The EUROIMMUN Anti-Glutamate receptor (type NMDA) IFA is intended for the qualitative determination of autoantibodies against glutamate receptor (type NMDA) in human serum. It is used as an aid in the diagnosis of anti-glutamate receptor (type NMDA) autoimmune encephalitis in conjunction with other laboratory and clinical findings.

Device Description

The EUROIMMUN IFA is an assay for standardized detection of anti-glutamate receptor (type NMDA) antibodies utilized in each laboratories familiar with indirect immunofluorescence. The non-transfected cells are used as a control to simplify differentiation of potential co-existing and non-specific reactivity such as ANA. The test kit consists of slides, which contain BIOCHIPs coated with glutamate receptor (type NMDA) transfected cells and non-transfected cells, fluorescein-labelled anti-human IgG (goat), a positive control for transforced volle and non new and of a negative control, a salt for preparation of PBS, Tween 20, embedding medium, cover glasses and an instruction booklet.

AI/ML Overview

The acceptance criteria and study proving the device meets them are detailed below based on the provided text.

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state quantitative acceptance criteria for sensitivity and specificity. However, based on the studies presented, we can infer the desired clinical performance. The reported device performance is directly from the clinical studies.

Metric	Acceptance Criteria (Inferred)	Reported Device Performance	Study
Sensitivity	High sensitivity (e.g., >90%)	100.0% (Study 1)	Study 1
		100.0% (Study 3)	Study 3
		100.0% (Study 4)	Study 4
		83.3% (Study 2)	Study 2
		Overall: 98.1%	Overall
Specificity	High specificity (e.g., >95%)	0.0% (Study 1 - other encephalopathies)	Study 1
		0.0% (Study 1 - healthy donors)	Study 1
		0.0% (Study 4 - other encephalopathies)	Study 4
		Overall: 100.0%	Overall

Note: The "acceptance criteria (inferred)" are based on typical expectations for diagnostic assays intended to aid in diagnosis. The document does not provide specific numerical targets prior to presenting the results.

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

The 'test set' for clinical performance was composed of samples across four clinical studies. The data provenance includes both retrospective and prospective elements.

Study 1: 47 serum samples (29 anti-glutamate receptor (type NMDA) encephalitis, 18 other encephalopathies) from the US (Prospective, though the specific collection method isn't detailed, it implies collection for diagnostic purposes). Additionally, 100 adult healthy blood donors from Germany (Prospective/Retrospective, general population screening).
Study 2: 2990 patients screened for encephalitis of unknown origin; 6 samples ultimately tested (6 women) from Germany (Retrospective).
Study 3: 8 samples from patients with anti-glutamate receptor (type NMDA) encephalitis from Germany (Prospective/Retrospective, not explicitly stated).
Study 4: 9 samples from patients with anti-glutamate receptor (type NMDA) encephalitis and 13 from patients with other encephalopathies from Italy (Prospective/Retrospective, not explicitly stated).

Combined Test Set Sample Sizes:

Positive cases (anti-NMDA encephalitis): 29 + 5 (from 6) + 8 + 9 = 51 (overall 52 based on table summary, possibly one case from study 2 was reclassified as positive, or a rounding difference)
Negative cases (other encephalopathies/healthy donors): 18 + 100 + 13 = 131

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

The document does not specify the number of experts or their qualifications who established the ground truth for the test set. It mentions "patients diagnosed with anti-gluatamate receptor (type NMDA) encephalitis" and "controls with other encephalopathies," implying established clinical diagnoses. It also states the device is used "in conjunction with other laboratory and clinical findings," suggesting that the ground truth patients were diagnosed by a combination of clinical specialists (e.g., neurologists) and potentially other laboratory tests, but the specific expert review process for the test set is not detailed.

4. Adjudication Method for the Test Set:

The document does not describe a formal adjudication method (e.g., 2+1, 3+1) for establishing the ground truth of the test set cases. The cases are described as "patients diagnosed with," implying that their diagnosis served as the ground truth.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance:

The document describes an indirect immunofluorescent antibody assay (IFA) which is a laboratory test requiring visual interpretation by a human. However, it does not involve AI or a multi-reader, multi-case (MRMC) comparative effectiveness study of human readers with or without AI assistance. The device is not an AI-based diagnostic tool for image analysis as described in the context of improving human reader performance.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

Not applicable. The device is an IFA kit, which inherently requires human interpretation of fluorescence under a microscope. It is not an algorithm that performs standalone analysis.

