EliA SymphonyS is intended for the in vitro, qualitative measurement of antibodies in human serum and plasma (Li-heparin, EDTA). EliA SymphonyS is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmD3 peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderna and polymyositis, in conjunction with other laboratory and clinical findings. EliA SymphonyS uses the EliA IgG method on the instrument Phadia 250.

EliA SymphonyS is intended for the in vitro, qualitative measurement of antibodies in human serum and plasma (Li-heparin, EDTA). EliA SymphonyS is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmD3 peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderma and polymyositis, in conjunction with other laboratory and clinical findings. EliA SymphonyS uses the EliA IgG method on the instrument Phadia 2500/5000.

Device Description

The method specific reagents on Phadia® 250 and Phadia® 2500/5000 are identical; they are only filled in different containers. Each device consists of:

EliA Symphony® Wells are coated with human recombinant U1RNP (RNP70, A. -C). SS-A/Ro (60 kDa. 52 kDa). SS-B/La. Centromere B. Scl-70. Jo-1 proteins and synthetic SmD3 peptide - 4 carriers (16 wells each), ready to use;
EliA Sample Diluent: PBS containing BSA, detergent and 0.095% sodium azide --6 bottles, 48 mL each, ready to use; or 6 bottles, 400 mL each, ready to use;
EliA IgG Conjugate 50 or 200: ß-Galactosidase labeled anti-IgG (mouse monoclonal antibodies) in PBS containing BSA and 0.06% sodium azide -6 wedge shaped bottles, 5 mL each, ready to use; or 6 wedge shaped bottles, 19 mL each, ready to use
EliA ANA Positive Control 250 or 2500/5000: Human serum containing lgG antibodies to dsDNA, RNP, Sm, Ro. La. Scl-70. CENP and Jo-1 in PBS containing BSA, detergent and 0.095% sodium azide - 6 single use vials, 0.3 mL each, ready to use;
-EliA Negative Control 250 or 2500/5000: Human sera from healthy donors in PBS containing BSA, detergent and 0.095% sodium azide - 6 single-use vials, 0.3 mL each, ready to use;
EliA IgG Calibrator Strips: Human IgG (0, 4, 10, 20, 100, 600 µg/L) in PBS containing BSA, detergent and 0.095% sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
-EliA IgG Curve Control Strips: Human IgG (20 µg/L) in PBS containing BSA, detergent and 0.095% sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
EliA IgG Calibrator Well: Coated with mouse monoclonal antibodies 4 carriers (12 wells each), ready to use.

The Phadia EliA Immunodiagnostic System is an automated system for immunodiagnostic testing. The EliA reagents are available as modular packages, each purchased separately. Apart from the EliA ANA Positive Control 250 or 2500/5000 and the EliA IqG/IqM/IgA Neqative Control 250 or 2500/5000, all packages listed above are required to carry out an EliA SymphonyS Test.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the EliA SymphonyS Immunoassay, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

