(38 days)
EliA ß2-Glycoprotein I IgA is intended for the in vitro semi-quantitative measurement of IgA antibodies directed to ß2-Glycoprotein I in human serum and plasma (Li-heparin, EDTA) to aid in the diagnosis of antiphospholipid syndrome (APS) as well as thrombotic disorders related to systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA B2-Glycoprotein I IgA uses the EliA IgA method on the instrument Phadia 2500/5000.
EliA Cardiolipin IgA is intended for the in vitro sem-quantitative measurement of IgA antibodies directed to cardiolipin in human serum and plasma (Li-heparin, EDTA) to aid in the diagnosis of antiphospholipid syndrome (APS) as well as thrombotic disorders related to systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA Cardiolipin IgA uses the EliA IgA method on the instrument Phadia 2500/5000.
The method-specific reagents are identical with K112414 (EliA B2-Glycoprotein I IqA) and K131821 (EliA Cardiolipin IqA), but are filled in containers specific for the Phadia 2500/5000 instrument. Each device consists of:
-Test Wells: EliA ß2-Glycoprotein I IqA Wells are coated with human ß2-Glycoprotein I antigen - 2 carriers (12 wells each), ready to use;
- EliA Cardiolipin IgA Wells are coated with bovine cardiolipin antigen and boyine ß2-glycoprotein I as co-factor - 2 carriers (12 wells each), ready to use;
- -EliA Sample Diluent: PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 6 bottles, 48 mL each, ready to use; or 6 bottles, 400 mL each, ready to use;
- -EliA IqA Conjuqate 50 or 200: ß-Galactosidase labeled anti-IgA (mouse monoclonal antibodies) in PBS containing BSA and 0.06% (w/v) sodium azide -6 wedge shaped bottles, 5 mL each, ready to use; or 6 wedge shaped bottles, 19 mL each, ready to use
- EliA IgA Calibrator Strips: Human IgA (0, 0.3, 1.5, 5, 15, 80 µg/L) in PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 5 strips, 6 singleuse vials per strip, 0.3 mL each, ready to use;
- -EliA IgA Curve Control Strips: Human IgA (20 µg/L) in PBS containing BSA, detergent and 0.095% (w/v) sodium azide – 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
- -EliA IgA 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. All packages are required to carry out EliA ß2-Glycoprotein I IgA and EliA Cardiolipin IgA tests.
Here's a breakdown of the acceptance criteria and study particulars for the EliA Beta2-Glycoprotein I IgA and EliA Cardiolipin IgA Immunoassays on the Phadia 2500/5000 instrument, based on the provided FDA 510(k) summary (K181329):
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria provided in the document are primarily for method comparison (regression analysis against the predicate device/instrument) and for the performance metrics of Positive Percent Agreement (PPA), Negative Percent Agreement (NPA), and Total Percent Agreement (TPA) when comparing the new instrument platforms (Phadia 2500/5000) to the predicate Phadia 250.
EliA ß2-Glycoprotein I IgA on Phadia 2500/5000
| Performance Metric | Acceptance Criteria (Implicit from approval) | Reported Device Performance (Worst Case Across 3 Instruments) |
|---|---|---|
| Method Comparison (vs. Phadia 250) | ||
| Slope | 0.9 - 1.1 | 0.98 - 1.02 |
| Intercept | Close to 0 | 0.22 - 0.85 |
| PPA (Equivocal considered Positive) | (Not explicitly stated, but high agreement expected) | 97.3% (90.6% – 99.7% CI) |
| NPA (Equivocal considered Positive) | (Not explicitly stated, but high agreement expected) | 80.0% (59.3% – 93.2% CI) |
| TPA (Equivocal considered Positive) | (Not explicitly stated, but high agreement expected) | 94.0% (87.4% – 97.8% CI) |
| PPA (Equivocal considered Negative) | (Not explicitly stated, but high agreement expected) | 100.0% (94.2% – 100% CI) |
| NPA (Equivocal considered Negative) | (Not explicitly stated, but high agreement expected) | 94.6% (81.8% – 99.3% CI) |
| TPA (Equivocal considered Negative) | (Not explicitly stated, but high agreement expected) | 98.0% (93.0% – 99.8% CI) |
| Precision | (Target uncertainty goal for LoQ: 20%; Implicitly, low %CV across runs/instruments) | Total CVs: Up to 26.2% for low conc., 6.6-9.7% for higher conc. |
| Linearity (R²) | Close to 1.00 (e.g., 0.99-1.00) | 1.00 |
| Limit of Detection (LoD) | (Implicitly, as low as possible for clinical utility) | 0.3 EliA U/mL |
| Limit of Quantitation (LoQ) | (Target uncertainty goal of 20%) | 1.1 EliA U/mL |
EliA Cardiolipin IgA on Phadia 2500/5000
| Performance Metric | Acceptance Criteria (Implicit from approval) | Reported Device Performance (Worst Case Across 3 Instruments) |
