EDIA ANTI-CCP

K062045 · Euro-Diagnostica AB · NHX · Dec 4, 2006 · Immunology

Device Facts

• Record ID: K062045
• Device Name: EDIA ANTI-CCP
• Applicant: Euro-Diagnostica AB
• Product Code: NHX · Immunology
• Decision Date: Dec 4, 2006
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.5775
• Device Class: Class 2

Intended Use

The EDIA™ anti-CCP test kit is an enzyme-linked immunosorbent assay (ELISA) for detection and semi-quantitation of IgG antibodies to Cyclic Citrullinated Peptides (CCP) in human sera and plasma. The assay is used to detect antibodies in a single specimen. The results of the assay are to be used as an aid to the diagnosis of Rheumatoid Arthritis (RA), in conjunction with other laboratory and clinical findings. The analysis should be performed by trained laboratory professionals. For in vitro diagnostic use.

Device Story

EDIA™ anti-CCP is an ELISA test kit for detecting IgG antibodies to Cyclic Citrullinated Peptides in human serum or plasma. Input: patient serum/plasma specimen. Principle: wells coated with CCP antigen capture specific antibodies; alkaline phosphatase-labeled anti-human IgG conjugate binds captured antibodies; substrate solution added to produce color intensity proportional to antibody concentration. Output: absorbance (optical density) measured and calculated against a calibrator curve to provide results in arbitrary units (U/mL). Used in clinical laboratories by trained professionals. Results aid physicians in diagnosing Rheumatoid Arthritis when combined with other clinical and laboratory findings.

Clinical Evidence

Clinical performance was evaluated using 416 RA patients and 793 non-RA controls (including healthy donors and various autoimmune/infectious disease states). Clinical sensitivity was 76% (95% CI: 72.1%-80.3%). Clinical specificity was 98.6% (782/793). Method comparison against the predicate device (n=678) showed 98.4% positive percent agreement and 99.4% negative percent agreement, with an overall agreement of 99.1%.

Technological Characteristics

ELISA-based immunoassay. Wells coated with Cyclic Citrullinated Peptides. Detection via alkaline phosphatase-labeled anti-human IgG conjugate and substrate solution. Measurement via optical density (absorbance). Standalone laboratory test kit. No specific software algorithm or connectivity described; manual or automated plate reader processing.

Indications for Use

Indicated for the detection and semi-quantitation of IgG antibodies to Cyclic Citrullinated Peptides (CCP) in human serum and plasma specimens to aid in the diagnosis of Rheumatoid Arthritis (RA). For use by trained laboratory professionals.

Regulatory Classification

Identification

A rheumatoid factor immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the rheumatoid factor (antibodies to immunoglobulins) in serum, other body fluids, and tissues. Measurement of rheumatoid factor may aid in the diagnosis of rheumatoid arthritis.

Predicate Devices

• Immunoscan RA anti-CCP test kit

Submission Summary (Full Text)

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JEL - 3 2006

K06204-5

Revised Summary of Safety and Effectiveness Information EDIA™ anti-CCP kit

1. Euro-Diagnostica AB, Medeon, SE-205 12 Malmo, Sweden Contact person: Ms. Annika Andersson Telephone: [phone] Fax: [phone] Date of preparation: October 16, 2006

II. Description of Device: The EDIA™ anti-CCP test kit is an enzyme-linked immunosorbent assay (ELISA) for detection and semi-quantitation of IgG antibodies to Cyclic Citrullinated Peptides (CCP) in human sera and plasma. The assay is used to detect antibodies in a single specimen. The results of the assay are to be used as an aid to the diagnosis of Rheumatoid Arthritis (RA), in conjunction with other laboratory and clinical findings. Trained laboratory professionals should perform the analysis. "For in vitro diagnostic use".

The wells are coated with Cyclic Citrullinated Peptides. During the first incubation, specific antibodies in diluted serum, will bind to the antigen coating.

The wells are then washed to remove unbound antibodies and other components. A conjugate of alkaline phosphatase labelled antibodies to human IgG binds to the antibodies in the wells in this second incubation.

After a further washing step, detection of specific antibodies is obtained by incubation with substrate solution. The amount of bound antibodies correlates to the colour intensity and is measured in terms of absorbance (optical density (OD)). The absorbance is then calculated against a calibrator curve and the results are given in arbitrary units.