Assessment Type	Acceptance Criteria	Reported Device Performance (EliA SymphonyS)
Precision	(Implicit, likely high agreement with expected result and low variability)	Phadia 250: • Sample 1 (Negative): 100% correct (0/0/84) • Sample 2 (Equivocal): 81.3% correct (0/205/47) • Sample 3 (Positive): 60.3% correct (152/100/0) • Sample 4 (Positive): 100% correct (252/0/0) • Sample 5 (Positive): 100% correct (252/0/0) • Sample 6 (Positive): 100% correct (250/0/0) Phadia 2500/5000: • Sample 1 (Negative): 79.8% correct (0/17/67) • Sample 2 (Equivocal): 85.7% correct (0/72/12) • Sample 3 (Equivocal): 91.7% correct (7/77/0) • Sample 4 (Equivocal): 65.5% correct (29/55/0) • Sample 5 (Positive): 100% correct (84/0/0) • Sample 6 (Positive): 100% correct (84/0/0) • Sample 7 (Positive): 100% correct (84/0/0)
Interference	No interference observed up to specified concentrations of endogenous and exogenous substances.	No interference observed up to specified concentrations for Bilirubin F (19.2 mg/dL), Bilirubin C (20.1 mg/dL), Hemoglobin (496 mg/dL), Lipemic factor (1%), Rheumatoid factor (500 IU/ml), Ibuprofen (21.9 mg/dL), Prednisone (0.0099 mg/dL), Hydroxychloroquine (0.225 mg/dL), Azathioprine (0.258 mg/dL), Losartan (1.14 mg/dL), and Infliximab (26.4 mg/dL). Range of blank/spiked sample ratio was 0.88-1.16 for endogenous and 0.83-1.13 for exogenous.
Cut-off	95th percentile of healthy population for setting the cut-off; 30 ANA positive samples with known reactivities should be found positive.	Cut-off: <0.7 Ratio (Negative), 0.7 - 1.0 Ratio (Equivocal), >1.0 Ratio (Positive). 95th percentile of healthy population was 0.3 Ratio. (No explicit statement on the 30 ANA positive samples being found positive, but it's implied by the method).
Method Comparison (vs. Predicate)	High agreement (Positive and Negative Percent Agreement) with the predicate device (EliA Symphony).	Equivocal results considered Negative: • Positive Percent Agreement: 97.6% (95% CI: 95.0 - 99.0)• Negative Percent Agreement: 98.3% (95% CI: 96.3 - 99.4)• Total Agreement: 97.9% (95% CI: 96.5 - 98.9) Equivocal results considered Positive: • Positive Percent Agreement: 92.3% (95% CI: 88.7 - 95.0)• Negative Percent Agreement: 98.1% (95% CI: 96.0 - 99.3)• Total Agreement: 95.3% (95% CI: 93.3 - 96.8)
Matrix Comparison	Plasma results (Li-heparin, EDTA) should not deviate from corresponding serum results and be within pre-defined specifications (implied by acceptable slopes and intercepts of Passing-Bablok regression).	• Serum vs. Li-heparin plasma: Slope 1.03 (95% CI: 0.98 to 1.05), Intercept -0.02 (95% CI: -0.03 to -0.00), R² 0.994 • Serum vs. EDTA plasma: Slope 0.98 (95% CI: 0.96 to 1.00), Intercept -0.03 (95% CI: -0.04 to -0.01), R² 0.997
Instrument Comparison	High correlation and agreement between Phadia 250 and Phadia 2500/5000 instruments (implied by acceptable regression analysis).	Intercept 0.06 (95% CI: 0.01 - 0.12), Slope 1.01 (95% CI: 0.99 - 1.03), R 0.992
Clinical Sensitivity & Specificity	(Implicit, likely demonstrating reasonable diagnostic performance for aid in clinical diagnosis)	EliA Symphony® – equivocal results evaluated as negative: • Sensitivity: 52.6% (95% CI: 45.3% - 59.8%) • Specificity: 94.8% (95% CI: 91.3% - 97.2%) EliA Symphony® – equivocal results evaluated as positive: • Sensitivity: 55.2% (95% CI: 47.9% - 62.3%) • Specificity: 94.4% (95% CI: 90.8% - 96.9%)
Reference Sera	Externally defined sera (CDC, AMLI) should be measured according to their target values.	CDC targets were met (all positive samples were positive, negative samples negative). AMLI targets were met except for two samples (AMLI 3 and 6) that showed negative results while the target was positive (not met by any single semi-quantitative EliA test or competitor).
Carry-over	Negligible effect without influencing assay results.	Negligible, "only a few RUs difference compared to the reference pipetting could be seen, which is too low to be expressed in U/mL." Disposable tips for Phadia 2500/5000 prevent sample to conjugate carry-over.

Study Details:

2. Sample Size and Data Provenance (Test Set)

Precision Study (Phadia 250): 5 samples, 252 replicates per sample (totaling 1260 determinations). Data provenance not explicitly stated, but clinical samples are generally used for such studies.
Precision Study (Phadia 2500/5000): 7 samples, 84 replicates per sample (totaling 588 determinations). Data provenance not explicitly stated.
Interference Study: 3 serum samples (negative, cut-off, high positive), analyzed in triplicates, repeated twice. Spiked with specific interfering substances. Data provenance not explicitly stated.
Cut-off Study: 70 apparently healthy blood donor samples from Caucasian individuals (equally distributed by sex and age). 30 ANA positive samples with known reactivities. Data provenance not explicitly stated.
Method Comparison Study: 633 serum samples from patients with various diagnoses (Mixed Connective Tissue Disease, Poly-/Dermatomyositis, Systemic Sclerosis, SLE, Sjögren's Syndrome, Bacterial Infection, HIV Infection, HCV Infection, HBV Infection, Rheumatoid Arthritis, Cancer). Data provenance not explicitly stated (likely retrospective clinical samples from diverse sources).
Matrix Comparison Study: 62 patients, serum, lithium heparin plasma, and EDTA plasma collected from the same patients. Data provenance not explicitly stated.
Instrument Comparison Study: 110 samples (81 positive, 10 equivocal, 19 negative). Data provenance not explicitly stated.
Clinical Sensitivity and Specificity Study: 444 clinically defined samples with a diagnosis from patients with various autoimmune diseases and control conditions (Mixed Connective Tissue Disease, Poly-/Dermatomyositis, Systemic Sclerosis, SLE, SLE/Lupus nephritis, Sjögren's Syndrome, Bacterial Infection, Viral Infection, Rheumatoid Arthritis, Celiac Disease, Crohn's Disease, Ulcerative Colitis, Graves' Disease, Hashimoto's Disease, primary Antiphospholipid Syndrome, PBC, Autoimmune hepatitis, Granulomatosis with Polyangiitis). Data provenance not explicitly stated (likely retrospective clinical samples from diverse sources).
Expected Values/Reference Range Study: 558 apparently healthy subjects (Caucasian, African American, Hispanic and Asian population) obtained from a blood bank. This suggests diverse geographic and demographic provenance for the "normal" population.

Most of the studies likely used retrospective clinical samples, given the disease-specific grouping. No specific country of origin is mentioned for individual studies, but the applicant is Phadia AB from Sweden, and the 510(k) contact is in the USA, implying potential multi-site studies or data collection.

