ARCHITECT ANTI-CCP (100 TEST), ARCHITECT ANTI-CCP (500 TEST), MODELS 1P65-25, 1P65-35
Device Facts
| Record ID | K083868 |
|---|---|
| Device Name | ARCHITECT ANTI-CCP (100 TEST), ARCHITECT ANTI-CCP (500 TEST), MODELS 1P65-25, 1P65-35 |
| Applicant | Axis-Shield Diagnostics, Ltd. |
| Product Code | NHX · Immunology |
| Decision Date | Sep 25, 2009 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 866.5775 |
| Device Class | Class 2 |
Indications for Use
The ARCHITECT Anti-CCP assay is a chemiluminescent microparticle immunoassay (CMIA) for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma on the ARCHITECT i 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 multicriterion diagnostic process, encompassing both clinical and laboratory-based assessments. The ARCHITECT Anti-CCP Calibrators are for the calibration of the ARCHITECT i System when used for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma. The ARCHITECT Anti-CCP Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT i System (reagents, calibrators and instrument) when used for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma.
Device Story
ARCHITECT Anti-CCP is a two-step chemiluminescent microparticle immunoassay (CMIA) for detecting IgG autoantibodies to cyclic citrullinated peptide (CCP) in human serum or plasma. The device uses CCP-coated paramagnetic microparticles and an acridinium-labeled mouse anti-human IgG conjugate. The system automatically performs sample pretreatment and incubation; anti-CCP antibodies in the sample bind to the microparticles, forming a complex that reacts to produce light (relative light units, RLUs). The RLU signal is directly proportional to the anti-CCP concentration. The assay is performed on ARCHITECT i System analyzers (i2000, i2000SR, i1000SR) in clinical laboratory settings by trained technicians. Results are used by physicians as one parameter in a multicriterion diagnostic process for Rheumatoid Arthritis. The device provides semi-quantitative results, aiding in clinical decision-making by identifying patients with elevated anti-CCP levels.
Clinical Evidence
Clinical performance was evaluated using 496 confirmed RA patients and 499 non-RA specimens (including healthy individuals and patients with other rheumatic/non-rheumatic diseases). Clinical sensitivity was 70.6% (95% CI: 66.3%-77.4%) and clinical specificity was 98.2%. Method comparison with the predicate (n=995) showed 99.3% total agreement, with an AUC of 0.873.
Technological Characteristics
CMIA technology; uses CCP-coated paramagnetic microparticles in phosphate buffer with bovine stabilizer; acridinium-labeled mouse anti-human IgG conjugate in MES buffer. Automated platform (ARCHITECT i series). Connectivity: networked/standalone instrument. Calibration: 6-point curve (4PLC, Y-weighted). Measuring range: 0.5–200 U/mL. Preservatives: sodium azide, Nipasept, Sarafloxacin.
Indications for Use
Indicated for the semi-quantitative determination of IgG autoantibodies to cyclic citrullinated peptide (CCP) in human serum or plasma as an aid in the diagnosis of Rheumatoid Arthritis (RA). For prescription use only.
Regulatory Classification
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.
Predicate Devices
- AxSYM Anti-CCP Assay (k063347)
Related Devices
- K153551 — ADVIA Centaur Anti-CCP IgG (aCCP) assay including Reagents and Calibrators, Quality Controls and Master Curve Materials. · Axis-Shield Diagnostics Limited · Aug 4, 2016
- K121576 — IMMULITE 2000 ANTI-CCP IGG ASSAY · Siemens Healthcare Diagnostics, Inc. · Apr 4, 2013
Submission Summary (Full Text)
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
A. 510(k) Number:
k083868
B. Purpose for Submission:
New Device
C. Measurand:
Human IgG autoantibodies to cyclic citrullinated peptide (CCP)
D. Type of Test:
Semi-quantitative chemiluminescent microparticle immunoassay (CMIA)