III. Predicate Device: The EDIA™ anti-CCP test is substantially equivalent to the. Immunoscan RA anti-CCP test kit. Equivalence is demonstrated by the following comparative results:

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Table 1. Percent agreement of the EDIA™ anti-CCP compared to the Immunoscan RA anti-CCP test kit. A total of 678 frozen retrospective sera were assayed. 416 from RA patients and 262 samples were apparently healthy blood donors.

| | | Predicate device<br>(Immunoscan RA anti-CCP) | |
|----------------|----------|----------------------------------------------|----------|
| New device | N = 678 | Positive | Negative |
| EDIA™ anti-CCP | Positive | 317 | 2 |
| | Negative | 5 | 354 |

| Positive Percent Agreement: 317/322 = 98.4% | 95% CI = 96.4 - 99.5% |
|---------------------------------------------|-----------------------|
| Negative Percent Agreement: 354/356 = 99.4% | 95% CI = 98.0 - 99.9% |
| Overall Percent Agreement: 671/678 = 99.0% | 95% CI = 97.9 - 99.6% |

The 95% confidence interval (CI) was calculated using the exact method.

Figure 1 Linear correlation between anti-CCP titres of 174 sera from RA patients with values <50 U/mL for the EDIA anti-CCP and <250 U/mL for the Immunoscan RA anti-CCP.

Image /page/1/Figure/5 description: This image is a scatter plot titled "Correlation Immunoscan RA anti-CCP and EDIA anti-CCP". The x-axis is labeled "EDIA anti-CCP (U/mL)" and ranges from 0 to 60. The y-axis is labeled "Immunoscan RA anti-CCP (U/mL)" and ranges from 0 to 350. A regression line is plotted with the equation y = 6.27x + 4.389 and an R-squared value of 0.8886.

Table 2. Clinical sensitivity and specificity. A total of 1209 frozen retrospective sera with clinical characterisation were assayed. The following table summarises the results.

| Sensitivity of EDIA™ anti-CCP for 416 sera from established RA patients | | |
|-------------------------------------------------------------------------|--|--|
|-------------------------------------------------------------------------|--|--|

| | n | negative | positive | Sensitivity |
|----------------------------------------|-----|----------|----------|-------------|
| Patients with clinically<br>defined RA | 416 | 99 | 317 | 76% |

Clinical Sensitivity: RA 317/416 = 76.2% 95% Cl = 72.1-80.3

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Clinical specificity for the EDIA™ anti-CCP for non-RA diseased patients and
asymptomatic individuals (healthy blood donors).

| | n | negative | positive | Specificity |
|-------------------------------------|-----|----------|----------|-------------|
| Healthy blood donors | 262 | 260 | 2 | 99% |
| Crohn's disease | 10 | 10 | 0 | 100% |
| Colitis ulcerosa | 10 | 10 | 0 | 100% |
| Systemic lupus erythematosus | 30 | 30 | 0 | 100% |
| Sjögren's syndrome | 17 | 16 | 1 | 94% |
| EBV | 5 | 5 | 0 | 100% |
| Parvo | 5 | 5 | 0 | 100% |
| Mycoplasma | 9 | 9 | 0 | 100% |
| Toxoplasma | 6 | 6 | 0 | 100% |
| Yersinia | 8 | 8 | 0 | 100% |
| Chlamydia | 5 | 4 | 1 | 80% |
| Malaria | 4 | 4 | 0 | 100% |
| Borrelia | 9 | 9 | 0 | 100% |
| Lues | 5 | 5 | 0 | 100% |
| Rubella | 5 | 5 | 0 | 100% |
| TPO-AB (anti-thyroid peroxidase ab) | 20 | 20 | 0 | 100% |
| Osteoarthritis | 21 | 21 | 0 | 100% |
| Endocarditis | 3 | 3 | 0 | 100% |
| Tuberculosis | 5 | 5 | 0 | 100% |
| Legionella | 4 | 4 | 0 | 100% |
| Salmonella | 3 | 3 | 0 | 100% |
| AST/ASH (anti-streptococcal ab) | 3 | 3 | 0 | 100% |
| Schistosomiasis | 4 | 4 | 0 | 100% |
| Chaga's disease | 3 | 3 | 0 | 100% |
| Scleroderma | 17 | 16 | 1 | 94% |
| Multiple sclerosis | 20 | 20 | 0 | 100% |
| Insulin dependent diabetes mellitus | 20 | 20 | 0 | 100% |
| Polymyositis / Dermatomysositis | 20 | 20 | 0 | 100% |
| Mixed connective tissue disease | 20 | 19 | 1 | 95% |
| MPO-ANCA positive. MP | 20 | 20 | 0 | 100% |
| PR3-ANCA positive. WG | 20 | 20 | 0 | 100% |
| Ds-DNA positive | 40 | 38 | 2 | 95% |
| Inflammatory bowel disease | 80 | 79 | 1 | 99% |
| nonRA autoimmune patients | 80 | 78 | 2 | 98% |
| TOTAL | 793 | 782 | 11 | 98.6% |