|---|---|---|
| Method Comparison (vs. Phadia 250) | ||
| Slope | 0.9 - 1.1 | 0.98 - 1.06 |
| Intercept | Close to 0 | -0.40 - 0.30 |
| PPA (Equivocal considered Positive) | (Not explicitly stated, but high agreement expected) | 100.0% (93.8% – 100% CI) |
| NPA (Equivocal considered Positive) | (Not explicitly stated, but high agreement expected) | 88.4% (74.9% – 96.1% CI) |
| TPA (Equivocal considered Positive) | (Not explicitly stated, but high agreement expected) | 95.0% (88.8% – 98.4% CI) |
| PPA (Equivocal considered Negative) | (Not explicitly stated, but high agreement expected) | 93.3% (81.7% – 98.6% CI) |
| NPA (Equivocal considered Negative) | (Not explicitly stated, but high agreement expected) | 94.6% (85.1% – 98.9% CI) |
| TPA (Equivocal considered Negative) | (Not explicitly stated, but high agreement expected) | 94.1% (87.5% – 97.8% CI) |
| Precision | (Target uncertainty goal for LoQ: 20%; Implicitly, low %CV across runs/instruments) | Total CVs: Up to 18.5% for low conc., 6.2-11.9% for higher conc. |
| Linearity (R²) | Close to 1.00 (e.g., 0.99-1.00) | 1.00 |
| Limit of Detection (LoD) | (Implicitly, as low as possible for clinical utility) | 0.3 APL-U/mL |
| Limit of Quantitation (LoQ) | (Target uncertainty goal of 20%) | 1.0 APL-U/mL |
Note: The document primarily outlines how the studies were performed and what the results were, rather than explicit pre-defined quantitative acceptance criteria for all metrics. For method comparison, it states: "The acceptance criteria for the method comparison (the slope for the regression lines should be 0.9 - 1.1 for single replicate to single replicate and intercept close to 0) were met." For LoQ, it mentions "a target uncertainty goal of 20%." For PPA/NPA/TPA, the high reported values and FDA clearance imply acceptance.
2. Sample Size and Data Provenance for Test Set
-
Method Comparison (Instrument Comparison):
- Sample Size: More than 100 serum samples (for each immunoassay).
- Data Provenance: Not explicitly stated, but serum samples were used. It is implied to be from patient populations relevant to the intended use. The samples included "≥20% of the samples within ±25% of the medical decision point," suggesting a distribution covering diagnostically relevant ranges.
- Retrospective/Prospective: Not specified, but typically such comparison studies use retrospectively collected samples for method validation.
-
Precision/Reproducibility:
- Sample Size: 5 serum samples. Each sample tested in 21 runs (3 instruments x 7 runs) with 4 replicates per run, totaling 84 replicates per serum sample.
- Data Provenance: Serum samples. Country of origin not specified.
- Retrospective/Prospective: Retrospective, as these are pre-collected serum samples.
-
Linearity/Assay Reportable Range:
- Sample Size: 4 patient serum samples.
- Data Provenance: Patient serum samples. Country of origin not specified.
- Retrospective/Prospective: Retrospective.
-
Detection Limit (LoB, LoD, LoQ):
- Sample Size:
- LoB: One blank sample measured in 33 replicates in each of two runs.
- LoD & LoQ: Three low-level serum samples measured in 11 replicates in each of two runs.
- Data Provenance: Blank samples and low-level serum samples. Country of origin not specified.
- Retrospective/Prospective: Retrospective.
- Sample Size:
3. Number of Experts and Qualifications for Ground Truth for the Test Set
- This device is an in-vitro diagnostic (IVD) immunoassay, not an AI or imaging device requiring human expert adjudication for ground truth. The "ground truth" for these studies refers to the reference method's result (e.g., predicate device Phadia 250 for method comparison) or the known characteristics of the samples (e.g., spiking for linearity, known concentration for precision controls).
- Therefore, the concept of "number of experts" or their "qualifications" for establishing ground truth in the context of an IVD assay's analytical performance studies is not applicable here.
4. Adjudication Method for the Test Set
- Not applicable as this is an IVD immunoassay, not an AI or imaging device requiring human subjective interpretation and adjudication. The "adjudication" is based on instrumental readings and comparison to defined calibrators and predicate device results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done. This is an IVD immunoassay, not a device that involves human "readers" interpreting cases in the context of medical imaging or clinical decision-making with or without AI assistance.