E. Applicant:
Axis-Shield Diagnostic Limited
F. Proprietary and Established Names:
ARCHITECT Anti-CCP
G. Regulatory Information:
1. Regulation section:
21 CFR § 866.5775, Rheumatoid Factor Immunological Test System
21 CFR § 862.1150, Calibrator
21 CFR § 862.1660, Quality control material (assayed and unassayed).
2. Classification:
Class II (Device)
Class II (Calibrator)
Class I (Quality control)
3. Product code:
NHX, Antibodies, anti-cyclic citrullinated peptide (CCP)
JIX, Calibrator, multi-analyte mixture
JJY, Multi-analyte controls, all kinds (assayed)
4. Panel:
Immunology (82)
Clinical Chemistry (75)
Clinical Chemistry (75)
H. Intended Use:
1. Intended use(s):
Reagents:
The ARCHITECT Anti-CCP assay is a chemiluminescent microparticle immunoassay (CMIA) for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma on the ARCHITECT i 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 multicriterion diagnostic process, encompassing both clinical and laboratory-based assessments.
Calibrators:
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The ARCHITECT Anti-CCP Calibrators are for the calibration of the ARCHITECT i System when used for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma.
**Controls:**
The ARCHITECT Anti-CCP Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT i System (reagents, calibrators and instrument) when used for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma.
2. **Indication(s) for use:**
Same as Intended Use
3. **Special conditions for use statement(s):**
For prescription use only
4. **Special instrument requirements:**
ARCHITECT i2000 and i2000SR and i1000SR, which are platforms of the ARCHITECT i system family
**I. Device Description:**
Each ARCHITECT Anti-CCP Reagent Kit (100 tests, 500 tests) contains 1 bottle of each of Microparticles, Conjugate, and Sample Diluent:
**Microparticles** – 1 Bottle (6.5 mL or 26.5 mL) CCP coated microparticles in phosphate buffer with surfactant and protein (bovine) stabilizer. Minimum concentration: 0.05% solids. Preservative: sodium azide;
**Conjugate** – 1 Bottle (5.8 mL or 25.8 mL) Mouse anti-human IgG: acridinium-labeled conjugate in MES buffer with surfactant and protein (bovine) stabilizer. Minimum concentration: 10 ng/mL. Preservatives: Nipasept and Sarafloxacin
**Sample Diluent** – 1 Bottle (9.8 mL or 50.0 mL) Phosphate buffer with surfactant and protein (bovine) stabilizer. Preservative: sodium azide.
**J. Substantial Equivalence Information:**
1. **Predicate device name(s):**
AxSYM Anti-CCP Assay
2. **Predicate 510(k) number(s):**
k063347
3. **Comparison with predicate:**
**Similarities:**
| Parameter | Submission device
ARCHITECT Anti-CCP | Predicate device
AxSYM
Anti-CCP |
| --- | --- | --- |
| Intended use | Semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma. 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 | Same |
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| Parameter | Submission device ARCHITECT Anti-CCP | Predicate device AxSYM Anti-CCP |
| --- | --- | --- |
| | information. Autoantibody levels represent one parameter in a multicriterion diagnostic process, encompassing both clinical and laboratory-based assessments. | |
| Capture antibody | Cyclic citrullinated peptide (CCP), second generation. | Same |
| Storage conditions | The ARCHITECT Anti-CCP Reagent Pack, Calibrator Pack and Control Pack must be stored at 2-8°C. | Same |
| Calibration | Semi-quantitative assay. 6-point calibration curve (4PLC, Y-weighted) generated and stored on the instrument. Calibrators A-F (0, 5, 25, 50, 100, 200 U/mL) | Same |
| Calibrator Range | 0-200 U/mL | Same |
| Suggested Cut-Off | 5 U/mL | Same |
Differences:
| Parameter | Submission device ARCHITECT Anti-CCP | Predicate device AxSYM Anti-CCP |
| --- | --- | --- |
| Assay Technology | Chemiluminescent Microparticle Immunoassay (CMIA) | Microparticle Enzyme Immunoassay (MEIA). |
| Substrate / Signal Generation | Acridinium Tracer | 4-Methylumbelliferyl phosphate |
| Assay dilution protocol | Auto-dilution (1:6) Manual-dilution (1:10) | Auto-dilution (1:10) Manual-dilution (1:10) |
| Sensitivity | Limit of Detection is 0.5 U/mL | Limit of Blank is 1.0 U/mL. |
| Measurable Range | 0.5 – 200 U/mL | 0 – 200 U/mL |
# K. Standard/Guidance Document Referenced (if applicable):
CLSI EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline
CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach
CLSI EP7-A2 - Interference Testing in Clinical Chemistry
CLSI EP9-A2 - Method Comparison and Bias Estimation Using Patient Samples
CLSI EP17-A: Protocols for Determination of Limits of Detection and Limits of Quantitation
# L. Test Principle:
The ARCHITECT Anti-CCP assay is a two-step immunoassay with an automated sample pretreatment for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum or plasma, using CMIA (chemiluminescent microparticle immunoassay) technology.