7. The Type of Ground Truth Used:

The ground truth used for the clinical studies appears to be based on clinical diagnosis of anti-glutamate receptor (type NMDA) encephalitis or other encephalopathies. For healthy controls, the implied ground truth is the absence of the disease. The phrase "patients diagnosed with" suggests a consensus among clinicians and potentially other diagnostic tests, but not explicitly pathology or a specific "outcomes data" in the sense of long-term follow-up beyond diagnosis.

8. The Sample Size for the Training Set:

The document does not describe a specific "training set" for the device, as it is a laboratory assay (IFA kit) rather than a machine learning or AI algorithm that requires a separate training phase with labeled data. The development of the assay likely involved internal optimization and validation, but this is not referred to as a "training set" in the context of device performance testing.

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

Not applicable, as a distinct training set (in the context of machine learning) is not described for this IFA kit.

Summary

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EUROIMMUN US INC.

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PREMARKET NOTIFICATION 510(K) SAFETY AND EFFECTIVENESS SUMMARY (as required by 21 CFR § 807.92)

A. 510(k)Number: K010017
Purpose for Submission: B.
New device C. Measurand:
- Autoantibodies against glutamate receptor (type NMDA)
D. Type of Test:
- Semi-quantitative indirect immunofluorescent antibody assay
E. Applicant:
- EUROIMMUN US INC.
Proprietary and Established Names: E. EUROIMMUN Anti-Glutamate receptor (type NMDA) IFA
G. Regulatory Information:
- 1. Requlation:
  - 21 CFR 866.5660 Multiple autoantibodies immunological test system
  - 1. Classification: Class II
  - 1. Product code: ેટાર
  - 1. Panel:

Immunology

H. Intended Use:

Intended use(s): 1.
The EUROIMMUN Anti-Glutamate receptor (type NMDA) IFA is intended for the qualitative determination of autoantibodies against glutamate receptor (type NMDA) in human serum. It is used as an aid in the diagnosis of anti-glutamate receptor (type NMDA) autoimmune encephalitis in conjunction with other laboratory and clinical findings.
1. Indication(s) for use: Same as intended use.
Special conditions for the use statement(s): 3.
For prescription use only.
Special instrument requirements: 4. Fluorescence microscope.

Device Description: l.

SEP 1 8 2010

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J. Substantial Equivalence Information:

Predicate device name (s): 1. EUROIMMUN ANCA IFA Granulocyte BIOCHIP Mosaic™ Test System.
Predicate 510(k) number(s): 2.
K083850
1. Comparison with predicate:

The EUROIMMUN ANCA IFA Granulocyte BIOCHIP Mosaic™ Test System was choosen as a device of equivalent method and technology. There is no exact predicate device available for the detection of antibodies against glutamate receptor (type NMDA).

Similarities
Item	New device	Predicate device
Intended Use	Semi-quantitative detection of antibodiesin human serum.	Same
Technology	IFABIOCHIP TITERPLANE technologyusing multiple substrates	Same
Procedure	Standard IFA technique; serumincubation with tissues/cells, followed bya wash step, incubation with fluorescein-labelled anti-human globulin, wash step,embedding and reading fluorescencewith a fluorescence microscope.	Same
Reagent	Fluorescein	Same
Sample type anddilution	Serum1:10 dilution	Same
Controls	Positive controlNegative control	Same
Cut Off Level	1:10 dilution	Same
Differences
Intended Use	Detection of antibodies againstglutamate receptor (type NMDA)	Detection of anti-neutrophil cytoplasmicantibodies (ANCA)

Standard/Guidance Document Referenced (if applicable): K.

cells

Glutamate receptor (type NMDA)

transfected cells and non-transfected

None referenced.

L. Test Principle:

Substrates

The procedure follows the TITERPLANE Technique developed by EUROIMMUN as an aid in standardize immunological analyses. The TITERPLANE Technique of EUROIMMUN was cleared previously via the FDA 510(k) processes under 510(k) No. K051489, K061408, K070763 and K083850.