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

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

For the "clinically defined samples" in the clinical sensitivity/specificity study, the "diagnosis from patients" would be considered the ground truth, presumably established by treating physicians based on clinical findings and other laboratory tests, but not by a specific panel of experts for the purpose of this device's validation.
Reference sera (CDC and AMLI) have "target" values, which are established by their respective institutions (Centers for Disease Control and Prevention, and Association of Medical Laboratory Immunologists) and represent a consensus or assigned value, but not necessarily a specific "number of experts" for this study.

4. Adjudication Method for the Test Set

The document does not mention any explicit adjudication method (e.g., 2+1, 3+1) for establishing the ground truth for the test set. Clinical diagnoses are typically made by single treating physicians, and reference materials have predefined target values.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. This device is an in vitro diagnostic immunoassay, which does not involve human readers interpreting results in the same way an imaging AI might. Its performance is measured directly through analytical and clinical studies against predicate devices or known clinical statuses.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)

Yes, the device performance described is standalone (algorithm only). The EliA SymphonyS Immunoassay is an automated system that measures antibody levels and provides a qualitative result (negative, equivocal, positive) based on predefined cut-offs, without direct human-in-the-loop interpretation during the measurement process. The "aid in clinical diagnosis" part implies that clinicians interpret the results in conjunction with other findings, but the device itself operates in a standalone manner.

7. Type of Ground Truth Used

The types of ground truth used include:

Clinical Diagnoses: For the clinical sensitivity/specificity study, the "diagnosis from patients with" various diseases (e.g., SLE, MCTD, Sjögren's syndrome) served as the ground truth. This is based on established clinical criteria for each disease.
Reference Material Targets: For the evaluation of CDC and AMLI sera, the "Target" reactivity/results defined by these external institutions were used as ground truth.
Expected Behavior: For precision, interference, carry-over, and cut-off studies, the ground truth is often the expected behavior of the assay (e.g., negative sample should be negative, spiked sample should show no interference, etc.) or statistically derived values from healthy populations.
Predicate Device Results: For the method comparison study, the results from the legally marketed predicate device (EliA Symphony) served as a comparative ground truth to demonstrate substantial equivalence.

8. Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of machine learning. This is an immunoassay, which typically relies on established biochemical reactions, calibration curves, and empirically determined cut-offs rather than a machine learning model that requires a discrete training phase with labeled data. The calibration curve is established using calibrator strips (human IgG at known concentrations).

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

As noted above, there isn't a "training set" in the machine learning sense for this immunoassay.

The calibration curve is established using EliA IgG Calibrator Strips, which contain human IgG at known concentrations (0, 4, 10, 20, 100, 600 µg/L). The "ground truth" for these calibrators is their precisely defined IgG concentrations, which are traceable to the International Reference Preparation (IRP) 67/86 of Human Serum Immunoglobulins A, G and M from WHO.
The cut-off values (0.7 Ratio and 1.0 Ratio) were established by evaluating 70 apparently healthy blood donor samples and taking into account the 95th percentile, along with testing 30 ANA positive samples with known reactivities. This is a form of empirical ground truth setting based on biological distribution and known positive/negative samples.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health and Human Services logo on the left and the FDA logo on the right. The FDA logo features the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.

November 29, 2019

Phadia AB % Sheryl Skinner Associate Director RA/QA Phadia US Inc. 4169 Commercial Avenue Portage, Michigan 49002

Re: K190710

Trade/Device Name: EliA Symphony Immunoassay Regulation Number: 21 CFR 866.5100 Regulation Name: Antinuclear antibody immunological test system Regulatory Class: Class II Product Code: LLL Dated: March 19, 2019 Received: March 19, 2019

Dear Sheryl Skinner:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

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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 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Leonthena R. Carrington -S

Lea Carrington Director Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K190710

Device Name EliA(TM) SymphonyS Immunoassay

Indications for Use (Describe)

EliA SymphonyS is intended for the in vitro, qualitative measurement of antibodies in human serum and plasma (Li-heparin, EDTA). EliA SymphonyS is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmD3 peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderma and polymyositis, in conjunction with other laboratory and clinical findings. EliA SymphonyS uses the EliA IgG method on the instrument Phadia 2500/5000.

Type of Use (Select one or both, as applicable)

☑ Prescription Use (Part 21 CFR 801 Subpart D)	☐ Over-The-Counter Use (21 CFR 801 Subpart C)
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510k Decision Summary Input A.6

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

A. 510(k) Number: K190710

B. Purpose for Submission: New device

C. Measurand:

Antinuclear IgG antibodies: SmD, RNP (70, A, C), SS-A (60 kDa, 52 kDa), SS-B, Centromere B, Scl-70, Jo-1

D. Type of Test:

Qualitative immunofluorescence assays

E. Applicant:

Phadia AB, Sweden Rapsgatan 7P P.O. Box 6460 SE-751 37 Uppsala, Sweden Tel: +46-18-16 50 60

510(k) Contact Person: Sheryl Skinner Associate Director, RA/QA ImmunoDiagnostics US Thermo Fisher Scientific Phadia US Inc. 4169 Commercial Avenue Portage, Mi 49002, USA Tel. 269.568.3603 sheryl.skinner@thermofisher.com

Date of Summary Preparation: November 25, 2019

F. Proprietary and Established Names:

EliA™ SymphonyS Immunoassay

G. Regulatory Information:

1. Regulation section:

21 CFR §866.5100, Antinuclear Antibody Immunological Test System

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1. Classification: Class II
1. Product code: LLL Extractable Antinuclear Antibody, Antigen, Control
1. Panel:

Immunology

H. Intended Use:

Intended use(s):

EliA Symphony® is intended for the in vitro, qualitative measurement of antinuclear IgG antibodies in human serum and plasma (Li-heparin, EDTA). EliA Symphony® is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmDs peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderma and polymyositis/dermatomyositis, in conjunction with other laboratory and clinical findings. EliA Symphony® uses the EliA IgG method on the instrument Phadia 250.

