(237 days)
The ADVIA Centaur® anti-CCP IgG (aCCP) assay is for in vitro diagnostic use in the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma (K2-EDTA and lithium heparin) using the ADVIA Centaur XP system. Detection of anti-CCP antibodies is used as an aid in the diagnosis of Rheumatoid Arthritis (RA) and should be used in conjunction with other clinical information. Autoantibody levels represent one parameter in a multi-criteria diagnostic process, encompassing both clinical and laboratory-based assessments.
Quality Control:
The ADVIA Centaur® Anti-CCP IgG (aCCP) quality control material is for in vitro diagnostic use to monitor the precision and accuracy of the ADVIA Centaur aCCP assay using the ADVIA Centaur systems.
Master Curve Material (MCM):
The ADVIA Centaur® Anti-CCP IgG (aCCP) Master Curve Material (MCM) is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur aCCP assay.
The ADVIA Centaur aCCP assay is a fully automated, two-step immunoassay using chemiluminescent technology. The assay utilizes an acridinium ester-labeled anti-human lgG as the Lite Reagent. The Solid Phase consists of biotinylated CCP coupled to streptavidin which is then coated onto magnetic latex microparticles.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Device Name: ADVIA Centaur® Anti-CCP IgG (aCCP) Assay
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" as a separate, quantitative table derived from a pre-defined standard (like a predicate device's performance). Instead, it compares the performance of the new device (ADVIA Centaur aCCP assay) to a predicate device (ARCHITECT Anti-CCP Assay) for several characteristics and implies that similar performance constitutes meeting the criteria for substantial equivalence. I will reconstruct a table showing the implied acceptance criteria (based on the predicate's performance or general expectations for such an assay) and the reported performance.
| Performance Metric | Implied Acceptance Criteria (Based on Predicate or General Assay Expectations) | Reported Device Performance (ADVIA Centaur aCCP Assay) |
|---|---|---|
| Intended Use | Semi-quantitative determination of IgG class anti-CCP antibodies, aid in RA diagnosis, used with other clinical info. | Matches: Semi-quantitative determination of IgG class anti-CCP antibodies, aid in RA diagnosis, used with other clinical info. |
| Assay Technology | Automated, Chemiluminescent Microparticle Immunoassay (CMIA) | Matches: Automated, Chemiluminescent Microparticle Immunoassay (CMIA) |
| Specimen Type | Human serum, serum separator tubes, human plasma (lithium heparin, potassium EDTA) | Matches: Human serum, serum separator tubes, human plasma (lithium heparin, potassium EDTA) |
| Capture Antibody | Cyclic citrullinated peptide (CCP), second generation | Matches: Cyclic citrullinated peptide (CCP), second generation |
| Conjugate Antibody | Mouse anti-human IgG: acridinium-labeled | Matches: Mouse anti-human IgG: acridinium-labeled |
| Storage Conditions | Intended Storage of 2-8 °C | Matches: Intended Storage of 2-8 °C |
| Calibrator Range | 0.0-200.0 U/mL | Matches: 0.0-200.0 U/mL |
| Suggested Cut-Off | 5.0 U/mL | Matches: 5.0 U/mL |
| Interference (Total Protein) | No interference from Total Protein (12 g/dL) | Matches: No interference from Total Protein (12 g/dL) |
| Interference (Rheumatoid Factor) | No interference from Rheumatoid Factor (200 IU/mL) | Matches: No interference from Rheumatoid Factor (200 IU/mL) |
| Cross-Reactivity (General) | No significant cross-reactivity with specified autoantibodies (e.g., SSA, SSB, Sm, RNP, Scl-70, TPO, Jo-1, ds-DNA, Ribosomal P) | Matches: No significant cross-reactivity with specified autoantibodies (SSA, SSB, Sm, RNP, Scl-70, TPO, Jo-1, ds-DNA, Ribosomal P). Also M2, Chromatin. |
| Sample Stability | Specimens stable for up to 7 days at 2-8ºC or 22 hours at 30ºC, avoid > 3 freeze/thaw cycles. | Separated specimens stable for up to 22 hours at room temp or up to 7 days at 2-8 ºC. Avoid > 2 freeze-thaw cycles. (Slight difference in freeze/thaw cycle recommendation, but generally comparable). |
