BRAHMS DIAGNOSTICA DYNOTEST TG-PLUS

K021057 · Brahms Diagnostica, LLC · MSW · Sep 17, 2002 · Immunology

Device Facts

• Record ID: K021057
• Device Name: BRAHMS DIAGNOSTICA DYNOTEST TG-PLUS
• Applicant: Brahms Diagnostica, LLC
• Product Code: MSW · Immunology
• Decision Date: Sep 17, 2002
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.6010
• Device Class: Class 2

Indications for Use

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 Story

DYNOtest Tg-pluS is a two-step immunoradiometric assay (IRMA) for quantitative thyroglobulin (Tg) measurement in human serum. Input: patient serum sample. Process: two-step coated tube technique; first incubation binds Tg to rabbit anti-human Tg polyclonal antibodies on polystyrene tubes; second incubation adds radioactive (I-125) mouse anti-human Tg monoclonal antibody tracer to form a sandwich complex. Output: radioactivity measured via gamma counter, proportional to Tg concentration. Includes a recovery test (adding known Tg buffer) to detect interfering anti-Tg antibodies or non-specific substances; recovery <70% or >130% indicates invalid results. Used in clinical laboratory settings by trained technicians. Results assist physicians in monitoring differentiated thyroid cancer patients for residual or metastatic disease. Benefits include improved detection of thyroid tissue presence when combined with radioiodine scans.

Clinical Evidence

Clinical study of 133 patients with thyroid cancer. Patients categorized into three groups: free of disease (n=51), active metastatic disease (n=35), and residual tissue (n=47). Overall clinical sensitivity 78.1% (64/82); specificity 90.2% (46/51). Sensitivity 100% for metastatic disease, 61.7% for residual tissue. Positive predictive value 92.8%, negative predictive value 71.9%. Interference study of 77 sera positive for Tg auto-antibodies showed 9% (7/77) had disturbed recovery.

Technological Characteristics

Two-step IRMA; polystyrene 12x75 mm tube solid phase; I-125 radioactive tracer; gamma counter detection. Quantitative range 0-250 ng/mL. Analytical sensitivity 0.08 ng/mL; functional sensitivity 0.1 ng/mL. Includes recovery test for interference detection. Manual assay format.

Indications for Use

Indicated for monitoring local or metastatic thyroid tissue in patients post-thyroid gland ablation (surgery/radioiodine) and detecting thyroid tissue in differentiated thyroid cancer patients in conjunction with radioiodine whole body scans following TSH stimulation or hormone withdrawal.

Regulatory Classification

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.

Special Controls

*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.

Predicate Devices

• Nichols Institute Diagnostics Chemiluminescence Thyroglobulin (K994140)

Reference Devices

• DYNOtest anti-TGn

Submission Summary (Full Text)

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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 LLC<br>35 B South Peachtree Street<br>Norcross, Georgia 30071 |
| Manufacturer: | BRAHMS AG<br>Neuendorfstrasse 25<br>16761 Hennigsdorf/Berlin<br>Germany |
| Contact Person: | William G. Frank<br>BRAHMS Diagnostica LLC<br>35 B South Peachtree Street<br>Norcross, Georgia 30071 |
| Device Name: | DYNOtest Tg-pluS |
| Common or Usual Name: | Immunoradiometric assay for the<br>quantitative determination of<br>thyroglobulin in human serum |
| Classification:<br>Regulation Number:<br>Product Code: | ClassII<br>866.601<br>MSW, Immunology |
| Substantial Equivalence To: | Nichols Institute Diagnostics<br>Chemiluminescence Thyroglobulin |

#### II. INTENDED USE

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

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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

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.

# 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-<br>pluS | ≤ 2.0<br>ng/mL | 2.1-4.9<br>ng/mL | 5.0-9.9<br>ng/mL | 10.0-29.9<br>ng/mL | 30.0-59.9<br>ng/mL | ≥ 60.0<br>ng/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 |
| 15.0-29.9<br>ng/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 aid<br>in the monitoring for the presence of<br>local and metastatic thyroid tissue in<br>patients who have had thyroid gland<br>ablation (using surgery with or<br>without radioactivity). DYNOtest<br>Tg-pluS is also indicated for<br>detecting the presence of thyroid<br>tissue in patients with differentiated<br>thyroid cancer when used with<br>radioiodine whole body scans after<br>recombinant thyrotropin (TSH)<br>stimulation or thyroid hormone<br>withdrawal. | The NID Chemiluminescent<br>Thyroglobulin assay is intended to aid<br>in monitoring for the presence of local<br>and metastatic thyroid tissue in<br>patients who have had prior<br>thyroidectomy (using surgery with or<br>without radioiodine). The assay is<br>also indicated for monitoring<br>thyroglobulin levels in combination<br>with radioiodine whole body scans<br>after either rhTSH administration or<br>thyroid hormone withdrawal for<br>detecting presence of thyroid tissue in<br>patients with well-differentiated<br>thyroid cancer. The assay should only<br>be used on patients who lack<br>thyroglobulin 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 [phone]. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at [phone]. 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 [phone] or [phone] 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

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.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use

OR

Over-The Counter

Deborah M. Moore

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