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CCP coated paramagnetic microparticles and prediluted sample are combined. Anti-CCP antibodies present in the sample bind to the CCP coated microparticles. The resulting chemiluminescent reaction is measured as relative light units (RLUs). A direct relationship exists between the amount of anti-CCP antibody in the sample and the RLUs detected by the ARCHITECT $i$ System optics.
# M. Performance Characteristics (if/when applicable):
# 1. Analytical performance:
a. Precision/Reproducibility:
Testing was performed in accordance with CLSI EP5-A2.
Precision of the Architect Anti-CCP assay was evaluated on the ARCHITECT $i$ system analyzers $i2000$ , $i2000\mathrm{SR}$ and $i1000\mathrm{SR}$ . Samples included two patient samples, 1 positive control and 4 QC panel samples and were assayed in duplicate in two runs for 20 days ( $n = 80$ for each control/sample). A calibration curve for each reagent lot was generated on each instrument during run 1 on day 1. The study results are summarized in the table below:
Imprecision of the Architect Anti-CCP Assay on Architect $i$ analyzers
| | | | | Within-Run | | Between-Run | | Between-Day | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Instrument No. | Sample | N | Mean (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| ARCHITECT i2000 | Positive Control | 80 | 24.5 | 0.73 | 3.0 | 0.27 | 1.1 | 0.23 | 0.9 | 0.81 | 3.3 |
| | QC Panel 2 | 80 | 10.9 | 0.30 | 2.7 | 0.53 | 4.9 | 0.00 | 0.0 | 0.61 | 5.6 |
| | QC Panel 3 | 80 | 28.6 | 0.63 | 2.2 | 1.82 | 6.4 | 0.33 | 1.2 | 1.95 | 6.8 |
| | QC Panel 4 | 80 | 66.7 | 1.40 | 2.1 | 3.61 | 5.4 | 1.09 | 1.6 | 4.03 | 6.0 |
| | QC Panel 5 | 80 | 135.3 | 6.36 | 4.7 | 5.04 | 3.7 | 0.00 | 0.0 | 8.11 | 6.0 |
| | Sample 1 | 80 | 2.8 | 0.07 | 2.6 | 0.09 | 3.1 | 0.01 | 0.4 | 0.11 | 4.0 |
| | Sample 2 | 80 | 181.4 | 6.67 | 3.7 | 6.56 | 3.6 | 2.53 | 1.4 | 9.69 | 5.3 |
| ARCHITECT i2000SR (1) | Positive Control | 80 | 26.7 | 0.68 | 2.6 | 0.28 | 1.1 | 0.00 | 0.0 | 0.74 | 2.8 |
| | QC Panel 2 | 80 | 11.3 | 0.26 | 2.3 | 0.52 | 4.6 | 0.00 | 0.0 | 0.58 | 5.2 |
| | QC Panel 3 | 80 | 30.3 | 0.60 | 2.0 | 1.53 | 5.1 | 0.34 | 1.1 | 1.68 | 5.5 |
| | QC Panel 4 | 80 | 72.7 | 1.92 | 2.6 | 4.46 | 6.1 | 0.00 | 0.0 | 4.85 | 6.7 |
| | QC Panel 5 | 80 | 154.1 | 5.02 | 3.3 | 10.7 | 6.9 | 0.00 | 0.0 | 11.82 | 7.7 |
| | Sample 1 | 80 | 2.7 | 0.07 | 2.4 | 0.08 | 2.8 | 0.04 | 1.6 | 0.11 | 4.0 |