Human granulocytes native antigen

Patient samples, controls and in separate steps conjugate and embedding medium are applied to the reaction fields of a reagent tray. The BIOCHIP slides are then placed into the recesses of the reagent tray, where all nold of a reagen the slide comact with the fluids, and the individual reactions commence simultaneously. The fluids are confined to the recessed wells eliminating the need to use a conventional "humidity chamber".

Patient samples are diluted 1:10 in PBS-Tween, 25 µl of each diluted patient sample are added to each reaction field of the reagent tray. Reactions are started by fitting the BIOCHIP slides containing the substrates reachion hold of the reagon traym rype NMDA transfected cells and non-transfected cells) into the corresponding recesses of the reagent tray and incubated for 30 minutes at room temperature. into the other antigens. After incubation the BIOCHIP slides are washed with PBS-Tween to opecific antibodies. In the meantime, 20 ul of fluorescein-labelled anti-human globulin are added to remove unbodne antibodios. In the means, the BIOCHIP slides placed into the recesses of the tray. After a

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30 minutes incubation at room temperature, the BIOCHIPs are again washed with PBS-Tween to remove any unbound fluorescein-labelled reagent. 10 ul of Embedding medium are placed for each reaction field on a cover glass and the BIOCHIP slides, with the BIOCHIPs facing downwards, placed onto the prepared cover glass. Fluorescence is read with a fluorescence microscope.

M. Performance Characteristics (where applicable):

Analytical performance: 1.

a. Precision/Reproducibility:
- Intra-assay reproducibility

The intra-assay reproducibility was determined by 10fold repeated measurements of 6 characterized positive and negative serum samples. The results did not exceed the acceptable deviation of fluorescence intensity of +/- 1 intensity level.

Inter-assay reproducibility

The inter-assay reproducibility was determined by repeated measurements of 6 characterized positive and negative serum samples at 5 different times. 2 slides were tested with each run. The results did not exceed the acceptable deviation of fluorescence intensity of +/- 1 intensity level. Lot to lot reproducibility

The inter-lot reproducibility was determined by measurements of 3 characterized positive and negative serum samples using 3 different kit lots. The results did not exceed the acceptable deviation of fluorescence intensity of +/- 1 intensity level.

b. Linearity/assay reportable range: Not applicable.
Traceability, Stability, Expected values (controls, calibrators or methods): C.

There is no recognized standard or reference material for autoantibodies against glutamate receptor (type NMDA).

d. Detection limit:
Not applicable.
Analytical specificity: e.
Cross-reactivity: Cross reactivity was investigated using 31 samples from patients with infectious and autoimmune encephalitis other than anti-qlutamate receptor (type NMDA) encephalitis. Samples positive for anti-GluR2, anti-VGKC and anti-zic4 (cerebellar degeneration) do not react with the qlutamate receptor (type NMDA).

Interference: Three different samples are spiked with potential interfering substances in 3 different concentrations and are incubated with the test system. The recovery in relation to the original sample (not spiked) is calculated. The deviation in fluorescence intensity level did not exceed +/- 1. No interference was observed with hemolytic, lipemic or icteric samples for concentrations of up to 500 mg/dl for hemoglobin, 2000 mg/dl for triglyceride and 40 mg/dl for bilirubin.

f. Assay cut-off:
Not applicable.
1. Comparison studies:
- Method comparison with predicate device: a. Not applicable.
- b. Matrix comparison: Not applicable.

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3. Clinical studies:

Prevalence and specificity: a.

Study 1: 47 serum samples from the US from patients diagnosed with anti-gluatamate receptor (type NMDA) encephalitis and controls with other encephalopathies, including anti-VGKC and AMPA receptor encephalitis, were examined. The panel comprised samples from 7 men and 40 women with an average age of 17 years (age range: 5 to 42 years; 1 unknown). In addition, sera of 100 adult healthy blood donors of mixed age and sex from Germany were analyzed. All samples from patients with anti-qlutamate receptor (type NMDA) encephalitis (29 sera) were tested positive with the transfected cells, while all disease control samples (18 sera) and healthy blood donors (100 sera) were negative.

Study 2: In a retrospective study, 2990 patients were screened for clinical symptoms of encephalitis of unknown origin. 5 of 6 samples fulfilling the criteria (6 women with an average age of 23 years, age range: 18 to 31 years; origin: Germany) were found positive for antibodies against glutamate receptor (type NMDA). The results support the fact that anti-glutamate receptor (type NMDA) encephalitis is a very frequent cause among these patients.