- The study involved comparing instrumental results of the new Phadia 2500/5000 platform to the predicate Phadia 250 platform.
6. Standalone Performance Study
- Yes, standalone performance studies were done. The precision, linearity, and detection limit studies are examples of standalone performance evaluations of the EliA immunoassays on the Phadia 2500/5000 instrument.
- The primary scope of this 510(k) submission was to introduce these previously cleared assays onto a new instrument platform (Phadia 2500/5000), meaning the "algorithm" (assay chemistry and measurement principle) itself was already established as effective and safe. The studies here demonstrate that this established assay performs equivalently on the new instrument.
7. Type of Ground Truth Used
- Method Comparison: The predicate device's results (EliA ß2-Glycoprotein I IgA on Phadia 250 instrument, K112414; EliA Cardiolipin IgA on Phadia 250 instrument, K131821) served as the "ground truth" or reference for assessing equivalence of the new instrument platform.
- Precision and Linearity: The values obtained from the predicate device or a well-characterized reference are used to establish control ranges and expected values. For linearity, known dilutions are used against expected concentrations.
- Detection Limit: Controlled blank samples and low-level spiked/characterized samples are used.
- Clinical Studies (reference): For clinical utility and cut-off determination mentioned as reviewed in K112414 and K131821, the ground truth would have been clinical diagnosis (e.g., confirmed APS or SLE) and outcomes data. This summary itself does not include new clinical ground truth studies for K181329.
8. Sample Size for the Training Set
- This type of submission (510(k) for a new instrument platform for existing assays) generally does not involve a "training set" in the context of machine learning or AI.
- For IVD assays, optimization and method development would involve numerous samples, but these are part of product development rather than a formal "training set" that would be distinct from a "test set" in the way AI/ML studies define them. The stability and calibration curves are established using a series of known calibrators and controls.
9. How the Ground Truth for the Training Set Was Established
- Not applicable in the AI/ML sense. For standard IVD assay development, ground truth for calibrators and controls is established through rigorous characterization, often against international reference materials or highly purified substances, and validated using established analytical methods and statistical approaches. The clinical cut-offs were derived from "clinical studies (s. K112414 and K131821)", meaning the previous submissions involved clinical data and patient diagnoses to define the clinically relevant ranges.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA acronym followed by the full name of the agency, "U.S. Food & Drug Administration," on the right. The FDA part of the logo is in blue, with the acronym in a solid blue square and the agency's name in a lighter shade of blue.
June 25, 2018
Phadia AB Martin Mann Senior Regulatory Affairs Manager Phadia US Inc. 4169 Commercial Avenue Portage, Michigan 49002
Re: K181329
Trade/Device Name: EliA B2-Glycoprotein I IgA Immunoassay, EliA Cardiolipin IgA Immunoassay Regulation Number: 21 CFR 866.5660 Regulation Name: Multiple autoantibodies immunological test system Regulatory Class: Class II Product Code: MSV, MID Dated: May 14, 2018 Received: May 18, 2018
Dear Martin Mann:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. Iisting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. 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 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); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR
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Part 820); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerelv.
Kelly Oliner -S
For Lea Carrington Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known)
Device Name
EliA(TM) ß2-Glycoprotein I IgA Immunoassay, EliA(TM) Cardiolipin IgA Immunoassay
Indications for Use (Describe)
EliA ß2-Glycoprotein I IgA is intended for the in vitro semi-quantitative measurement of IgA antibodies directed to ß2-Glycoprotein I in human serum and plasma (Li-heparin, EDTA) to aid in the diagnosis of antiphospholipid syndrome (APS) as well as thrombotic disorders related to systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA B2-Glycoprotein I IgA uses the EliA IgA method on the instrument Phadia 2500/5000.
EliA Cardiolipin IgA is intended for the in vitro sem-quantitative measurement of IgA antibodies directed to cardiolipin in human serum and plasma (Li-heparin, EDTA) to aid in the diagnosis of antiphospholipid syndrome (APS) as well as thrombotic disorders related to systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA Cardiolipin IgA uses the EliA IgA 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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A.1 510(k) Summary of Safety and Effectiveness per 21CFR 807.92(c).
This summary of safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR Part 807.92.