| Imprecision (Within-Lab %CV) | Predicate: Within-run CV of 2.0% to 4.7% and total CV of 2.8 to 7.7% (2.7 to 195.3 U/mL). New device design spec: < /= 7.0% for < 50.00 U/mL and < /= 10% for > 50 U/mL. | Meets Design Spec: Ranged from 3.0 to 4.3% (2.37 to 111.53 U/mL). |
| Sensitivity (Limit of Detection) | ≤ 0.5 U/mL | Better: 0.40 U/mL (design goal was ≤ 1.50 U/mL) |
| Measurable Range | 0.5 - 200.0 U/mL | Comparable/Slightly Wider: 0.40 – 200.0 U/mL |
| On-board Reagent Stability | Max 30 days | Better: Max 60 days |
| High Dose Hook | Not explicitly stated but assumed desirable to avoid. | Patient samples up to 3000.00 U/mL will assay > 200.00 U/mL (no high-dose hook effect within this range). |
| Interference (General) | No significant effects from hemolyzed, icteric, lipemic samples within specified limits. | Hemolyzed (1000 mg/dL Hb), Icteric (40 mg/dL unconj/conj bilirubin), Lipemic (1500 mg/dL Intralipid, 2450 mg/dL triglycerides). Biotin (500 ng/dL), Caprine IgG (6 g/dL). |
| Dilution Linearity (Recovery) | Not explicitly stated but assumed desirable to be within an acceptable range (e.g., 80-120%). | Sample 1 (140.63 U/mL) diluted 1:10 showed 107.87% recovery. Sample 2 (180.08 U/mL) diluted 1:10 showed 105.62% recovery. |
| Clinical Concordance (Overall % Agreement) | "Substantially equivalent performance" to predicate. Implicitly, high agreement. | 96.84% (CI 93.89 - 98.39%) with ARCHITECT Anti-CCP. |
| Clinical Sensitivity (RA diagnosis) | "Substantially equivalent performance." Implicitly, acceptable sensitivity for RA. | 68.08% (CI 62.5-73.3%) |
| Clinical Specificity (Non-RA population) | "Substantially equivalent performance." Implicitly, acceptable specificity for RA. | 97.17% (CI 95.22-98.49%) |
2. Sample Sizes and Data Provenance:
- Test Set (Clinical Performance):
- Method Comparison Study: 253 samples (143 confirmed positive for RA, and 110 samples where other auto-antibodies may be present). Data provenance not explicitly stated (e.g., country of origin, retrospective/prospective), but it is a clinical study.
- Clinical Sensitivity and Specificity Study: 767 patient samples.
- 307 confirmed-positive RA subjects.
- 460 non-RA subjects with potentially cross-reacting conditions (22 subgroups).
- Data provenance not explicitly stated (e.g., country of origin, retrospective/prospective).
- Training Set: Not explicitly mentioned for this type of in vitro diagnostic assay. Immunoassays are generally calibrated and validated, not "trained" in the machine learning sense. The "training" in this context would likely refer to the development and optimization of the assay reagents and parameters.
3. Number of Experts and Qualifications for Ground Truth (Test Set):
- For RA Confirmation: "307 confirmed-positive RA subjects that were classified according to the American College of Rheumatology criteria." This implies expert clinical diagnosis based on established criteria, but the specific number and qualifications of individuals making these diagnoses are not provided.
- For Non-RA Subjects: "22 subgroups of non-RA subjects (n=460) with potentially cross-reacting conditions." This also implies clinical diagnosis by experts, but details are not provided.
- For Autoantibody Presence (Method Comparison): "110 samples where other auto-antibodies may be present." This suggests expert determination of autoantibody status, but details are not given.
4. Adjudication Method for the Test Set:
Not applicable or explicitly stated as this is an immunoassay, not an imaging device requiring expert adjudication of reader interpretations. The ground truth for clinical sensitivity and specificity is based on clinical diagnosis (American College of Rheumatology criteria for RA).
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
No, an MRMC comparative effectiveness study was not done. This type of study is typically performed for imaging devices or AI tools that assist human readers in interpretation. The ADVIA Centaur anti-CCP IgG assay is a standalone diagnostic laboratory test.
