The Varelisa ReCombi CTD Screen EIA kit is designed for the qualitative determination of ten antinuclear antibodies in human serum or plasma to aid in the diagnosis of systemic rheumatic diseases such as SLE (systemic lupus erythematosus), drug-induced lupus, scleroderma (progressive systemic sclerosis), MCTD (mixed connective tissue disease), SS (Sjögren's syndrome) and polymyositis/dermatomyositis. The Varelisa ReCombi CTD Screen detects antibodies against dsDNA, RNP (RNP70,A,C), Sm (B,B',D), SS-A/Ro(52 kDa,60 kDa), SS-B/La, Scl-70, CENP-B, Histone, Ribosomal P Protein and Jo-1 in a single microwell.

Device Description

The new device is an enzyme-linked immunosorbent assay (ELISA) using microtiter plates as the solid phase. The plate wells are coated with antinuclear antigens, which allow anti-nuclear antibodies (sample) to react with the immobilized antigens. The conjugate is rabbit anti-human IgG horseradish peroxidase (HRP), which uses 3, 3'5, 5' tetramethylbenzidine dihydrochloride (TMB) as substrate. The kit contains calibrator and negative control. The kit also contains sample diluent, wash buffer concentrate and stop solution.

AI/ML Overview

Here's an analysis of the provided text regarding the acceptance criteria and study for the Varelisa ReCombi CTD Screen, organized according to your requested information:

Device Acceptance Criteria and Performance Study

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined quantitative acceptance criteria (e.g., "sensitivity must be > X%" or "specificity must be > Y%") for the Varelisa ReCombi CTD Screen. Instead, the study aims to demonstrate laboratory equivalence and substantial equivalence to a predicate device (Varelisa® ReCombi ANA Screen K993108). The performance metrics reported are focused on the agreement between the new device's results and clinical definitions of samples, compared to the predicate device.

Performance Metric	Varelisa ReCombi CTD Screen Performance	Predicate Device Performance	Difference (New Device - Predicate Device)	95% Confidence Interval for Difference
Agreement for Positive Cases	87.4%	85.2%	2.2%	[-1.7%, 5.0%]
(CTD samples clinically defined as positive)
Agreement for Negative Cases	79.0%	84.0%	-5.0%	[-11.8%, -0.2%]
(Control samples clinically defined as negative)

Implicit Acceptance Criteria (based on the provided information):

Substantial Equivalence: The primary "acceptance criterion" is to demonstrate substantial equivalence to the predicate device. This is achieved through comparability in intended use, assay principle, and performance characteristics.
Comparable Performance: The agreement rates for both positive (CTD) and negative (control) samples should be comparable to the predicate device, with differences falling within acceptable confidence intervals (though specific thresholds for these intervals are not explicitly stated as acceptance criteria). The presented data suggests the differences are deemed acceptable for substantial equivalence.
"Performs according to state-of-the-art expectations": This is a qualitative statement in the summary implying that the device's overall performance is considered modern and effective for its purpose.

2. Sample Sizes Used for the Test Set and Data Provenance

Test Set Size:
- Clinical Samples: 183 CTD (Connective Tissue Disease) samples.
- Control/Negative Samples: 100 disease controls, plus "samples from apparently healthy subjects (normal population)" (specific number not given for the normal population, but the "100 disease controls" are used for the negative agreement calculation).
- Total: At least 283 samples (183 CTD + 100 disease controls). The text also mentions "clinically defined sera and for international reference sera" and "samples from apparently healthy subjects (normal population)," suggesting the reported numbers might be a subset of a broader validation set.
Data Provenance: Not explicitly stated, but the manufacturer is based in Germany, implying the study could have been conducted there or in collaboration with other European institutions. The mention of "international reference sera" suggests a diverse set of samples. The study appears to be retrospective, as it analyzed "results obtained for clinically defined sera."