510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT COMBINATION TEMPLATE
A. 510(k) Number: K181329
B. Purpose for Submission:
Adding previously cleared assays on a new instrument platform (Phadia® 2500/5000)
C. Measurands:
Anti-ß2-qlycoprotein | IgA autoantibodies Anti-cardiolipin IgA autoantibodies
D. Type of Test:
Semi-quantitative measurement immunoassays
E. Applicant:
Phadia AB Rapsgatan 7P P.O. Box 6460 SE-751 37 Uppsala, Sweden Tel: +46-18-16 50 60
510(k) Contact Person: Martin Mann Requlatory Affairs Manager Phadia US Inc. 4169 Commercial Avenue Portage, Mi 49002, USA +1 (-269-492) -1957 (Phone) +1 (-269-492) -7541 (Fax) martin.mann@thermofisher.com
Date of Summary Preparation: Mav 15, 2018
F. Proprietary and Established Names: EliA™ ß2-Glycoprotein I IgA Immunoassay EliA™ Cardiolipin IgA Immunoassay
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G. Regulatory Information:
-
- Requlation section: 21 CFR §866.5660 Multiple autoantibodies immunological test system
-
- Classification: Class II
-
- Product code:
MSV System, Test, Antibodies, ß2-Glycoprotein I (ß2-GPI) MID System, Test, Anti-Cardiolipin Immunological
-
- Panel: Immunology (82)
H. Intended use(s):
- Intended use(s):
EliA ß2-Glycoprotein I IgA is intended for the in vitro semi-quantitative measurement of IgA antibodies directed to ß2-Glycoprotein I in human serum and plasma (Li-heparin, EDTA) to aid in the diagnosis of antiphospholipid syndrome (APS) as well as thrombotic disorders related to systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA ß2-Glycoprotein I IgA uses the EliA IgA method on the instrument Phadia 2500/5000.
EliA Cardiolipin IgA is intended for the in vitro semi-quantitative measurement of IgA antibodies directed to cardiolipin in human serum and plasma (Li-heparin, EDTA) to aid in the diagnosis of antiphospholipid syndrome (APS) as well as thrombotic disorders related to systemic lupus erythematosus (SLE) in conjunction with other laboratory and clinical findings. EliA Cardiolipin IgA uses the EliA IgA 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: ব
Performance studies were obtained from the Phadia® 2500/5000 instrument This device is not for point-of-care use.
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. Device Description:
The method-specific reagents are identical with K112414 (EliA B2-Glycoprotein I IqA) and K131821 (EliA Cardiolipin IqA), but are filled in containers specific for the Phadia 2500/5000 instrument. Each device consists of:
- -Test Wells: EliA ß2-Glycoprotein I IqA Wells are coated with human ß2-Glycoprotein I antigen - 2 carriers (12 wells each), ready to use;
- EliA Cardiolipin IgA Wells are coated with bovine cardiolipin antigen and boyine ß2-glycoprotein I as co-factor - 2 carriers (12 wells each), ready to use;
- -EliA Sample Diluent: PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 6 bottles, 48 mL each, ready to use; or 6 bottles, 400 mL each, ready to use;
- -EliA IqA Conjuqate 50 or 200: ß-Galactosidase labeled anti-IgA (mouse monoclonal antibodies) in PBS containing BSA and 0.06% (w/v) sodium azide -6 wedge shaped bottles, 5 mL each, ready to use; or 6 wedge shaped bottles, 19 mL each, ready to use
- EliA IgA Calibrator Strips: Human IgA (0, 0.3, 1.5, 5, 15, 80 µg/L) in PBS containing BSA, detergent and 0.095% (w/v) sodium azide - 5 strips, 6 singleuse vials per strip, 0.3 mL each, ready to use;
- -EliA IgA Curve Control Strips: Human IgA (20 µg/L) in PBS containing BSA, detergent and 0.095% (w/v) sodium azide – 5 strips, 6 single-use vials per strip, 0.3 mL each, ready to use;
- -EliA IgA 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. All packages are required to carry out EliA ß2-Glycoprotein I IgA and EliA Cardiolipin IgA tests.