6. Standalone Performance:
Yes, standalone performance was done. The entire document describes the standalone performance of the ADVIA Centaur aCCP assay in various analytical and clinical studies (linearity, dilution linearity, detection capability, high dose hook, cross-reactivity, interference, precision, specimen collection comparison, clinical concordance with a predicate, and clinical sensitivity/specificity against clinical diagnosis). The results presented are solely the performance of the algorithm/assay without human intervention in the result determination.
7. Type of Ground Truth Used:
- Analytical Performance: Based on reference materials, spiked samples with known concentrations, or established analytical methods.
- Clinical Performance (Sensitivity/Specificity):
- RA Diagnosis: American College of Rheumatology criteria (clinical diagnosis) for RA.
- Non-RA Status: Clinical diagnosis of various conditions (22 subgroups).
- Method Comparison: The predicate device (ARCHITECT Anti-CCP Assay) results were used as a reference point for agreement.
8. Sample Size for the Training Set:
Not applicable in the machine learning sense. For an immunoassay, "training" is typically assay development, which involves optimizing reagents and parameters. The document doesn't specify sample sizes used during the development phase.
9. How the Ground Truth for the Training Set Was Established:
Not applicable. For an immunoassay, ground truth during development would involve well-characterized samples (e.g., confirmed positive/negative for CCP antibodies, known concentrations) to optimize the assay's performance characteristics. Specific details on this are not provided in the summary.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
August 4, 2016
Axis-Shield Diagnostics Ltd Dr. Claire L. Dora Regulatory Affairs Manager The Technology Park, Luna Place Dundee, DD2 1XA, UK
Re: K153551
Trade/Device Name: ADVIA Centaur® Anti-CCP IgG (aCCP) Assay ADVIA Centaur® Anti-CCP IgG (aCCP) Quality Controls ADVIA Centaur® Anti-CCP IgG (aCCP) Master Curve Materials Regulation Number: 21 CFR 866.5775 Regulation Name: Rheumatoid Factor Immunological Test System Regulatory Class: II Product Code: NHX, JJX Dated: July 18, 2016 Received: July 19, 2016
Dear Dr. Dora:
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. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements
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as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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 Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
Kelly Oliner -S
FOR
Leonthena R. Carrington, MS, MBA, MT(ASCP) 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) K153551
Device Name
ADVIA Centaur® anti-CCP IgG (aCCP) Assay ADVIA Centaur® anti-CCP IgG (aCCP) Quality Control ADVIA Centaur® anti-CCP IgG (aCCP) Master Curve Material (MCM)
Indications for Use (Describe)
The ADVIA Centaur® anti-CCP IgG (aCCP) assay is for in vitro diagnostic use in the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma (K2-EDTA and lithium heparin) using the ADVIA Centaur XP system. Detection of anti-CCP antibodies is used as an aid in the diagnosis of Rheumatoid Arthritis (RA) and should be used in conjunction with other clinical information. Autoantibody levels represent one parameter in a multi-criteria diagnostic process, encompassing both clinical and laboratory-based assessments.
Quality Control:
The ADVIA Centaur® Anti-CCP IgG (aCCP) quality control material is for in vitro diagnostic use to monitor the precision and accuracy of the ADVIA Centaur aCCP assay using the ADVIA Centaur systems.
Master Curve Material (MCM):
The ADVIA Centaur® Anti-CCP IgG (aCCP) Master Curve Material (MCM) is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur aCCP assay.
| 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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510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K1535551.