| | Sample 2 | 80 | 195.3 | 7.20 | 3.7 | 9.77 | 5.0 | 0.00 | 0.0 | 12.14 | 6.2 |
| ARCHITECT i1000SR (1) | Negative Control | 80 | 0.03 | 0.04 | 144.7 | 0.00 | 0.0 | 0.02 | 77.4 | 0.05 | 164.1 |
| | Positive Control | 80 | 25.03 | 0.83 | 3.3 | 0.00 | 0.0 | 0.71 | 2.9 | 1.10 | 4.4 |
| | Panel 1 | 80 | 11.52 | 0.46 | 4.0 | 0.00 | 0.0 | 0.16 | 1.4 | 0.49 | 4.2 |
| | Panel 2 | 80 | 66.62 | 2.85 | 4.3 | 0.00 | 0.0 | 1.12 | 1.7 | 3.06 | 4.6 |
| | Panel 3 | 80 | 142.84 | 7.48 | 5.2 | 2.07 | 1.4 | 3.51 | 2.5 | 8.51 | 6.0 |
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To cover the assay range, an additional seven patient samples were analyzed later in duplicate in 4 runs for 5 days (n=40 for each sample) on one of each of the instrument platforms. The results are summarized in the table below:
Imprecision of the Architect Anti-CCP Assay on Architect $i$ analyzers
| | | | | Within-Run | | Between-Run | | Between-Day | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Instrument No. | Sample | N | Mean (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| ARCHITECT i1000SR (2) | Additional Sample 1 | 40 | 2.4 | 0.06 | 2.6 | 0.00 | 0.0 | 0.02 | 0.8 | 0.07 | 2.8 |
| | Additional Sample 2 | 40 | 2.2 | 0.09 | 4.0 | 0.01 | 0.4 | 0.00 | 0.0 | 0.09 | 4.0 |
| | Additional Sample 3 | 40 | 4.2 | 0.07 | 1.7 | 0.06 | 1.3 | 0.05 | 1.3 | 0.10 | 2.5 |
| | Additional Sample 4 | 40 | 4.6 | 0.10 | 2.1 | 0.06 | 1.3 | 0.00 | 0.0 | 0.11 | 2.5 |
| | Additional Sample 5 | 40 | 4.5 | 0.09 | 1.9 | 0.08 | 1.8 | 0.00 | 0.0 | 0.12 | 2.6 |
| | Additional Sample 6 | 40 | 164.5 | 4.55 | 2.8 | 1.90 | 1.2 | 1.53 | 0.9 | 5.16 | 3.1 |
| ARCHITECT i2000SR (2) | Additional Sample 1 | 40 | 2.4 | 0.058 | 2.4 | 0.02 | 0.7 | 0.01 | 0.2 | 0.06 | 2.5 |
| | Additional Sample 2 | 40 | 2.2 | 0.062 | 2.8 | 0.05 | 2.2 | 0.00 | 0.0 | 0.08 | 3.5 |
| | Additional Sample 3 | 40 | 4.1 | 0.048 | 1.2 | 0.00 | 0.0 | 0.05 | 1.3 | 0.07 | 1.7 |
| | Additional Sample 4 | 40 | 4.5 | 0.13 | 2.8 | 0.05 | 1.1 | 0.00 | 0.0 | 0.14 | 3.0 |
| | Additional Sample 5 | 40 | 4.5 | 0.07 | 1.6 | 0.08 | 1.7 | 0.10 | 2.2 | 0.14 | 3.2 |
| | Additional Sample 6 | 40 | 153.6 | 4.77 | 3.1 | 1.91 | 1.2 | 0.00 | 0.0 | 5.14 | 3.3 |
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| | | | | Within-Run | | Between-Run | | Between-Day | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Instrument No. | Sample | N | Mean (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| | Additional Sample 7 | 40 | 185.1 | 6.46 | 3.5 | 3.76 | 2.0 | 2.75 | 1.5 | 7.96 | 4.3 |
