tg-pluS assay and the Nichols Institute Diagnostics Chemiluminescent Thyroglobulin assay.

	DYNOtest® Tg-pluS	NID Chemiluminescent Tg
Analyte	Thyroglobulin	Thyroglobulin
Specimen	Serum	Serum
Intended Use	DYNOtest Tg-pluS is intended to aidin the monitoring for the presence oflocal and metastatic thyroid tissue inpatients who have had thyroid glandablation (using surgery with orwithout radioactivity). DYNOtestTg-pluS is also indicated fordetecting the presence of thyroidtissue in patients with differentiatedthyroid cancer when used withradioiodine whole body scans afterrecombinant thyrotropin (TSH)stimulation or thyroid hormonewithdrawal.	The NID ChemiluminescentThyroglobulin assay is intended to aidin monitoring for the presence of localand metastatic thyroid tissue inpatients who have had priorthyroidectomy (using surgery with orwithout radioiodine). The assay isalso indicated for monitoringthyroglobulin levels in combinationwith radioiodine whole body scansafter either rhTSH administration orthyroid hormone withdrawal fordetecting presence of thyroid tissue inpatients with well-differentiatedthyroid cancer. The assay should onlybe used on patients who lackthyroglobulin autoantibodies.
Result	ng/mL	ng/mL

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	DYNOtest® Tg-pluS	NID Chemiluminescent Tg
Format	Two-step immunometric assay that	Immunometric assay that measures
	measures radiation from I 125 to	chemiluminescence to determine
	determine results . Two antigen	results. The assay uses a biotinylated
	specific antibodies that recognize	goat antibody for capture and an
	different binding sites on the	acridinium-labeled mouse monoclonal
	thyroglobulin molecule are used in	antibody for detection.
	excess.
Solid Phase	Polystyrene 12 x 75 mm tube	Avidin-coated bead
Reader	Gamma counter	Luminometer
Standard	CRM 457 -- In the DYNOtest Tg-	CRM 457 -- 1.0 ng/mL Tg = 1.0
	pluS assay 1.0 ng/mL Tg = 2.0	ng/mL CRM 457
	ng/mL CRM 457
Incubation	Overnight	Overnight
Reportable Range	0 - 250 ng/mL	0 - 100 ng/mL
Sensitivity	Analytical = 0.08 ng/mL	Analytical = 0.07 ng/mL
	Functional == 0.1 ng/mL	Functional = 0.5 ng/mL
Precision	% CV from 1.5 - 5.6%	% CV from 3.6 - 6.4%
(Intra-Assay %CV)	5 samples from 0.4 - 55 ng/mL	6 samples from 1.1 -- 94 ng/mL
Precision	% CV from 2.2-6.4%	% CV from 5.0 - 22%
(Inter-Assay % CV)	5 samples from 0.4 - 55 ng/mL	6 samples from 0.4 - 36 ng/mL
Dilution Parallelism	N = 5; 93.9-99.6%	N = 5; 83-120%
Recovery	N = 5; 96.1 - 102%	N = 3; 94.1 - 107.5%
High Dose Hook	Up to 30,500 ng/mL	Up to 1,000 ng/mL
Controls	2	2

V. Clinical Performance

In a clinical study to evaluate the performance of DYNOtest Tg-pluS conducted at a single site, 133 patients diagnosed with thyroid cancer were assigned to one of three clinical categories: (1) patients believed free of normal and malignant thyroid tissue, n = 51; (2) patients with active metastatic disease, n = 35; and (3) patients with residual thyroid/thyroglossal duct remnants, n = 47. Assignment to each category was based on Tg results from a reference method (immunochemiluminescent method) combined with results from radioiodine whole body scans following TSH stimulation by administration of recombinant TSH or withdrawal of thyroid hormone therapy. All 133 patients had negative thyroid autoantibody results.

	Reference Methodology
	Pos.	Neg
DYNOtest Tg pluS	64	5
	18	46

A cut-off value of > 1.0 ng/mL was used to indicate those patients with suspect local or metastatic disease. When patients were assessed using the reference methods described. DYNOtest Tg-pluS demonstrated an overall clinical sensitivity of 78.1% (64/82) and a specificity of 90.2% (46/51). The positive predictive value was 92.8% (64/69) and the negative predictive value was 71.9% (46/64). The sensitivity of DYNOtest Tg pluS was

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100% (35/35) in patients with active metastatic disease and 61.7% (29/47) in patients with residual thyroid/thyroglossal duct remnants. The specificity of DYNOtest Tg pluS in patients free of normal and malignant tissue was 90.2% (46/51).

Interference from Thyroglobulin auto-antibodies

In a separate study, interference from Tg auto-antibodies was tested in 77 sera that had tested positive for Tg auto antibodies using a radioimmunometric assay (DYNOtest anti-TGn), (minimum 65.2 kilounits/L; maximum, 8150 kilounits/L; median, 181 kilounits/L). Recovery (50 µg/L) was disturbed in the DYNOtest Tg pluS assay in seven sera (9%). Recovery was considered undisturbed if measured Tg values were 70 - 130% of the added Tg. Except for one serum sample, all sera with disturbed recoveries had Tg values <1 µg/L and autoantibodies > 800 kilounits/L.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/5/Picture/1 description: The image shows the logo for the Department of Health & Human Services, USA. The logo is circular and contains the text "DEPARTMENT OF HEALTH & HUMAN SERVICES, USA" around the perimeter. In the center of the logo is a stylized image of three abstract shapes that resemble a person embracing another person.

od and Drug Administration 98 Gaither Road ockville MD 20850

Mr. William G. Frank General Manager BRAHMS Diagnostica, LLC 35 B South Peachtree Street Norcross, Georgia 30071

K021057 Trade/Device Name: DYNOtest Tg-pluS Regulation Number: 21 CFR § 866.6010 Regulation Name: Tumor Associated Antigen Immunological Test System Regulatory Class: II Product Code: MSW Dated: July 12, 2002 Received: July 18, 2002

Dear Mr. Frank:

Re:

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. Iisting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such 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 801); 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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Page 2

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Putman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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K021057/A'

1. Indications for Use Statement

510(k) Number (if known): K021057 Device Name: DYNOtest Tg-pluS

Indications For Use

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use

Over-The Counter

Deborah M. Moore

(Division Sign-Off) Division of Clinical Laboratory Devices 510(k) Number_________________________________________________________________________________________________________________________________________________________________

Regulation Number and Section

§ 866.6010 Tumor-associated antigen immunological test system.

(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.