Study 3: 8 samples from patients with anti-glutamate receptor (type NMDA) encephalitis (origin: Germany) were investigated. The panel comprised samples from 3 men and 5 women with an average age of 25 years (age range: 16 to 39 years). All samples were found positive for antiqlutamate receptor (tpye NMDA).

Study 4: 9 samples from patients with anti-glutamate receptor (type NMDA) encephalitis and 13 samples from patients with other encephalopathies (origin: Italy) were investigated. The panel comprised samples from 8 men and 14 women with an average age of 47 years (age range: 9 to 89 years). All samples from patients with anti-glutamate receptor (type NMDA) encephalitis (9 sera) were tested positive with the transfected cells, while all disease control samples (13 sera) were negative.

Panel		n	EUROIMMUN Anti-Glutamate receptor (type NMDA) IFA
			positive	% positive	95% C.I.
Study 1	Patients with anti-glutamate receptor(type NMDA) encephalitis	29	29	100.0%	88.1 - 100.0%
	Patients with other encephalopathies	18	0	0.0%	0.0 - 18.5%
	Healthy blood donors	100	0	0.0%	0.0 - 3.6%
Study 2	Patients with encephalitis of unknownorigin	6	5	83.3%	35.9 - 99.6%
Study 3	Patients with anti-glutamate receptor(type NMDA) encephalitis	8	8	100.0%	63.1 - 100.0%
Study 4	Patients with anti-glutamate receptor(type NMDA) encephalitis	9	9	100.0%	66.4 - 100.0%
	Patients with other encephalopathies	13	0	0.0%	0.0 - 24.7%
Overall sensitivity		52	51 positive	98.1%	89.7 - 100.0%
Overall specificity		131	131 negative	100.0%	97.2 - 100.0%

Other clinical supportive data (when a. and b. are not applicable): b. Not applicable.

Clinical cut-off: 4.
See Assay cut-off.

Expected values/Reference range: 5.

The levels of the anti-glutamate receptor (type NMDA) antibodies (IgG) were analyzed with the EUROIMMUN Anti-Glutamate receptor (type NMDA) IFA in a panel of 120 sera from normal healthy adult blood donors of mixed age and gender. All samples were found negative. The reference range was determined as titer 1: < 10.

Proposed Labeling: N.

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

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O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

Date

Signature

Kathryn Kohl, Managing Director Typed Name, Title

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized caduceus, which is a symbol of medicine, with three lines representing the serpent and staff. The logo is surrounded by the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" in a circular arrangement.

Public Health Service

Food & Drug Administration 10903 New Hampshire Avenue Building 66 Silver Spring, MD 20993

EUROIMMUN US INC. c/o Ms. Kathryn Kohl Managing Director . 429 Rockaway Valley Road Unit 1200 Boonton Township, NJ 07005

SEP 1 3 2010

Re: K100017

Trade/Device Name: EUROIMMUN Anti-Glutamate receptor (type NMDA) IFA Regulation Number: 21 CFR§866.5660 Regulation Name: Multiple Autoantibodies Immunological Test System Regulatory Class: Class II. Product Code: OSK Dated: August 4, 2010 Received: August 9, 2010

Dear Ms. Kohl:

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 class II (Special Controls), 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

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Page 2 - Ms. Kathryn Kohl

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); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (OS) 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.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. 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

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

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) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely vours.

e m Chan

Maria M. Chan, 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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EUROIMMUN US INC.

510(k) Number (if known): K100017

Device Name: Anti-Glutamate receptor (type NMDA) IFA

Indications For Use:

INDICATIONS FOR USE STATEMENT

Prescription Use X (Part 21 CFR 801 Subpart D)

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

Concurrence of CDRH, Office of Device Evaluation (OIVD)

AND/OR

Leena

Division Sign-Off

510

Office of In Vitro Diagnost Device Evaluation an

•

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ATTACHMENT 2

SEP 1 3 2010

Over-The-Counter Use

(21 CFR 801 Subpart C)

Regulation Number and Section

§ 866.5660 Multiple autoantibodies immunological test system.

(a)
Identification. A multiple autoantibodies immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when the body's own tissues are injured by autoantibodies).(b)
Classification. Class II (performance standards).