| ARCHITECT i1000SR (3) | Additional Sample 1 | 40 | 2.6 | 0.06 | 2.5 | 0.01 | 0.4 | 0.08 | 3.0 | 0.10 | 3.9 |
| | Additional Sample 2 | 40 | 2.3 | 0.06 | 2.5 | 0.00 | 0.0 | 0.05 | 2.1 | 0.08 | 3.3 |
| | Additional Sample 3 | 40 | 4.3 | 0.11 | 2.4 | 0.00 | 0.0 | 0.13 | 2.9 | 0.16 | 3.8 |
| | Additional Sample 4 | 40 | 4.7 | 0.10 | 2.2 | 0.05 | 1.1 | 0.10 | 2.2 | 0.15 | 3.3 |
| | Additional Sample 5 | 40 | 4.6 | 0.09 | 1.9 | 0.03 | 0.6 | 0.08 | 1.7 | 0.12 | 2.6 |
| | Additional Sample 6 | 40 | 163.3 | 6.13 | 3.8 | 0.00 | 0.0 | 0.00 | 0.0 | 6.13 | 3.8 |
| | Additional Sample 7 | 40 | 192.9 | 6.79 | 3.5 | 2.91 | 1.5 | 0.00 | 0.0 | 7.39 | 3.8 |
# b. Linearity/assay reportable range:
# Linearity:
The linearity of the Architect Anti-CCP assay was assessed with four samples on all three instruments. Samples were serially diluted to cover the assay measuring range. Data were analyzed in accordance with CLSI EP6-A. The ARCHITECT Anti-CCP assay linear range was determined as $0.1\mathrm{U / mL}$ to $246.5\mathrm{U / mL}$ . The data is summarized in the table below:
| Instrument | Test Range (U/ml) | Slope (95% CI) | Y-intercept (95% CI) | R2 | %CV Range |
| --- | --- | --- | --- | --- | --- |
| i2000 | 0.1 - 6.7 | 0.95 (0.91 to 1.00) | 0.31 (0.14 to 0.47) | 0.9966 | 1.2 to 2.7 |
| | 0.0 - 48.7 | 0.99 (0.98 to 1.01) | 0.52 (0.09 to 0.95) | 0.9996 | 1.4 to 3.4 |
| | 0.0 - 98.5 | 0.98 (0.95 to 1.01) | 0.20 (-1.34 to 1.74) | 0.9987 | 1.2 to 3.8 |
| | 0.1 - 244.4 | 0.91 (0.88 to 0.95) | -1.9 (-6.9 to 3.1) | 0.9982 | 0.8 to 3.9 |
| i2000SR | 0.1 - 6.5 | 0.96 (0.93 to 1.00) | 0.25 (0.10 to 0.39) | 0.9973 | 1.3 to 3.9 |
| | 0.0 - 48.5 | 1.00 (0.99 to 1.02) | 0.34 (-0.10 to 0.78) | 0.9996 | 0.7 to 3.4 |
| | 0.1 - 94.6 | 1.00 (0.99 to 1.01) | 0.41 (-0.22 to 1.04) | 0.9998 | 1.0 to 4.3 |
| | 0.1 - 257.4 | 0.98 (0.95 to 1.01) | -1.85 (-6.19 to 2.48) | 0.9985 | 1.8 to 3.2 |
| i1000SR | 0.2 - 7.1 | 0.99 (0.93 to 1.04) | 0.34 (0.12 to 0.56) | 0.9952 | 0.3 to 2.7 |
| | 0.2 - 47.5 | 1.01 (0.99 to 1.02) | 0.27 (-0.17 to 0.72) | 0.9996 | 1.7 to 4.0 |
| | 0.0 - 94.6 | 1.00 (0.98 to 1.02) | -0.22 (-1.20 to 0.76) | 0.9995 | 1.9 to 4.6 |
| | 0.2 - 272.3 | 0.97 (0.94 to 1.01) | -0.97 (-6.62 to 4.67) | 0.9977 | 2.3 to 8.8 |
The assay measurement (reportable) range is $0.5\mathrm{U / ml}$ to $200.0\mathrm{U / mL}$ .