Submission correspondent:
Dr Claire Dora Regulatory Affairs Manager Axis-Shield Diagnostics Ltd. The Technology Park Dundee DD2 1XA, Scotland, UK
Device Name:
ADVIA Centaur® anti-CCP IgG (aCCP) assay ADVIA Centaur® anti-CCP IgG (aCCP) Quality Control ADVIA Centaur® anti-CCP IgG (aCCP) Master Curve Material (MCM)
Reagents:
Classification Name: Antibodies, ANTI-CYCLIC CITRULLINATED PEPTIDE (CCP) Trade Name: ADVIA Centaur® anti-CCP IgG (aCCP) assay Common Name: Anti-CCP test Governing Regulation: 866.5775 Device Classification: Class II Classification Panel: Immunology Product Code: NHX
Quality Control:
Classification Name: Single (Specified) Analyte Control Trade Name: ADVIA Centaur® anti-CCP IgG (aCCP) quality control material Common Name: Control Governing Regulation: 862.1660 Device Classification: Class I Classification Panel: Clinical Chemistry Product Code: JJX
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Master Curve Materials:
Classification Name: Single (Specified) Analyte Control Trade Name: ADVIA Centaur® anti-CCP IgG (aCCP) Master Curve Material (MCM) Common Name: Control Governing Regulation: 862.1660 Device Classification: Class I Classification Panel: Clinical Chemistry Product Code: JJX
Legally marketed device to which equivalency is claimed:
ARCHITECT Anti-CCP Assay (K083868)
Intended Use of Device:
The ADVIA Centaur® anti-CCP IgG (aCCP) assay is for in vitro diagnostic use in the semiquantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma (K2-EDTA and lithium heparin) using the ADVIA Centaur XP system. Detection of anti-CCP antibodies is used as an aid in the diagnosis of Rheumatoid Arthritis (RA) and should be used in conjunction with other clinical information. Autoantibody levels represent one parameter in a multi-criteria diagnostic process, encompassing both clinical and laboratory-based assessments.
Quality Control:
The ADVIA Centaur® Anti-CCP IgG (aCCP) quality control material is for in vitro diagnostic use to monitor the precision and accuracy of the ADVIA Centaur aCCP assay using the ADVIA Centaur systems.
Master Curve Material (MCM):
The ADVIA Centaur® Anti-CCP IgG (aCCP) Master Curve Material (MCM) is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur aCCP assay.
Description of Device:
The ADVIA Centaur aCCP assay is a fully automated, two-step immunoassay using chemiluminescent technology. The assay utilizes an acridinium ester-labeled anti-human lgG as the Lite Reagent. The Solid Phase consists of biotinylated CCP coupled to streptavidin which is then coated onto magnetic latex microparticles.
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Comparison of Technological Characteristics:
The ADVIA Centaur aCCP assay and the ARCHITECT Anti-CCP are both automated immunoassays for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma. The ADVIA Centaur System and ARCHITECT i System share similar detection methods both utilizing chemiluminescent microparticle immunoassay (CMIA) technology. Both assays also demonstrated substantial equivalence in terms antibodies employed and units of measure.
| Similarities | ||
|---|---|---|
| Parameter | Submission deviceADVIA Centaur® aCCP | Predicate deviceARCHITECT Anti-CCP |
| Intended use | Intended for the semi-quantitativedetermination of the IgG class ofautoantibodies specific to cycliccitrullinated peptide (CCP) in human serumor plasma using the ADVIA Centaur XPsystem. Detection of anti-CCP antibodies isused as an aid in the diagnosis ofRheumatoid Arthritis (RA) and should beused in conjunction with other clinicalinformation. Autoantibody levels representone parameter in a multi-criteria diagnosticprocess, encompassing both clinical andlaboratory-based assessments. | Intended for the semi-quantitativedetermination of the IgG class ofautoantibodies specific to cyclic citrullinatedpeptide (CCP) in human serum or plasma onthe ARCHITECT i System. Detection of anti-CCP antibodies is used as an aid in thediagnosis of Rheumatoid Arthritis (RA) andshould be used in conjunction with otherclinical information. Autoantibody levelsrepresent one parameter in a multicriteriondiagnostic process, encompassing bothclinical and laboratory-based assessments. |