MP = Microscopic polyangiitis

:

WG = Wegener's granulomatosis

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# Clinical specificity

| Blood donors | 260/262 = 99.2% | 95% CI = 97.3 - 99.9% |
|--------------------|-----------------|-----------------------|
| Crohn's disease | 10/10 = 100% | 95% CI = 69.2 - 100% |
| Colitis ulcerosa | 10/10 = 100% | 95% CI = 69.2 - 100% |
| SLE | 30/30 = 100% | 95% CI = 88.4 - 100% |
| Sjorgen's syndrome | 16/17 = 94.1% | 95% CI = 71.3 - 99.8% |
| EBV | 5/5 = 100% | 95% CI = 47.8 - 100% |
| Parvo | 5/5 = 100% | 95% CI = 47.8 - 100% |
| Mycoplasma | 9/9 = 100% | 95% CI = 66.4 - 100% |
| Toxoplasma | 6/6 = 100% | 95% CI = 54.1 - 100% |
| Yersinia | 8/8 = 100% | 95% CI = 63.1 - 100% |
| Chlamydia | 4/5 = 80% | 95% CI = 28.4 - 99.5% |
| Malaria | 4/4 = 100% | 95% CI = 39.8 - 100% |
| Borrelia | 9/9 = 100% | 95% CI = 66.4 - 100% |
| Lues | 5/5 = 100% | 95% CI = 47.8 - 100% |
| Rubella | 5/5 = 100% | 95% CI = 47.8 - 100% |
| TPO-AB | 20/20 = 100% | 95% CI = 83.2 - 100% |
| Osteoarthritis | 21/21 = 100% | 95% CI = 83.9 - 100% |
| Endocarditis | 3/3 = 100% | 95% CI = 29.2 - 100% |
| Tuberculosis | 5/5 = 100% | 95% CI = 47.8 - 100% |
| Legionella | 4/4 = 100% | 95% CI = 39.8 - 100% |
| Salmonella | 3/3 = 100% | 95% CI = 29.2 - 100% |
| AST/ASH | 3/3 = 100% | 95% CI = 29.2 - 100% |
| Schistosomiasis | 4/4 = 100% | 95% CI = 39.8 - 100% |
| Chaga's disease | 3/3 = 100% | 95% CI = 29.2 - 100% |
| Scleroderma | 16/17 = 94.1% | 95% CI = 71.3 - 99.8% |
| Multiple Sclreosis | 20/20 = 100% | 95% CI = 83.2 - 100% |
| IDDM | 20/20 = 100% | 95% CI = 83.2 - 100% |
| PM/DM | 20/20 = 100% | 95% CI = 83.2 - 100% |
| MCTD | 19/20 = 95% | 95% CI = 75.1 - 99.9% |
| MP | 20/20 = 100% | 95% CI = 83.2 - 100% |
| WG | 20/20 = 100% | 95% CI = 83.2 - 100% |
| ds-DNA positive | 38/40 = 95% | 95% CI = 83.1 - 99.4% |
| IBD | 79/80 = 98.6% | 95% CI = 93.2 - 100% |
| nonRA autoimmune | 78/80 = 97.5% | 95% CI = 91.3 - 99.7% |

The 95% confidence interval (CI) was calculated using the exact method.

·

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| | High<br>(U/mL) | Medium<br>(U/mL) | Low<br>(U/mL) |
|--------|----------------|------------------|---------------|
| Mean | 173.9 | 34.0 | 9.9 |
| S.D. | 13.8 | 0.6 | 0.2 |
| % C.V. | 7.9 | 1.9 | 2.1 |
| | Low<br>(U/mL) | Low<br>(U/mL) | Low<br>(U/mL) |
| Mean | 11.8 | 7.8 | 9.7 |
| S.D. | 0.5 | 0.1 | 0.4 |
| %C.V. | 4.0 | 1.9 | 4.4 |

- Table 3. Intra-assay precision was determined by testing six different samples eight times each.
- Table 4. Inter-assay precision was determined by testing six different samples eight times each. Results were obtained for three different runs.

| | High<br>(U/mL) | Medium<br>(U/mL) | Low<br>(U/mL) |
|--------|----------------|------------------|---------------|
| Mean. | 183.8 | 36.6 | 9.3 |
| S.D. | 19.5 | 3.0 | 0.9 |
| % C.V. | 10.6 | 8.2 | 9.8 |
| | Low<br>(U/mL) | Low<br>(U/mL) | Low<br>(U/mL) |
| Mean | 11.9 | 7.8 | 10.6 |
| S.D. | 0.8 | 0.7 | 0.9 |
| %C.V. | 6.3 | 9.5 | 8.9 |