EliA Symphony® is intended for the in vitro, qualitative measurement of antinuclear IgG antibodies in human serum and plasma (Li-heparin, EDTA). EliA SymphonyS is based on human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa), SSB/La, Centromere B, Scl-70, Jo-1 proteins and a synthetic SmDs peptide as antigen and is useful as an aid in the clinical diagnosis of patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, scleroderma and polymyositis/dermatomyositis, in conjunction with other laboratory and clinical findings. EliA Symphony® uses the EliA IgG method on the instrument Phadia 2500/5000.

Indication(s) for use: Same as intended use
Special conditions for use statement(s): For prescription use only

Special instrument requirements: 4. Phadia® 250 or Phadia® 2500/5000

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Device Description: -

The method specific reagents on Phadia® 250 and Phadia® 2500/5000 are identical; they are only filled in different containers. Each device consists of:

EliA Symphony® Wells are coated with human recombinant U1RNP (RNP70, A. -C). SS-A/Ro (60 kDa. 52 kDa). SS-B/La. Centromere B. Scl-70. Jo-1 proteins and synthetic SmD3 peptide - 4 carriers (16 wells each), ready to use;
EliA Sample Diluent: PBS containing BSA, detergent and 0.095% sodium azide --6 bottles, 48 mL each, ready to use; or 6 bottles, 400 mL each, ready to use;
EliA IgG Conjugate 50 or 200: ß-Galactosidase labeled anti-IgG (mouse monoclonal antibodies) in PBS containing BSA and 0.06% sodium azide -6 wedge shaped bottles, 5 mL each, ready to use; or 6 wedge shaped bottles, 19 mL each, ready to use
EliA ANA Positive Control 250 or 2500/5000: Human serum containing lgG antibodies to dsDNA, RNP, Sm, Ro. La. Scl-70. CENP and Jo-1 in PBS containing BSA, detergent and 0.095% sodium azide - 6 single use vials, 0.3 mL each, ready to use;
-EliA Negative Control 250 or 2500/5000: Human sera from healthy donors in PBS containing BSA, detergent and 0.095% sodium azide - 6 single-use vials, 0.3 mL each, ready to use;
EliA IgG Calibrator Strips: Human IgG (0, 4, 10, 20, 100, 600 µg/L) in PBS containing BSA, detergent and 0.095% sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
-EliA IgG Curve Control Strips: Human IgG (20 µg/L) in PBS containing BSA, detergent and 0.095% sodium azide - 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
EliA IgG Calibrator Well: Coated with mouse monoclonal antibodies 4 carriers (12 wells each), ready to use.

J. Substantial Equivalence Information:

Predicate device name(s) and 510(k) number(s): EliA Symphony Immunoassay, Phadia AB K072149

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2. Comparison with predicate device:

EliA Symphony® Immunoassay – Similarities to predicate device

Feature	Predicate Device	New Device
	EliA Symphony	EliA SymphonyS
Intended Use	EliA Symphony is intended for thein vitro, qualitative measurement ofantinuclear IgG antibodies in humanserum and plasma (heparin, EDTAand citrate). EliA Symphony isbased on human recombinantU1RNP (RNP 70, A, C), SS-A/Ro(60 kDa, 52 kDa), SSB/La,Centromere B, Scl-70, Jo-1 proteinsand native purified Sm proteins asantigen and is useful as an aid inthe clinical diagnosis of patientswith systemic lupus erythematosus(SLE), mixed connective tissuedisease (MCTD), Sjögren'ssyndrome, scleroderma andpolymyositis/ dermatomyositis, inconjunction with other laboratoryand clinical findings. EliA Symphonyuses the EliA IgG method on theinstruments Phadia 100 and Phadia250.	EliA SymphonyS is intended for thein vitro, qualitative measurement ofantinuclear IgG antibodies in humanserum and plasma (Li-heparin,EDTA). EliA SymphonyS is basedon human recombinant U1RNP(RNP 70, A, C), SS-A/Ro (60 kDa,52 kDa), SSB/La, Centromere B,Scl-70, Jo-1 proteins and asynthetic SmD3 peptide as antigenand is useful as an aid in the clinicaldiagnosis of patients with systemiclupus erythematosus (SLE), mixedconnective tissue disease (MCTD),Sjögren's syndrome, sclerodermaand polymyositis/dermatomyositis,in conjunction with other laboratoryand clinical findings. EliASymphonyS uses the EliA IgGmethod on the instruments Phadia250 and Phadia 2500/5000.
Internal Controls	Positive and negative Controlprovided with EliA ANA PositiveControl 100 and 250 and EliAIgG/IgM/IgA Negative Control 100and 250, resp.	Positive and negative Controlprovided with EliA ANA PositiveControl 250 / 2500/5000 and EliAIgG/IgM/IgA Negative Control 250 /2500/5000, resp.
Calibration	6-point total IgG Calibration6 vials of human IgG at concentrations of0 - 4 - 10 - 20 - 100 - 600 μg/L
Assay Type	ELISA
Type of test	qualitative
Reported Unit	Ratio
Antigen	human recombinant U1RNP (RNP 70, A, C), SS-A/Ro (60 kDa, 52 kDa),SS-B/La, Centromere B, Scl-70, Jo-1 proteins
Sample Dilution	1:100
Cut-off	Negative <0.7 RatioEquivocal 0.7 – 1.0 RatioPositive >1.0 Ratio
Feature	Predicate DeviceEliA Symphony	New DeviceEliA Symphonys
Instrumentation	EliA Symphony uses the EliA IgG method on the instruments Phadia 100 and 250.	EliA Symphonys uses the EliA IgG method on the instruments Phadia 250 and Phadia 2500/5000.
Sample type	Serum or plasma (heparin, EDTA, citrate)	Serum or plasma (Li-heparin, EDTA)No use of citrate plasma
Antigen	native purified Sm proteins	Synthetic SmD3 peptide