# ORDAC (Over Range Detection and Correction):
The automatic auto-dilution protocol for samples $>50~\mathrm{U / mL}$ was assessed using twelve anti-CCP serum samples with 4 samples for each assay range (50 to $150~\mathrm{U / mL}$ , 160 to $200~\mathrm{U / mL}$ , and 200 to $1200~\mathrm{U / mL}$ ). Samples were tested neat, auto-diluted and manually diluted (1:10 with negative control) in the
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ARCHITECT Anti-CCP assay in replicates of 5. The auto-dilution is a 1:6 dilution of the sample performed onboard the ARCHITECT instrument using ARCHITECT wash buffer. For samples >50.0 U/mL (range 58.7 to 785.0 U/mL), the autodiluted samples had a mean difference of ±10% when compared to the expected value calculated from the manual dilution. The overall mean % difference was calculated for all samples as detailed in the table below:
| Range | Sample | Heat mean | Auto dilution mean | Autodilute *6 | Manual dilution mean | Manual *10 | % Diff for Manual vs Heat | % Diff for Auto vs Heat | % Diff for Auto vs Manual |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 200 - 1200 | 1 | 305.8* | 76.1 | 456.4 | 45.3 | 453.0 | N/A | N/A | 0.7 |
| | 2 | 485.9* | 84.0 | 504.1 | 48.3 | 482.7 | N/A | N/A | 4.4 |
| | 3 | 1477.6* | 132.8 | 796.8 | 74.4 | 743.8 | N/A | N/A | 7.1 |
| | 4 | 245.8* | 122.4 | 734.6 | 78.5 | 785.0 | N/A | N/A | -6.4 |
| 160 - 200 | 5 | 169.2 | 36.7 | 220.2 | 21.0 | 209.9 | 24.1 | 30.1 | 4.9 |
| | 6 | 170.7 | 32.0 | 192.0 | 18.8 | 187.9 | 10.1 | 12.5 | 2.2 |
| | 7 | 187.8 | 35.7 | 213.9 | 20.7 | 207.0 | 10.2 | 13.9 | 3.3 |
| | 8 | 169.7 | 32.8 | 196.8 | 19.5 | 194.6 | 14.7 | 15.9 | 1.1 |
| 50 - 150 | 9 | 58.7 | 10.9 | 65.3 | 6.1 | 61.4 | 4.5 | 11.1 | 6.3 |
| | 10 | 62.0 | 11.7 | 70.1 | 6.9 | 69.2 | 11.6 | 13.1 | 1.3 |
| | 11 | 61.4 | 12.0 | 72.0 | 6.9 | 69.0 | 12.3 | 17.3 | 4.4 |
| | 12 | 132.8 | 27.9 | 167.2 | 16.5 | 165.2 | 24.4 | 25.9 | 1.2 |
Overall % Difference: 14.0 17.5 2.6
c. Traceability, Stability, Expected values (controls, calibrators, or methods):
There is no recognized standards for anti-CCP. Values for calibrators and controls are arbitrary assigned.
Calibrators: the stability performance of the ARCHITECT Anti-CCP Calibrators was established in k063347.
Unopened calibrators can be stored at 2 – 8°C for up to 27 months.
In-use/open calibrators can be stored at 2 – 8°C for up to 27 months.
Controls: the stability performance of the ARCHITECT Anti-CCP Controls was established in k063347.
Unopened control vials can be stored at 2 – 8°C for up to 27 months.
In-use/open control vials can be stored at 2 – 8°C for up to 27 months.
Reagents storage conditions:
Unopened reagents can be stored at 2 – 8°C for up to 14 months.
Open reagents can be stored, if returning to 2 – 8°C between time points, for up to 14 months.
Onboard the ARCHITECT i instrument reagents can be stored for a maximum of 30 days.
The calibration curve is valid for 30 days.
The recommended minimum quality control requirement for the ARCHITECT Anti-CCP assay is that a single sample of each control be tested every 24 hours, each day of use.
Sample storage conditions:
The sponsor presented a study supporting the storage of specimens for up to 7 days at 2 – 8°C or 22 hours at 30°C after the date of collection. For longer storage, the recommended storage temperature is -20°C or colder.