Table 5. Batch to batch variation was determined by testing six different samples eight times each. Results were obtained for three different batches.

| | High<br>(U/mL) | Medium<br>(U/mL) | Low<br>(U/mL) |
|--------|----------------|------------------|---------------|
| Mean | 232.5 | 41.6 | 11.5 |
| S.D. | 30.9 | 4.5 | 1.3 |
| % C.V. | 13.3 | 10.8 | 11.2 |
| | Low<br>(U/mL) | Low<br>(U/mL) | Low<br>(U/mL) |
| Mean | 14.1 | 9.8 | 13.0 |
| S.D. | 1.2 | 1.0 | 1.2 |
| %C.V. | 8.3 | 10.4 | 9.3 |

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| Sample | Dilution | Mean<br>Measured<br>Concentration<br>(U/mL) | Calculated<br>Concentration<br>(U/mL) | Dilution<br>Corrected %<br>Recovery |
|--------|----------|---------------------------------------------|---------------------------------------|-------------------------------------|
| 1 | 1/100 | 205.0 | 205.0 | 100 |
| | 1/200 | 110.5 | 102.5 | 108 |
| | 1/400 | 47.3 | 51.3 | 92 |
| | 1/800 | 24.8 | 25.6 | 97 |
| | 1/1600 | 10.8 | 12.8 | 84 |
| Sample | Dilution | Mean<br>Measured<br>Concentration<br>(U/mL) | Calculated<br>Concentration<br>(U/mL) | Dilution<br>Corrected %<br>Recovery |
| 2 | 1/100 | 138.9 | 138.9 | 100 |
| | 1/200 | 70.3 | 69.5 | 101 |
| | 1/400 | 40.4 | 34.7 | 116 |
| | 1/800 | 18.3 | 17.4 | 105 |
| | 1/1600 | 8.7 | 8.7 | 100 |
| Sample | Dilution | Mean<br>Measured<br>Concentration<br>(U/mL) | Calculated<br>Concentration<br>(U/mL) | Dilution<br>Corrected %<br>Recovery |
| 3 | 1/100 | 47.3 | 47.3 | 100 |
| | 1/200 | 26.7 | 23.6 | 113 |
| | 1/400 | 13.0 | 11.8 | 110 |
| | 1/800 | 6.3 | 5.9 | 107 |
| | 1/1600 | 3.0 | 3.0 | 103 |

Table 6. Dilution recovery was determined by testing five serial dilutions of three different patient samples.

### Limit of detection

The detection limit of the assay was determined by running the zero calibrator 12 times on three different lots. The detection limit of 0.5 U/mL was calculated by finding the mean plus two standard deviations.

#### Interference study

Three low positive samples were spiked to the following concentrations in diluted serum samples; Billrubin F at 0.188 mg/dL, Bilirubin C at 0.2 mg/dL, Haemoglobin at 453 mg/dL, Chyle at 0.24 U/dL and Rheumatoid Factor at 200 IU/mL. The data indicates that the assayed concentrations do not interfere with the anti-CCP results.

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## DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized human figure with three arms reaching upwards, and it is surrounded by the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" in a circular arrangement. The figure is black, and the text is also black. The logo is simple and recognizable.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Euro-Diagnostica AB c/o Ms. Annika Andersson Regulatory Affairs Specialist Medeon SE-205 12 Malmő Sweden

DEC - 4 2006

Re: k062045

Trade/Device Name: EDIA™ Anti-CCP Regulation Number: 21 CFR 866.5775 Regulation Name: Rheumatoid Factor Immunological Test System Regulatory Class: Class II Product Code: NHX Dated: July 14, 2006 Received: July 19, 2006

Dear Ms. Andersson:

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.

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 Section 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), please contact the Office of Compliance at [phone]. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-frec number [phone] or [phone] or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Robert W. Beckerf

Robert L. Becker, Jr., M.D., Ph.D Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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# Indications for Use

510(k) Number (if known):

Device Name: EDIA™ anti-CCP

Indications For Use: The EDIA™ anti-CCP test kit is an enzyme-linked immunosorbent assay (ELISA) for detection and semi-quantitation of IgG antibodies to Cyclic Citrullinated Peptides (CCP) in human sera and plasma. The assay is used to detect antibodies in a single specimen. The results of the assay are to be used as an aid to the diagnosis of Rheumatoid Arthritis (RA), in conjunction with other laboratory and clinical findings. The analysis should be performed by trained laboratory professionals.

Prescription Use × (21 CFR 801 Subpart D)

AND/OR

Over-The-Counter Use (21 CFR 807 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Mana M Chan

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety Page 1 of 1

510(k) K062045