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EliA Symphony® – Differences to predicate device

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

CLSI EP07_ED3, Interference in Clinical Chemistry, April 2018

L. Test Principle:

The EliA wells are molded cups comparable to excised wells from a microtiter plate. They are made of polystyrene and are coated with the respective antigen. The wells are at the same time a holder of the coupled antigen for convenient automation and a reaction chamber with reaction/washing solution handling based on pipetting to add and aspiration to remove liquids.

The specific antigen for the antibodies to be detected is bound to the EliA solid phase component (EliA Well).

Test	Antigen coated to the wells
EliA Symphonys	human recombinant U1RNP (RNP70, A, C) proteinshuman recombinant SS-A/Ro (60 kDa, 52 kDa) proteinshuman recombinant SS-B/La proteinhuman recombinant Centromere B proteinhuman recombinant Scl-70 proteinhuman recombinant Jo-1 proteinsynthetic SmD3 peptide

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If present in the patient's specimen, antibodies to these proteins bind to their specific antigen. After washing away non-bound antibodies, enzyme-labeled antibodies against human IgG antibodies (EliA IgG Conjugate) are added to form an antibodyconjugate complex. After incubation, non-bound conjugate is washed away and the bound complex is incubated with a Development Solution. After stopping the reaction, the fluorescence in the reaction mixture is measured. The assay directly measures the amount of antibody of interest bound to the antigen coating the EliA well, therefore the higher the value of fluorescent signal detected by the instrument, the higher the amount of antibody bound and detected in the sample tested. To evaluate test results, the response for patient samples is compared directly to the response for calibrators.

M. Performance Characteristics (if/when applicable):

Analytical performance:

a. Precision/Reproducibility:

To determine the precision of the assay on the Phadia 250 and the Phadia 2500/5000 instrument, the variability was assessed on 5 samples. Three lots were used to determine the precision of the assay on Phadia 250 (totaling 252 replicate determinations per sample).

One lot was used to determine the precision of the assay on Phadia 2500/5000.

EliA Symphony® on Phadia 250:

To determine the precision of the assay on the Phadia 250 instrument, the variability was assessed in a study with 21 runs by examining the samples in 252 replicates on 3 instruments over 7 days. The data was calculated against the calibration curve from Day 1. The results of the statistical evaluation are given in the table below.

Sample	MeanRatio	Range ofRatios	ExpectedResult	RepeatabilityPositive/Equivocal/Negative	%Correct
1	0.48	0.38 - 0.59	Negative	0/0/84	100
2	0.76	0.63 - 0.96	Equivocal	0/205/47	81.3
3	1.0	0.91 - 1.13	Positive	152/100/0	60.3
4	4.4	3.8 - 5.1	Positive	252/0/0	100
5	23.2	20.8 - 26.2	Positive	252/0/0	100
6	42.9	34.4 - 54.0	Positive	250/0/0	100

Qualitative evaluation:

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EliA SymphonyS on Phadia 2500/5000:

To determine the precision of the assay on the Phadia 2500/5000 instrument, the variability was assessed in a study with 21 runs by examining the samples in 84 replicates on 3 instruments over 7 days. The data was calculated against the calibration curve from Day 1. The results of the statistical evaluation are given in the table below.

Qualitative evaluation:

Sample	MeanRatio	Range ofRatios	ExpectedResult	RepeatabilityPositive/Equivocal/Negative	%Correct
1	0.63	0.41 – 0.84	Negative	0/17/67	79.8
2	0.76	0.61 – 0.87	Equivocal	0/72/12	85.7
3	0.92	0.76 – 1.04	Equivocal	7/77/0	91.7
4	0.98	0.90 – 1.07	Equivocal	29/55/0	65.5
5	4.2	3.7 – 4.6	Positive	84/0/0	100
6	28.1	25.5 – 33.1	Positive	84/0/0	100
7	47.1	41.0 – 54.6	Positive	84/0/0	100

b. Linearity/assay reportable range:

Not applicable for a qualitative Screening assay

Hook Effect/Outside the Range Results:

n.a.