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

The document does not specify the "number of experts" or their "qualifications" involved in establishing the ground truth. It refers to "clinically defined sera" and "clinical definitions of samples," implying that the ground truth for CTD status (positive/negative) was established through clinical diagnosis, likely by physicians or rheumatologists, based on a comprehensive set of clinical criteria, medical history, and other diagnostic tests.

4. Adjudication Method for the Test Set

The adjudication method is not explicitly described. Given that the ground truth is derived from "clinical definitions," it likely represents a consensus clinical impression rather than a specific adjudication process between multiple readers of the assay results.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not performed. This device is an in vitro diagnostic (IVD) kit for lab testing, not an AI-assisted diagnostic tool that helps human readers interpret images or complex data. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply to this submission.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance study was conducted. The reported "Agreement (%)" for both positive and negative samples (87.4% and 79.0%, respectively) represents the performance of the Varelisa ReCombi CTD Screen itself when tested against clinically defined samples, without human intervention in the result interpretation beyond standard lab protocols for reading ELISA plates (e.g., using a microplate reader). The ELISA kit itself is the "algorithm" in this context.

7. Type of Ground Truth Used

The ground truth used was clinical definitions/diagnosis of systemic rheumatic diseases. The text mentions "clinically defined sera" and "clinical definitions of samples," indicating that the diagnosis of CTD (or lack thereof for control samples) was established through medical evaluation of patients.

8. Sample Size for the Training Set

The document does not specify a training set size. This is common for traditional IVD kits as their development often involves iterative optimization and validation rather than a distinct "training set" in the machine learning sense. The "development" of the new device is mentioned in comparison to the predicate, implying an engineering and chemistry-focused development process rather than algorithmic training.

9. How the Ground Truth for the Training Set Was Established

Since a specific "training set" is not mentioned, the method for establishing ground truth for such a set is also not specified. If any internal validation or optimization was done during development, the ground truth would likely have been established similarly to the test set: through clinical definitions and classification of samples.

Summary

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510(K) SUMMARY OF SAFETY AND 9. EFFECTIVENESS

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

Assigned 510(k) Number:	K050967
Date of Summary Preparation:	June 15, 2005
Manufacturer:	Sweden Diagnostics (Germany) GmbHMunzinger Strasse 7D-79111 Freiburg, Germany
Company Contact Person:	Michael LinssManager, Compliance & QualitySweden Diagnostics (Germany) GmbHMunzinger Strasse 7D-79111 Freiburg, Germany+49-761-47805-310 (Phone)+49-761-47805-335 (Fax)
Device Name:	Varelisa ReCombi CTD Screen
Common Name:	Antinuclear antibodyimmunological test system

Classification

Product Name	Product Code	Class	CFR
Varelisa® ReCombi CTD Screen	LJM	II	866.5100

Substantial Equivalence to

Varelisa® ReCombi ANA Screen (510(k) number: K993108)

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Intended Use Statement of the New Device

Intended use/Indication for use

Special condition for use statement

The device is for prescription use only.

Special instrument requirements

A microplate reader capable of measuring OD at 450 mm and 620 mm is required.

General Description of the New Device

Test Principle of the New Device

Varelisa ReCombi CTD Screen is an indirect noncompetitive enzyme immunoassay for the qualitative determination of 10 antinuclear antibodies in serum or plasma. The wells of a microplate are coated with human recombinant and native purified nuclear antigens and dsDNA. Antibodies specific for the nuclear antigens present in a patient sample bind to these nuclear antigens.

In a second step the enzyme labeled second antibody (conjugate) binds to the antigen-antibody complex which leads to the formation of an enzyme labeled conjugate-antibody-antigen complex. The enzyme labeled antigen-antibody complex converts the added substrate to form a colored solution.

The rate of color formation from the chromogen is a function of the amount of conjugate complexed with the bound antibody and thus is proportional to the initial concentration of the respective antibodies in the patient sample.