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d. Detection limit:
The limit of blank (LoB) and limit of detection (LoD) was determined in accordance with CLSI document EP17-A. To determine the Limit of Blank (LoB), Calibrator A $(0.0\mathrm{U / mL})$ was used. The mean concentration $(\mathrm{U / mL})$ result and standard deviation (SD) for 60 replicates of Calibrator A were calculated. To determine Limit of Detection (LoD)/Limit of Quantitation (LoQ) one lot of ARCHITECT Anti-CCP Reagents, Calibrators and kit Controls were run in duplicate followed by 5 low level anti-CCP negative samples in replicates of 4, on 5 individual days. The results are summarized in the table below:
LoB/LoD/LoQ Data Summary:
| | i2000 Instrument/ reagent lot combination | i2000SR Instrument/ reagent lot combination | i1000SR Instrument 1 | i1000SR Instrument 2 |
| --- | --- | --- | --- | --- |
| Limit of Blank (U/mL) | 0.02 | 0.01 | 0.01 | 0.01 |
| Limit of Detection (U/mL) | 0.09 | 0.11 | 0.03 | 0.02 |
| Limit of Quantitation (U/mL) | 0.09 | 0.11 | 0.03 | 0.02 |
The ARCHITECT Anti-CCP assay was designed to have a limit of detection of $\leq 0.5\mathrm{U / mL}$ . The values for LoB (0.02 U/mL) and LoD (0.11 U/mL) have been quoted in the ARCHITECT Anti-CCP Reagent insert as representative data.
d. Hook effect:
A study was performed on one each of i2000, i2000SR and i1000SR instruments to assess high dose hook effect. No high dose hook effect was observed for any of the three instruments when a sample containing approximately $2000\mathrm{U / mL}$ of anti-CCP antibody was assayed.
e. Analytical specificity:
Interference of endogenous compounds: A study was done in accordance with CLSI document EP7-A2. Five serum specimens with anti-CCP levels across the assay range (0.5 to $200.0\mathrm{U / mL}$ ) were supplemented with the potentially interfering compounds at several concentrations. There was no interference observed at the following concentrations:
| Potential Interfering Substance | Concentration |
| --- | --- |
| Bilirubin | 20 mg/dL |
| Hemoglobin | 800 mg/dL |
| Total Protein | 12 g/dL |
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| Triglyceride | 3000 mg/dL |
| --- | --- |
| Rheumatoid factor | 200 IU/mL |
| Red Blood Cells | 0.4% |
Cross reactivity: A study was performed according to CLSI Document EP7-A2. Samples were spiked with different concentrations of the interferent autoantibodies. An anti-CCP negative serum samples was used as a negative control sample. The results are summarized in the following table:
| Sample | Interferent Autoantibodies | Concentration of autoantibodies tested (U/mL) | % Difference from control |
| --- | --- | --- | --- |
| 1 | Sm/RNP | 9.07 | 0.8 |
| 2 | Sm/RNP | 9.51 | -0.3 |
| 3 | SCL-70 | 6.38 | 6.3 |
| 4 | SCL-70 | 5.37 | 8.0 |
| 5 | TPO | 2.13 | 9.3 |
| 6 | TPO | 5.26 | 3.8 |
| 7 | ANA | 3.87 | 5.5 |
| 8 | ANA | 2.97 | 3.0 |
| 9 | Jo-1 | 2.72 | 3.7 |
| 10 | Jo-1 | 2.22 | 3.0 |
| 11 | ds-DNA | 42.8 | 6.0 |
| 12 | ds-DNA | 53 | -0.9 |
| 13 | ds-DNA | >200 | 5.8 |
| 14 | Jo-1 | 82.5 | 4.4 |
| 15 | Jo-1 | 93 | -5.4 |
| 16 | Ribosomal P | 48 | 2.5 |
| 17 | SCL-70 | 110 | 3.7 |
| 18 | Sm/RNP | >100 | -1.2 |
| 19 | Sm/RNP | RNP 2.5 OD @ 1:100 High positive Sm | 9.2 |
| 20 | SSa/SSb/AMA | SSA 87
SSB 30
AMA 40 | 2.9 |
e. Assay cut-off:
A $5.0\mathrm{U / mL}$ cut-off was selected to maintain consistency with the other Anti-CCP assays including the predicate for the ARCHITECT Anti-CCP.
Result of $\geq 5.0\mathrm{U / ml}$ is considered positive and a result of $< 5.0~\mathrm{U / ml}$ is considered negative.