J. Substantial Equivalence Information:
- Predicate device name(s) and 510(k) number(s): EliA ß2-Glycoprotein I IgA on Phadia 250 instrument, K112414 EliA Cardiolipin IgA on Phadia 250 instrument, K131821
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2. Comparison with predicate device:
EliA APS IgA Immunoassays on Phadia 250 and Phadia 2500/5000 instruments – Similarities to predicate devices
| Feature | Predicate DevicePhadia 250 | New DevicePhadia 2500/5000 |
|---|---|---|
| Intended UseEliA Cardiolipin IgA | EliA Cardiolipin IgA is intendedfor the in vitro semi-quantitativemeasurement of IgA antibodiesdirected to cardiolipin in humanserum and plasma (heparin,EDTA, citrate) to aid in thediagnosis of antiphospholipidsyndrome (APS) as well asthrombotic disorders related tosystemic lupus erythematosus(SLE) in conjunction with otherlaboratory and clinical findings.EliA Cardiolipin IgA uses the EliAIgA method on the instrumentPhadia 250. | EliA Cardiolipin IgA is intendedfor the in vitro semi-quantitativemeasurement of IgA antibodiesdirected to cardiolipin in humanserum and plasma (Li-heparin,EDTA) to aid in the diagnosis ofantiphospholipid syndrome(APS) as well as thromboticdisorders related to systemiclupus erythematosus (SLE) inconjunction with other laboratoryand clinical findings. EliACardiolipin IgA uses the EliA IgAmethod on the instrumentPhadia 2500/5000. |
| Intended UseEliA β2-GlycoproteinI IgA | EliA β2-Glycoprotein I IgA isintended for the in vitro semi-quantitative measurement of IgAantibodies directed to β2-Glycoprotein I in human serumand plasma (heparin, EDTA,citrate) to aid in the diagnosis ofantiphospholipid syndrome(APS) as well as thromboticdisorders related to systemiclupus erythematosus (SLE) inconjunction with other laboratoryand clinical findings. EliA β2-Glycoprotein I IgA uses the EliAIgA method on the instrumentPhadia 250. | EliA β2-Glycoprotein I IgA isintended for the in vitro semi-quantitative measurement of IgAantibodies directed to β2-Glycoprotein I in human serumand plasma (Li-heparin, EDTA)to aid in the diagnosis ofantiphospholipid syndrome(APS) as well as thromboticdisorders related to systemiclupus erythematosus (SLE) inconjunction with other laboratoryand clinical findings. EliA β2-Glycoprotein I IgA uses the EliAIgA method on the instrumentPhadia 2500/5000. |
| Analyticaltechnology:Immuno-fluorescencemeasurement | Same | Same |
| Assay process | Same | Same |
| Common, dedicatedPhadia reagents | Same | Introduction of new articlenumbers for Development |
| Solution, Stop Solution andWashing Solution is only due tolarger filling volumes which arerequired for the biggerinstruments Phadia 2500/5000 | ||
| Result calculationsoftware; PhadiaInformation DataManager (IDM) | Same | Same |
| Sample volume | 90 µL (20 µL of non-dilutedsample) | 90 µL (20 µL of non-dilutedsample) |
| Incubationtemperature | 37°C | 37°C |
| Conjugate volume | 90 µL | 90 µL |
| DevelopmentSolution Volume | 90 µL | 90 µL |
| Stop SolutionVolume | 200 µL | 200 µL |
| Assay set-up | Random access | Random access |
| Reagent packagingsize | Various/Common | Various/CommonIntroduction of new articlenumber for EliA Sample Diluent(83-1071-01) is only due tolarger filling volume. |
| Onboard storage ofreagents | Yes | Yes |
| Time to 1st result | ~2 h | ~2 h |
| Feature | Predicate DevicePhadia 250 | New DevicePhadia 2500/5000 |
| Sample matrix;Serum or plasmatype as indicated inthe DFU dependenton assay | Serum or plasma (heparin,EDTA, citrate) | Serum or plasma (Li-heparin,EDTA) |
| Daily throughput | ~250 tests | ~2500/5000 tests |
| Sample Dilution | Phadia 250 uses a steel pipetteto dilute the samples in DilutionPlates (Art.No. 12-3907-08) | Phadia 2500/5000 usesdisposable Pipette Tips in Racks(Art No. 12-3805-04) forpipetting samples in DilutionWell (Art.No. 12-4005-69) |
| Risk for carry-over | The warning "DO NOT REUSE"in the Phadia 250 DFU for EliAConjugates is due to the fact thata low risk of conjugatecontamination by carry-over fromsamples was identified. In orderto reduce the risk, the single usestatement for the conjugate wasincluded in the Phadia 250 DFU. | When running EliA tests on thePhadia 2500/5000 instruments,there is no need for this warningstatement because theseinstruments use disposable tipsfor pipetting samples and aseparate pipette for theconjugate, and carry-over fromsamples to conjugate isimpossible. |
| Loading of EliACarriers | EliA carriers are loaded manuallyon the Loading Tray from wherethey can be processed directly ortransferred to the cooled storagecompartment. | The Phadia 2500/5000instruments do not have such aLoading Tray. The EliA carriersare loaded into racks which aredirectly transferred to the cooledstorage compartment |
| Barcode reader | The Phadia 250 instrument hasa built-in barcode reader at thefront of the instrument, but theoperator needs to scan thebarcodes manually by showingthe reagents to the barcodereader. Alternatively, theoperator can also enter thecharacters below the barcodemanually. | The Phadia 2500/5000instruments dispose of a built-inbarcode reader, and thereagents are on a moving beltwhich conveys them past thebarcode reader. The lot-specificinformation will be readautomatically by the instrumentduring loading. |
| Process time / Timeto patient result | Phadia 250 needs 1 minute toprocess one Well.Phadia 250 provides the resultsat a one minute interval. | Phadia 2500/5000 instrumentsprocess two Wells in parallel in48 seconds.Phadia 2500/5000 provides theresults at a 24 seconds interval. |
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EliA APS IgA Immunoassays on Phadia 250 and Phadia 2500/5000 instruments – Differences to predicate device
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K. Standard/Guidance Document Referenced (if applicable):
CLSI EP05-A3; Evaluation of Precision Performance of Quantitative Measurement Methods: September 2014
CLSI EP06-A Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach: April 2003
CLSI EP17-A, Protocols for Determination of Limits of Detection and Limits of Quantification: October 2004.