The reportable range as shown on the laboratory reports (instrument print-outs) is from 0.09 to 60 Ratio.

Results below 0.09 Ratio are reported as "below" and evaluated as "negative", results above 60 Ratio are reported as "above" and evaluated as "positive".

c. Traceability, Stability, Expected values (controls, calibrators, or methods): Traceability:
The IgG calibrators are traceable (via unbroken chain of calibrations) to the International Reference Preparation (IRP) 67/86 of Human Serum Immunoglobulins A, G and M from WHO. New batches of IgG calibrators are compared to a secondary standard (standardized with the IRP) or the IRP directly and adjusted accordingly to meet the correct concentration.

The instrument measures specific IgG concentrations in µg/L. By using a conversion factor given by the lot-specific code of the EliA™ test well, the results are automatically converted to Ratio.

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Stability:

Data for Open and closed real-time stability and Onboard stability of EliA lgG reagents and general EliA reagents on Phadia 250 and Phadia 2500/5000 instrument were already cleared with several other EliA tests, e.g. under K141375 (EliA M2 on PH250). For Phadia 2500/5000 instrument, they were already cleared under K061165/A003 (EliA CCP).

Shelf life:

The stability of EliA SymphonyS Wells was evaluated with both, a real-time and accelerated/stress study. The results support stability of the test under the recommended storage of 2 - 8°C for up to 18 months.

Onboard stability:

The onboard stability EliA Symphony® carriers (containing the antigen coated wells) was tested over 4 weeks using 3 positive and 2 negative samples only on the Phadia 250 instrument. As the storage conditions in the Phadia 2500/5000 instrument are similar, the results can also be used for stability claims for the Phadia 2500/5000. The onboard stability for the Phadia 250 instrument was determined to be 28 days at 2-8°C.

Open Stability:

Stability after first opening of the foilbag containing the EliA SymphonyS wells was tested and determined to be 9 months at 2-8°C.

d. Detection limit:
N/A for a qualitative test

e. Analytical specificity:

Endogenous Interference: A study was run to investigate whether high concentrations of potentially interfering substances in serum, like bilirubin, hemoqlobin, lipemic factor and rheumatoid factor adversely affect the results of the new device. Three serum samples were prediluted in EliA Sample Diluent and spiked with the different interfering substances or their respective blank solutions, and analyzed in triplicates. A calibration curve was run in duplicate. The runs were repeated twice. One batch of EliA antigen wells and one batch of system reagents were used throughout the studies.

One neqative sample, one sample with a concentration around the cut-off and one high positive sample were tested. The ratio of blank/spiked sample ranged from 0.88 - 1.16 for EliA SymphonyS. No interference was observed up to the concentrations listed in the table below:

Potential InterferingCompound	Concentration inundiluted sample
Bilirubin F	19.2 mg/dL

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Trad. 510(k) submission for EliA SymphonyS K190710.510kSummary.FINAL.doc A.6-9

Bilirubin C	20.1 mg/dL
Hemoglobin	496 mg/dL
Lipemic factor	1%
Rheumatoid factor	500 IU/ml

Exogenous Interference: In addition, interference by five selected exogenous substances was evaluated according to CLSI Guideline EP07-3rd Edition. The same study protocol as described above was used to analyze interference of a non-steroid anti-inflammatory drug (Ibuprofen), an oral steroid (Prednisone), an anti-malarial drug (Hydroxychloroquine), a diseasemodifying anti-rheumatic drug (Azathioprine), an anti-hypertensive agent (Losartan) and a rheumatologic biologic (Infliximab) in serum samples. The concentration of the substances are based on CLSI Guideline EP37 1st Edition.

One negative sample, one sample with a concentration around the cut-off and one high positive sample were tested. The ratio of blank/spiked sample ranged from 0.83 – 1.13 for EliA Symphony®. No interference was observed up to the concentrations listed in the table below:

Substance	Concentration inundiluted serum sample
Ibuprofen	2,19E+01 mg/dL21.9 mg/dL
Prednisone	9,90E-03 mg/dL0.0099 mg/dL
Hydroxychloroquine	2,25E-01 mg/dL0.225 mg/dL
Azathioprine	2,58E-01 mg/dL0.258 mg/dL
Losartan	1,14E+00 mg/dL1.14 mg/dL
Infliximab	2.64E+01 mg/dL26.4 mg/dL

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Reference sera: Externally defined sera should be measured according to their target values as mentioned by the institution CDC and AMLI. Evaluation of CDC sera on EliA SymphonyS:

Sample	Reactivity/IIF	Target	EliASymphonys[Ratio]
CDC ANA #1	Homogeneous, RimPattern (dsDNA)	Negative	0.6
CDC ANA #2	Speckled Pattern(SS-B/La)	Positive	18.9
CDC ANA #3	Speckled	Positive	92.6
CDC ANA #4	U1-RNP	Positive	21.7
CDC ANA #5	Sm	Positive	25.9
CDC ANA #6	nucleolar	Negative	0.3
CDC ANA #7	SS-A/Ro	Positive	23.5
CDC ANA #8	CENP	Positive	10.6
CDC ANA #9	Scl-70	Positive	18.9
CDC ANA #10	Jo-1	Positive	14.7
CDC ANA #11	PM-Scl	Negative	0.2
CDC ANA #12	Rib-P	Negative	0.1