| Assay Technology | Automated.Chemiluminescent MicroparticleImmunoassay (CMIA) | Automated.Chemiluminescent MicroparticleImmunoassay (CMIA) |
| Substrate / SignalGeneration | Acridinium Tracer | Acridinium Tracer |
| Specimen type | Human serum and serum separator tubes.Human plasma collected in lithium heparinand potassium EDTA tubes | Human serum and serum separator tubes.Human plasma collected in lithium heparinand potassium EDTA tubes |
| Capture antibody | Cyclic citrullinated peptide (CCP), secondgeneration. | Cyclic citrullinated peptide (CCP), secondgeneration. |
| Conjugate antibody | Mouse anti-human IgG: acridinium-labeled. | Mouse anti-human IgG: acridinium-labeled. |
| Storage conditions | Intended Storage of 2-8 °C. | Intended Storage of 2-8 °C. |
| Calibrator Range | 0.0-200.0 U/mL | 0.0-200.0 U/mL |
| Suggested Cut-Off | 5.0 U/mL | 5.0 U/mL |
| Interference | No interference fromTotal Protein (12 g/dL)Rheumatoid Factor (200 IU/mL) | No interference fromTotal Protein (12 g/dL)Rheumatoid Factor (200 IU/mL) |
| Cross- Reactivity | No significant cross-reactivity of the CCPantigen with any of these otherautoantibodies (SSA, SSB, Sm, RNP, Scl-70,TPO, Jo-1, ds-DNA, and Ribosomal P). | No significant cross-reactivity of the CCPantigen with any of these otherautoantibodies (SSA, SSB, Sm, RNP, Scl-70,TPO, Jo-1, ds-DNA, and Ribosomal P). |
| Similarities | ||
| Parameter | Submission deviceADVIA Centaur® aCCP | Predicate deviceARCHITECT Anti-CCP |
| Sample Stability | Separated specimens are stable for up to22 hours at room temperature or up to 7days at 2-8 ºC.Avoid more than 2 freeze-thaw cycles. | Specimens may be stored for up to 7 days at2-8ºC or 22 hours at 30ºC after the date ofcollection. For longer storage, storespecimens at -20ºC or colder.Avoid more than three freeze/thaw cycles. |
Comparison of the subject device with the predicate device:
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| Differences | ||
|---|---|---|
| Parameter | Submission deviceADVIA Centaur® Anti-CCP | Predicate deviceARCHITECT Anti-CCP |
| Calibration | Semi-quantitative assay.10-point master calibration curve (4PL, Y-weighted) generated and stored on the lot-specific aCCP master curve card.The ADVIA Centaur aCCP assay utilises a 2-point operator-initiated calibration. The assay calibration covers 0 to 200 U/mL | Semi-quantitative assay. 6-point calibration curve (4PLC, Y-weighted) generated and stored on the instrument. The ARCHITECT Anti-CCP Standard Calibrators A-F (0.0, 5.0, 25.0, 50.0, 100.0, 200.0 U/mL) |
| Expected Values inAsymptomatic Population | The median was established at 0.74 U/mL.(Mean 95% Confidence Limits of 0.25 -1.87 U/mL) in a representative study | Specimen values ranged from < 0.5 U/mL to 2.5 U/mL in a representative study |
| Imprecision | Within-Lab % CV was designed to be < /= 7.0% for CCP concentrations < 50.00 U/mL and =10% for levels /= 50 U/mL. Within Lab %CV ranged from 3.0 to 4.3% from 2.37 to 111.53 U/mL. | Within-run CV of 2.0% to 4.7% and total CV of 2.8 to 7.7% from 2.7 to 195.3 U/mL. |
| Assay dilution protocol | No auto-dilution capabilities.Manual dilution only (1:10) | Auto-dilution (1:6) |
| Sensitivity | Limit of Detection ≤ 0.40 U/mL | Limit of Detection ≤ 0.5 U/mL |
| Interference | No interference from:Biotin (500 ng/dL)Bilibrubin - Conj & unconj (40 mg/dL)Haemoglobin (1000 mg/dL)Triglycerides (2450 mg/dL)Intralipid (1500 mg/dL)Caprine IgG (6 g/dL)HAAA | No interference fromBilibrubin (20 mg/dL)Red blood cells (0.4%)Haemoglobin (800 mg/dL)Triglycerides (3000 mg/dL) |
| Cross- Reactivity | No significant cross-reactivity of the CCP antigen with any of these other autoantibodies (M2, Chromatin). | No significant cross-reactivity of the CCP antigen with any of these other autoantibodies (ANA, AMA). |
| Measurable Range | 0.40 – 200.0 U/mL | 0.5 - 200.0 U/mL |
| On-board Reagent Stability | Reagents can be stored on-board for a maximum of 60 days | Reagents can be stored on-board for a maximum of 30 days |
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Summary of Non-Clinical Performance:
The ADVIA Centaur aCCP assay demonstrated substantially equivalent performance to the ARCHITECT Anti-CCP assay. A summary of the non-clinical performance data included in this 510(k) submission has been presented.