CLSI EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples
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 EliA wells are coated with bovine cardiolipin antigen, or with human β2-Glycoprotein I antigen. If present in the patient's specimen, antibodies to these proteins bind to the specific antigen. After washing away non-bound antibodies, enzyme-labeled antibodies against human IgA antibodies (EliA IgA Conjugate) are added to form an antibody-conjugate 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 higher the response value, the more specific IgA is present in the specimen. 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, the variability was assessed in a study with five serum samples totaling in 21 runs (3 instruments x 7 runs). The study was performed with 1 run/day over a period of 7 days. Each serum sample was tested in four replicates/run giving in total 84 replicates per serum sample. The data was calculated against the calibration curve from Day 1.
We included only one lot of EliA ß2-Glycoprotein I IgA Well and EliA Cardiolipin IgA Well on the Phadia 2500/5000 instrument, as data for inter-lot-variation has already been shown in K112414 and K131821.
The results are summarized in the table below:
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| Mean(EliAU/mL) | Within-Run | Between-Run | Between-Instrument | TotalImprecision | ||||
|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | |
| 1.6 | 0.1 | 8.0 | 0.2 | 9.8 | 0.4 | 23.0 | 0.4 | 26.2 |
| 8.0 | 0.3 | 3.7 | 0.3 | 3.5 | 0.3 | 4.2 | 0.5 | 6.6 |
| 10.4 | 0.4 | 3.7 | 0.5 | 5.0 | 0.4 | 3.4 | 0.7 | 7.1 |
| 42.8 | 1.4 | 3.3 | 2.2 | 5.2 | 1.2 | 2.8 | 2.9 | 6.7 |
| 136.6 | 6.6 | 4.8 | 10.3 | 7.5 | 5.1 | 3.7 | 13.2 | 9.7 |
EliA β2-Glycoprotein I IgA on Phadia 2500/5000
EliA Cardiolipin IgA on Phadia 2500/5000
| Mean(APL- | Within-Run | Between-Run | Between-Instrument | TotalImprecision | ||||
|---|---|---|---|---|---|---|---|---|
| U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 2.1 | 0.2 | 7.2 | 0.2 | 7.9 | 0.3 | 15.1 | 0.4 | 18.5 |
| 13.5 | 0.8 | 5.6 | 0.3 | 2.3 | 0.2 | 1.4 | 0.8 | 6.2 |
| 19.4 | 0.7 | 3.9 | 1.1 | 5.5 | 0.6 | 3.0 | 1.4 | 7.4 |
| 93.0 | 5.4 | 5.8 | 1.4 | 1.5 | 4.8 | 5.2 | 7.4 | 7.9 |
| 153.0 | 10.7 | 7.0 | 12.0 | 7.9 | 8.5 | 5.5 | 18.2 | 11.9 |
b. Linearity/assay reportable range:
Four patient serum samples were diluted in sample diluent and tested with one batch of EliA ß2-Glycoprotein I IgA and EliA Cardiolipin IgA Immunoassays and one set of system reagents on Phadia 2500/5000. The results of the regression analysis are summarized below:
EliA β2-Glycoprotein I IgA on Phadia 2500/5000
| Dilution range(EliA U/mL) | Slope | Intercept | R2 |
|---|---|---|---|
| 0.4 — 66.6 | 1.00 | 0.24 | 1.00 |
| 5.2 — 205.2 | 1.03 | -0.12 | 1.00 |
| 6.4 – 242.8 | 1.02 | -0.46 | 1.00 |
| 5.5 – 198.8 | 1.02 | 1.80 | 1.00 |
The reportable range (Limit of Detection, upper limit) for EliA $2-Glycoprotein I IgA is from 0.3 to 183 EliA U/mL. The measuring range (Limit of Quantitation, upper limit) is from 1.1 to 183 EliA U/mL.