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Device Comparison

The new device is developed as successor of the predicate device. Both assays the now assay principle and indications for use. They are indirect share the bains asseme immunoassays for qualitative determination of IgG antibodies against antinuclear antigens in serum and plasma. Both assays antioodies "agains" annote dilutions and use identical reagents (including the coolimions the bande to the relevant scientific literature both assays state in the Intended Use, that the measuring of antinuclear antibodies aids in the diagnosis of Connective Tissue Diseases such as SLE (systemic lupus erythematosus), scleroderma (progressive systemic sclerosis), MCTD (mixed connective tissue disease), SS (Sjögren's syndrome) and polymyositis/ dermatomyositis.

Differences do exist but do not affect the tenor of the "Intended Use" and do not Differences as entor Safety and Effectiveness" questions. The new device uses two additional antigens (Histone, Rib-P) and a synthetic peptide derived from the human SmD protein plus recombinant SmBB' instead of Sm antigen purified from calf thymus (complex consisting of SmBB' and SmD). Minor differences pertain to increased volumina of the reagents and leaving out the prewashing step of the antigen strips. The Wash buffer does no longer contain NaN3 and the substrate TMB is of lower concentration because the substrate incubation step is increased to 30 min.

Laboratory equivalence

The comparability of predicate device and new device is supported by a data set including

results obtained for clinically defined sera and for international . reference sera.
results obtained for samples from apparently healthy subjects . (normal population).
results obtained within a comparison study analyzing 100 . disease controls and 183 CTD samples.

Analysis of Agreement between individual test results and clinical definitions of samples.

	Varelisa ReCombi CTD Screen		Predicate Device		Difference betweenassays (%)
	Agreement(%)	95% ConfidenceInterval (CI)	Agreement(%)	95% CI	Varelisa ReC. CTDScreen -Predicate Device	95% CI
Positive(CTDsamples)	87.4	81.7 - 91.9%	85.2	79.3 -90.0%	2.2	-1.7 -5.0%
Negative(Controlsamples)	79.0	69.7 - 86.5%	84.0	75.3 -90.6%	- 5.0	-11.8 --0.2%

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In summary, all available data support that the new device is substantially equivalent to the predicate device and that the new device performs according to state-of-the-art expectations.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administratio 2098 Gaither Road Rockville MD 20850

JUN 2 8 2005

Mr. Michael Linss Manager, Compliance and Quality Sweden Diagnostics (Germany) GmbH Munzinger Strasse 7 D-79111 Freiburg, Germany

K050967 Re:

Trade/Device Name: Varelisa ReCombi CTD Screen Regulation Number: 21 CFR 866.5100 Regulation Name: Antinuclear antibody immunological test system Regulatory Class: Class II Product Code: LJM Dated: April 15, 2005 Received: April 18, 2005

Dear Mr. Linss:

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 Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). 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.

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Page 2 -

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0484. 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-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html

Sincerely yours,

Robert Beckerh

Robert L. Becker, Jr., MD, P& Director Division of Immunology and Hematology 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:

Device Name:

K050967

Varelisa ReCombi CTD Screen

Indications For Use:

The Varelisa ReCombi CTD Screen EIA kit is designed for the qualitative determination of ten antinuclear antibodies in human serum or plasma to addinathe diagnosis of systemic rheumatic diseases such as SLE (systemic ipus erythematosus), drug-induced lupus, scleroderma (progressive systemic sclerosis), MCTD (mixed connective tissue disease), SS (Sjögren's syndrome) and polynysitis/ dermatomyositis. The Varelisa ReCombi CTD Screen detects antibodies against dsDNA, RNP (RNP70,A,C), Sm (B,B',D), SS-A/Ro(52 kDa,60 kDa), SS-B/La, Scl-70, CENP-B, Histone, Ribosomal P Protein and Jo-1 in a single miorovell.

Prescription Use V (Part 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 Device Evaluation (ODE)

Mani Chow

Division Sign-Off

Office of In Vitro Dia Device Evaluation and

510(k) Ks50967

Regulation Number and Section

§ 866.5100 Antinuclear antibody immunological test system.

(a)
Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).(b)
Classification. Class II (performance standards).