Linearity
Linearity was evaluated according to the CLSI protocol EP6-A. Three samples containing high levels of anti-CCP IgG were mixed with a pool of negative serum. The resulting sample mixtures were assayed for anti-CCP IgG. The ADVIA Centaur aCCP assay is linear from 0.40-200.00 U/mL.
Dilution Linearity
Two samples containing high levels of anti-CCP IgG (140.63 and 180.08 U/mL) were diluted 1:10 (1 part sample plus 9 parts diluent) with Multi-Diluent 1 and assayed for recovery and parallelism. Representative data from the study is shown below.
| Sample | Dilution | Observed(U/mL) | Expected(U/mL) | Recovery % |
|---|---|---|---|---|
| 1 | - | 140.63 | ||
| 1:10 | 151.70 | 14.06 | 107.87 | |
| 2 | - | 180.08 | ||
| 1:10 | 190.20 | 18.01 | 105.62 |
Measuring Interval
The ADVIA Centaur aCCP assay measures anti-CCP IgG concentrations from 0.40-200.0 U/mL.
Detection Capability
The ADVIA Centaur aCCP assay is designed to have a Limit of Detection (LoD) of less than 1.50 U/mL. The LoD was determined as described in CLSI Document EP17-A2.
The LoD is defined as the lowest concentration of anti-CCP IgG that can be detected with greater than or equal to 95% probability. The LoD was determined to be 0.40 U/mL.
High Dose Hook
Patient samples with high anti-CCP IgG levels can cause a paradoxical decrease in the Relative Light Units (RLUs) (high-dose hook effect). In this assay, patient samples with anti-CCP IgG levels as high as 3000.00 U/mL will assay greater than 200.00 U/mL.
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Cross-reactivity
Cross-reactivity was tested in the presence and absence of anti-CCP IgG according to CLSI EP7-A2 using the ADVIA Centaur aCCP assay. Populations evaluated in the study included Sm, RNP, SSB, Scl-70, Jo-1, Ribosomal P, M2, TPO, ds-DNA, SSA and Chromatin. The study showed no clinically significant cross-reactivity of the CCP antigen with any of these auto-antibodies.
Interference
Interfering substances at the levels indicated in the table below were tested as described in CLSI Document EP7-A2 using the ADVIA Centaur aCCP assay. Potential interference in the ADVIA Centaur aCCP assay is designed to be less than or equal to 10%.
| Serum specimens that are | Have an insignificant effect on the assay up to |
|---|---|
| hemolyzed | 1000 mg/dL of hemoglobin |
| icteric | 40 mg/dL of unconjugated bilirubin |
| icteric | 40 mg/dL of conjugated bilirubin |
| lipemic | 1500 mg/dL of lipemia (Intralipid) |
| lipemic | 2450 mg/dL of triglycerides |
The following substances at the levels indicated caused no significant interference in anti-CCP IgG measurement.
| Substances | Concentrations |
|---|---|
| Biotin | 500 ng/dL |
| Caprine IgGª | 6 g/dL |
| Total Protein | 12 g/dL |
| Rheumatoid Factor | 200 IU/mL |
a Caprine IgG was used to avoid interference with human IgG sensitive to CCP.
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Precision
Precision was evaluated according to the CLSI protocol EP5-A2. Assay precision was designed to have Within-Laboratory %CV less than or equal to 7.0% for levels less than 50.00 U/mL and less than or equal to 10% for levels greater than 50.00 U/mL.