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| Dilution range(APL-U/mL) | Slope | Intercept | R2 |
|---|---|---|---|
| 0.5 – 49.5 | 1.01 | 0.40 | 1.00 |
| 1.8 – 91.3 | 0.98 | -0.25 | 1.00 |
| 2.4 - 147.0 | 0.98 | -1.45 | 1.00 |
| 4.4 – 221.6 | 1.00 | 3.76 | 1.00 |
EliA Cardiolipin IgA on Phadia 2500/5000
The reportable range (Limit of Detection, upper limit) for EliA Cardiolipin IgA is from 0.3 to 181 APL-U/mL. The measuring range (Limit of Quantitation, upper limit) is from 1.0 to 181 APL-U/mL.
Statements included in the package inserts: "Please note that concentration values between LoD and LoQ may show a higher uncertainty." "Please note that due to differing binding characteristics of the antibodies in patient samples, not all sera can be diluted linearly within the measuring range."
- Traceability, Stability, Expected values (controls, calibrators, or methods): C. The EliA IqA method was previously reviewed in K062787.
- d. Detection limit:
The limit of blank (LoB) and limit of detection (LoD) studies were performed on the Phadia 2500/5000 instrument. One blank sample and three low level serum samples were measured in thirty-three and eleven replicates, respectively, in each of two runs.
EliA ß2-Glycoprotein I IqA:
The LoD for EliA ß2-Glycoprotein I IgA is 0.3 EliA U/mL, determined consistent with the guidelines in CLSI document EP17-A2 and with proportions of false positives (α) less than 5% and false negatives (β) less than 5%; based on 132 determinations with 66 blank and 66 low level replicates; and LoB of 0.1 EliA U/mL.
The LoQ for EliA ß2-Glycoprotein I IgA is 1.1 EliA U/mL, determined consistent with the guidelines in CLSI document EP17-A2, based on 66 determinations, and a target uncertainty goal of 20%.
The results are summarized in the table below:
| EliA β2-Glycoprotein I IgA (EliA U/mL) | LoB | LoD | LoQ |
|---|---|---|---|
| Phadia 2500/5000 | 0.1 | 0.3 | 1.1 |
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EliA Cardiolipin IgA:
The LoD for EliA Cardiolipin IgA is 0.3 APL-U/mL, determined consistent with the guidelines in CLSI document EP17-A2 and with proportions of false positives (a) less than 5% and false negatives (β) less than 5%; based on 132 determinations with 66 blank and 66 low level replicates; and LoB of 0.1 APL-U/mL.
The LoQ for EliA Cardiolipin IgA is 1.0 APL-U/mL, determined consistent with the quidelines in CLSI document EP17-A2, based on 66 determinations, and a target uncertainty goal of 20%.
The results are summarized in the table below:
| EliA Cardiolipin IgA (APL-U/mL) | LoB | LoD | LoQ |
|---|---|---|---|
| Phadia 2500/5000 | 0.1 | 0.3 | 1.0 |
Analytical specificity: e.
Interference: Previously reviewed in K112414 and K131821 Carry-over: 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.
- f. Assay cut-off:
The ranges (negative, equivocal, positive) recommended for the evaluation of the test results were derived from the clinical studies (s. K112414 and K131821).
EliA ß2-Glvcoprotein | IgA Well
| < 7 EliA U/mL | Negative |
|---|---|
| 7 – 10 EliA U/mL | Equivocal |
| > 10 EliA U/mL | Positive |
EliA Cardiolipin IgA Well
| < 14 APL-U/mL | Negative |
|---|---|
| 14 – 20 APL-U/mL | Equivocal |
| > 20 APL-U/mL | Positive |
-
- Comparison studies:
- Method comparison with predicate device (Instrument comparison): a. See 2c Instrument Comparison below
Matrix comparison: b.
Previously reviewed under K112414 and K131821.
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Instrument comparison C.
In the Method Comparison studies for the two EliA tests included in this submission, more than 100 serum samples (≥20% of the samples within ±25% of the medical decision point) were run in single replicates on one Phadia 250 and three Phadia 2500/5000 instruments. The acceptance criteria for the method comparison (the slope for the regression lines should be 0.9 - 1.1 for single replicate to single replicate and intercept close to 0) were met for EliA ß2-Glycoprotein I IgA and EliA Cardiolipin IgA.