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Sample	Reactivity/IIF	Target	EliAS[Ratio]
AMLI 1	Negative	Negative	0.5
AMLI 2	Sm / RNP	Positive	3.4
AMLI 3	RNP / Sm	Positive	0.1
AMLI 4	SS-A/Ro	Positive	1.4
AMLI 5	SS-B/La	Positive	8.8
AMLI 6	Scl-70	Positive	0.1
AMLI 7	Jo-1	Positive	1.7
AMLI 8	CENP / Sm / Scl-70 / Jo-1	Positive	3.3
AMLI 9	dsDNA / SS-A/Ro / SS-B/La	Positive	49.4
AMLI 10	Negative	Negative	0.2

Evaluation of AMLI sera on EliA SymphonyS:

The targets were met for AMLI Consensus Reference Panel, except for two serum samples (AMLI 3 and 6). Both samples showed negative results, while the target is positive. The defined targets could not be met by any single semi-quantitative EliA test nor by competitor screening assays. Therefore, the targets defined by AMLI could not be confirmed.

Carry-over: A study was carried out on a Phadia 250 instrument using the test EliA Ro. cleared under K082759. A serum sample was diluted 1:2 and 1:20 using instrument dilution and manual dilution. A lower dilution factor than the default one (1:100) was chosen to challenge the system. Only a few RUs difference compared to the reference pipetting could be seen, which is too low to be expressed in U/mL. The observed carry over effect is therefore negligible without any influence to assay results.

Phadia 2500/5000 instruments use disposable tips for pipetting samples and a separate pipette for the conjugate, therefore carry-over from samples to conjugate is impossible.

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f. Assay cut-off:
A study was performed on 70 apparently healthy blood donor samples from Caucasian individuals equally distributed by sex and age in order to evaluate expected values for EliA Symphony® in the normal population and to confirm the defined cut-off. The samples were measured on the Phadia 250 instrument. The 95th percentile was taken into account for setting the cut-off. Additionally, 30 ANA positive samples with known reactivities against all antigens contained in EliA Symphony® were tested and should be found positive with the proposed test evaluation.

The following values were selected for the cut-off:

EliA SymphonyS
<0.7 Ratio	Negative
0.7 - 1.0 Ratio	Equivocal
>1.0 Ratio	Positive

In case of equivocal results, it is recommended to retest the patient after 8-12 weeks.

In the case of a positive result, it is suggested that further confirmatory testing on individual antigen(s) be performed.

1. Comparison studies:
Method comparison with predicate device: a.

A total of 633 serum samples were collected with a diagnosis from patients with Mixed Connective Tissue Disease (n = 46), Poly-/ Dermatomyositis (n = 78), Systemic Sclerosis (n = 87), SLE (n = 97), Sjögren's Syndrome (n = 96), Bacterial Infection (n = 20), HIV Infection (n = 27), HCV Infection (n = 36), HBV Infection (n = 36), Rheumatoid Arthritis (n = 85), Cancer (n = 25).

Samples were analyzed with the EliA Symphony® and EliA Symphony assays. The results are summarized in the tables below:

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N = 633	EliA Symphony	EliA Symphony	Total
	positive:> 1.0 Ratio	negative:\u2264 1.0 Ratio
EliA Symphonyspositive:> 1.0 Ratio	279	6	285
EliA Symphonysnegative:\u2264 1.0 Ratio	7	341	348
Total	286	347	633

EliA Symphony® - equivocal results considered negative

	Calculation	Agreement (%)	95% Cl
Positive PercentAgreement	100% x 279/286	97.6	95.0 - 99.0
Negative PercentAgreement	100% x 341/347	98.3	96.3 - 99.4
TotalAgreement	100% x (279+341)/633	97.9	96.5 - 98.9

EliA Symphony® - equivocal results considered positive

N = 633	EliA Symphony	EliA Symphony	Total
	positive:> 0.7 Ratio	negative:≤ 0.7 Ratio
EliA SymphonySpositive:> 0.7 Ratio	287	6	293
EliA SymphonySnegative:≤ 0.7 Ratio	24	316	340
Total	311	322	633

	Calculation	Agreement (%)	95% CI
Positive PercentAgreement	$100% x 287/311$	92.3	88.7 - 95.0
Negative PercentAgreement	$100% x 316/322$	98.1	96.0 - 99.3
TotalAgreement	$100% x (287+316)/633$	95.3	93.3 - 96.8

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b. Matrix comparison:

Serum, lithium heparin plasma and EDTA plasma were collected from the same patients (n = 62) to demonstrate that the plasma results do not deviate from the corresponding serum results and are within the pre-defined specifications. Samples were spiked with a serum sample of high antibody titer to generate a range of reactivity. Samples were tested in duplicates. Passing & Bablok regression plots were generated using the first replicate only and by plotting the concentration observed from the control tube (serum) versus the concentration for each test collection tube. The corresponding slopes of regression and coefficient determination are summarized in the tables below:

	Rangetested[Ratio]	Slope(95% CI)	Intercept(95% CI)	R2
Serum vs. Li-heparin plasma	0.09 – 72.0	1.03(0.98 to 1.05)	-0.02(-0.03 to -0.00)	0.994
Serum vsEDTA plasma	0.09 – 68.5	0.98(0.96 to 1.00)	-0.03(-0.04 to -0.01)	0.997

c. Instrument comparison

Performance of EliA SymphonyS was evaluated on the Phadia 250 and Phadia 2500/5000 instruments using 81 positive, 10 equivocal and 19 negative samples. The samples were analyzed in single replicates on one Phadia 250 and one Phadia 2500/5000 instrument giving a total of two measurements per sample. The regression analysis results are summarized as follows:

	Intercept	Slope	R
Estimate	0.06	1.01	0.992
95% CI	0.01 - 0.12	0.99 - 1.03

Clinical studies: ဒ.
Clinical sensitivity and specificity: a.

444 clinically defined samples with a diagnosis from patients with Mixed Connective Tissue Disease (n = 22), Poly-/ Dermatomyositis (n = 10), Systemic Sclerosis (n = 32), SLE (n = 83), SLE/Lupus nephritis (n=19), Sjögren's Syndrome (n = 28), Bacterial Infection (n = 30), Viral Infection (n = 30), Rheumatoid Arthritis (n = 40), Celiac Disease (n=28), Crohn's Disease (n=22), Ulcerative Colitis (n=22), Graves' Disease (n=28), Hashimoto's Disease (n=10), primary Antiphospholipid Syndrome (n=28), PBC (n=5), Autoimmune hepatitis (n=6), Granulomatosis with Polyangiitis (n=1), were used to determine sensitivity and specificity of the assay. The results are summarized in the tables below.

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n=444	DiagnosticGroup	DiseaseControls	Total
Positive test> 1.0 Ratio	102	13	115
Negative test<= 1.0	92	237	329
Total	194	250	444

		EliA Symphony® – equivocal results evaluated as negative:

Sensitivity (95% CI): 52.6% (45.3% - 59.8%) Specificity (95% CI): 94.8% (91.3% - 97.2%)

EliA Symphony® – equivocal results evaluated as negative:

	DiagnosticGroup	DiseaseControls	Total
n=444
Positive test> 0.7 Ratio	107	14	121
Negative test≤ 0.7	87	236	323
Total	194	250	444

Sensitivity (95% CI): 55.2% (47.9% - 62.3%) Specificity (95% CI): 94.4% (90.8% - 96.9%)

The table below shows the results for each clinical subgroup where the equivocal results evaluated as negative

Diagnostic groups	n	No (%)PositiveEliASymphonyS	No (%)PositiveEliASymphony
Systemic lupus erythematosus (SLE)	83	37 (44.6%)	39 (47.0%)
SLE (Lupus Nephritis)	19	13 (68.4%)	13 (68.4%)
Mixed connective tissue disease (MCTD)	22	16 (72.7%)	14 (63.6%)
Systemic sclerosis (SSC)	32	16 (50.0%)	16 (50.0%)
Sjögren's syndrome (SS)	28	17 (60.7%)	17 (60.7%)
Poly-/Dermatomyositis (PM/DM)	10	3 (30.0%)	3 (30.0%)
Rheumatoid arthritis (RA)	40	0 (0%)	0 (0%)
Celiac disease	28	0 (0%)	0 (0%)
Crohn's disease	22	0 (0%)	0 (0%)
Ulcerative colitis	22	1 (4.5%)	0 (0%)
Graves' disease	28	1 (3.6%)	1 (3.6%)
Hashimoto's disease	10	1 (10.0%)	1 (10.0%)
Primary antiphospholipid syndrome (pAPS)	28	4 (14.3%)	4 (14.3%)
Primary Biliary Cirrhosis (PBC)	5	0 (0%)	0 (0%)
Autoimmune hepatitis (AIH)	6	3 (50.0%)	3 (50.0%)
Granulomatosis with Polyangiitis (GPA,formerly called Wegener's Granulomatosis)	1	0 (0%)	0 (0%)
Bacterial Infections	30	2 (6.7%)	2 (6.7%)

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Viral infections (EBV, HBV, HCV, etc.)	30	1 (3.3%)	1 (3.3%)

b. Other clinical supportive data: Not applicable

Clinical cut-off: 4.

Same as assay cut-off

5. Expected values/Reference range:

Antibody prevalence in autoimmune patients varies widely depending on disease area. The proportion of sera from a normal population found positive for the antinuclear antibodies covered by the EliA Symphony® test is below 1%. Expected values may vary depending on the population tested.

The frequency distribution for antinuclear antibodies was investigated in a group of apparently healthy subjects equally distributed by age and gender, using sera from Caucasian, African American, Hispanic and Asian population obtained from a blood bank.

The results are given in the table below:

Test	n =	RangeMin-Max(Ratio)	No. ofpos./equivocalresults	Median(Ratio)	Mean(Ratio)	95thpercentile	99thpercentile
EliA Symphonys	558	0.0 – 25.9	7 / 5	0.1	0.3	0.3	1.1

N. Proposed Labeling:

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

O. Conclusion:

All available data support that both immunoassays, the new device EliA Symphonys and its predicate device EliA Symphony perform substantially equivalent.

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

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).