Six serum precision panels were prepared with anti-CCP IgG concentrations spanning the measuring interval. Each sample was tested in replicates of 2 in two runs per day over 20 days. One ADVIA Centaur system was used and one reagent lot giving a total of 80 observations per sample. Representative data from the study is shown in the following table.
| Repeatability | Within-Lab | |||||
|---|---|---|---|---|---|---|
| SpecimenType | N | Mean(U/mL) | SD(U/mL) | CV(%) | SD(U/mL) | CV(%) |
| Sample 1 | 80 | 2.37 | 0.09 | 3.9 | 0.10 | 4.3 |
| Sample 2 | 80 | 3.75 | 0.12 | 3.1 | 0.13 | 3.6 |
| Sample 3 | 80 | 6.73 | 0.22 | 3.3 | 0.25 | 3.6 |
| Sample 4 | 80 | 42.01 | 1.09 | 2.6 | 1.27 | 3.0 |
| Sample 5 | 80 | 55.34 | 1.73 | 3.1 | 2.01 | 3.6 |
| Sample 6 | 80 | 111.53 | 3.30 | 3.0 | 3.64 | 3.3 |
Specimen Collection Comparison
The ADVIA Centaur aCCP assay was evaluated using different specimen matrices and collection tube types.
A clinical specimen collection study was performed. Any negative anti-CCP IgG values were excluded. The specimen anti-CCP IgG values ranged from 0.41-180.82 U/mL. Linear regression analysis was performed and no significant difference between tube types was observed. The following results were obtained:
| Serum Vs. | n | Slope | Intercept | r |
|---|---|---|---|---|
| Serum Separator Tube | 50 | 1.01 | 0.05 | 1.00 |
| K2-EDTA | 51 | 0.98 | 0.03 | 1.00 |
| Lithium heparin | 49 | 1.00 | 0.11 | 0.98 |
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Summary of Clinical Performance:
The ADVIA Centaur anti-CCP IgG assay demonstrated substantially equivalent performance to the ARCHITECT Anti-CCP assay as indicated by a clinical concordance and method comparison study.
Method Comparison
253 samples (143 samples confirmed positive for RA, and 110 samples where other auto-antibodies may be present) were tested. The diagnostic concordance between the ADVIA Centaur aCCP and the Abbott ARCHITECT anti-CCP assays is 96.84% (Confidence Interval (CI) 93.89 - 98.39%). The following results were obtained:
| ARCHITECT anti-CCP assay | ||||
|---|---|---|---|---|
| ADVIA CentauraCCP assay | Positive | Negative | Total | |
| Positive | 121 | 4 | 125 | |
| Negative | 4 | 124 | 128 | |
| Total | 125 | 128 | 253 |
Overall % Agreement (95% Confidence Interval (CI) 96.84% (93.89-98.39%). Positive % Agreement (95% Confidence Interval (CI)) 96.80% (92.06-98.75%). Negative % Agreement (95% Confidence Interval (CI)) 96.88% (92.24-98.78%).
Clinical Sensitivity and Specificity
Clinical sensitivity and specificity were determined using 767 patients samples. The following results were obtained:
| Clinical Diagnosis | ||||
|---|---|---|---|---|
| ADVIA CentauraCCP assay | Positive | Negative | Total | |
| Positive | 209 | 13 | 222 | |
| Negative | 98 | 447 | 545 | |
| Total | 307 | 460 | 767 |
Clinical Sensitivity (Exact 95% Confidence Interval (CI)) 68.08% (62.5-73.3%).
Clinical Specificity (Exact 95% Confidence Interval (CI)) 97.17% (95.22-98.49%).
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The sensitivity assessment of the ADVIA Centaur aCCP assay was conducted on 307 confirmed-positive RA subjects that were classified according to the American College of Rheumatology criteria.
The specificity assessment of the ADVIA Centaur aCCP assay was conducted on 22 subgroups of non-RA subjects (n=460) with potentially cross-reacting conditions.
Conclusion:
Based on the performance characteristics the ADVIA Centaur aCCP assay is substantially equivalent to the predicate device.
The results presented in this 510(k) premarket submission demonstrate that the candidate assay (ADVIA Centaur® anti-CCP IgG (aCCP) assay, K153551) performance is substantially equivalent to the predicate assay (ARCHITECT Anti-CCP Assay (K083868) The similarities and differences between the candidate assay and the predicate assay are presented in the tables starting on page 3/10.
§ 866.5775 Rheumatoid factor immunological test system.
(a)
Identification. A rheumatoid factor immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the rheumatoid factor (antibodies to immunoglobulins) in serum, other body fluids, and tissues. Measurement of rheumatoid factor may aid in the diagnosis of rheumatoid arthritis.(b)
Classification. Class II (performance standards).