EliA β2-Glycoprotein | IgA:
| Instrument | Intercept | 95% Cl | Slope | 95% Cl |
|---|---|---|---|---|
| PH2500/5000 A | 0.85 | 0.58 to 1.26 | 0.98 | 0.95 to 1.01 |
| PH2500/5000 B | 0.44 | -0.20 to 0.76 | 1.02 | 0.99 to 1.04 |
| PH2500/5000 C | 0.22 | -0.06 to 0.53 | 1.01 | 0.98 to 1.05 |
equivocal results considered positive
| criteria | PH2500/5000 A | PH2500/5000 B | PH2500/5000 C |
|---|---|---|---|
| PPA | 98.7% | 97.3% | 98.7% |
| 95% CI | 92.8% – 100% | 90.6% – 99.7% | 92.8% – 100% |
| NPA | 80.0% | 88.0% | 84.0% |
| 95% CI | 59.3% – 93.2% | 68.8% – 97.5% | 63.9% – 95.5% |
| TPA | 94.0% | 94.9% | 95.0% |
| 95% CI | 87.4% – 97.8% | 88.6% – 98.3% | 88.7% – 98.4% |
equivocal results considered negative
| criteria | PH2500/5000 A | PH2500/5000 B | PH2500/5000 C |
|---|---|---|---|
| PPA | 100.0% | 100.0% | 100.0% |
| 95% CI | 94.3% – 100% | 94.2% – 100% | 94.3% – 100% |
| NPA | 94.6% | 97.3% | 100.0% |
| 95% CI | 81.8% – 99.3% | 85.8% – 99.9% | 90.5% – 100% |
| TPA | 98.0% | 99.0% | 100.0% |
| 95% CI | 93.0% – 99.8% | 94.5% – 100% | 96.4% – 100% |
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EliA Cardiolipin IgA:
| Instrument | Intercept | 95% Cl | Slope | 95% Cl |
|---|---|---|---|---|
| PH2500/5000 A | 0.30 | -0.01 to 0.56 | 0.98 | 0.96 to 1.01 |
| PH2500/5000 B | -0.27 | -0.64 to 0.01 | 0.99 | 0.95 to 1.02 |
| PH2500/5000 C | -0.40 | -0.90 to -0.15 | 1.06 | 1.04 to 1.10 |
equivocal results considered positive
| criteria | PH2500/5000 A | PH2500/5000 B | PH2500/5000 C |
|---|---|---|---|
| PPA | 100.0% | 100.0% | 100.0% |
| 95% CI | 93.8% – 100% | 93.8% – 100% | 93.8% – 100% |
| NPA | 88.4% | 97.7% | 95.3% |
| 95% CI | 74.9% – 96.1% | 87.7% – 99.9% | 84.2% – 99.4% |
| TPA | 95.0% | 99.0% | 98.0% |
| 95% CI | 88.8% – 98.4% | 94.6% – 100% | 93.0% – 99.8% |
equivocal results considered negative
| criteria | PH2500/5000 A | PH2500/5000 B | PH2500/5000 C |
|---|---|---|---|
| PPA | 95.6% | 93.3% | 97.8% |
| 95% CI | 84.9% – 99.5% | 81.7% – 98.6% | 88.2% – 99.9% |
| NPA | 94.6% | 94.6% | 94.6% |
| 95% CI | 85.1% – 98.9% | 85.1% – 98.9% | 85.1% – 98.9% |
| TPA | 95.0% | 94.1% | 96.0% |
| 95% CI | 88.8% – 98.4% | 87.5% – 97.8% | 90.2% – 98.9% |
- ဒေ.
က Clinical studies: - Clinical sensitivity: a. Not applicable.
- b. Clinical specificity: Not applicable.
- c. Other clinical supportive data (when a. and b. are not applicable): Clinical performance values were reviewed in K112414 and K131821.
- Clinical cut-off: 4. Same as assay cut-off.
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Expected values/Reference range: 5.
The frequency distribution for anti-ß2-Glycoprotein I IgA and anti-cardiolipin IgA antibodies was investigated in a group of apparently healthy subjects equally distributed by age and gender, using sera from a Caucasian population obtained from a blood bank.
The results are given in the table below:
| Test | n = | Median(EliA U/mL;APL-U/mL) | 95thpercentile | 99thpercentile |
|---|---|---|---|---|
| EliA ß2-Glycoprotein IIgA on Phadia2500/5000 | 400 | 1.8 | 4.1 | 9.5 |
| EliA Cardiolipin IgAon Phadia 2500/5000 | 400 | 2.8 | 6.6 | 16.5 |
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 instrument platforms, Phadia 250 and Phadia 2500/5000 perform substantially equivalent when using the EliA ß2-Glycoprotein I IgA and EliA Cardiolipin IgA immunoassays.
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
§ 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).