2. Comparison studies:
a. Method comparison with predicate device was performed according to CLSI EP9-2A. Results are shown in the table below:
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| Analyzers | Range (U/mL) | n | Slope (95% CI) | Intercept (95% CI) | r (95% CI) |
| --- | --- | --- | --- | --- | --- |
| i2000SR vs. AxSYM | 0.5 to 1200 | 370 | 1.10 (1.06 to 1.13) | -2.03 (-3.84 to -1.07) | 0.95 (0.93 to 0.96) |
| | 0.5 to 200 | 234 | 0.93 (0.90 to 0.96) | -0.19 (-0.45 to 0.30) | 0.94 (0.93 to 0.95) |
| i2000 vs. i2000SR | 0.5 to 200 | 62 | 0.978 (0.96 to 1.00) | 0.130 (-0.05 to 0.27) | 0.99 (0.98 to 0.99) |
| i1000SR vs. i2000SR | 0.5 to 1200 | 96 | 0.99 (0.98 to 1.02) | 0.01 (-0.18 to 0.12) | 1.00 |
Using a cut-off of 5.0 U/mL for the ARCHITECT Anti-CCP assay, the concordance results between ARCHITECT and AxSYM are summarized in the following tables:
| All Specimens (n = 995) | AxSYM Anti-CCP Result | | |
| --- | --- | --- | --- |
| | | POS | NEG |
| ARCHITECT i2000SR | POS | 356 | 3 |
| Anti-CCP Result | NEG | 4 | 632 |
| % Positive agreement | | 98.9% | |
| % Negative agreement | | 99.5% | |
| % Total Agreement | | 99.3% | |
A Receiver Operator Characteristic (ROC) analysis was performed between the ARCHITECT Anti-CCP and AxSYM Anti-CCP assays using the 995 specimens. The area under the curve (AUC) for the ARCHITECT Anti-CCP assay was 0.873 (95% Confidence Interval: 0.849-0.897) and 0.872 (95% Confidence Interval: 0.848-0.896) for the AxSYM Anti-CCP assay.
b. Matrix comparison:
Study was performed on i2000, i2000SR and i1000SR instruments. The aim was to determine the type of anticoagulant collection tubes that can be used with the ARCHITECT Anti-CCP assay. 18 matched serum/plasma negative samples were spiked with different concentrations of anti-CCP positive sample (concentration approximately 4340 U/mL): 5 U/mL, 5 - 10 U/mL, and 10 - 200 U/mL. Samples were tested in replicates of five. The percent difference of anti-CCP concentration from the same samples obtained in the control collection tube (Serum) versus the other collection tube types tested (plastic serum separator (SST), plastic K2EDTA plasma, and plastic Lithium Heparin plasma separator) met the sponsor's design claim criteria:
{10}
- ±15% for samples with anti-CCP concentrations > 10.0 U/mL (i.e. above 2x the diagnostic cut-off)
- ±10% for samples with anti-CCP concentrations > 5.0 U/mL and < 10.0 U/mL (i.e. 1x to 2x the diagnostic cut-off)
- ±0.5 U/mL samples with anti-CCP concentrations < 5.0 U/mL (i.e. below 1x the diagnostic cut-off).
The ARCHITECT Anti-CCP assay is therefore able to test specimens collected in the following blood collection tubes: serum, serum separator (SST), K2EDTA plasma, and Lithium Heparin plasma separator.
## 3. Clinical studies:
a. Clinical Sensitivity:
The clinical sensitivity was determined for confirmed RA individuals (n=496). Using a cut-off of 5.0 U/mL, the % clinical sensitivity was calculated to be 70.6% as indicated below:
| Specimen Category | Total (n) | Anti-CCP Positive (n) | % Sensitivity (95% CI) |
| --- | --- | --- | --- |
| Confirmed RA | 496 | 350 | 70.6 (66.3%-77.4%) |
The clinical sensitivity is comparable to that of the predicate device, AxSYM Anti-CCP which is 70.8% (95% CI 66.5%-74.7%)
b. Clinical specificity:
The clinical specificity was determined for 499 non-RA specimens (299 from patients with other rheumatic and non-rheumatic disorders and 200 asymptomatic apparently healthy individuals). The other non-RA diseases tested were ankylosing spondylitis, autoimmune thyroiditis/Hashimoto's disease, Crohn's disease, dermatomyositis, Epstein Barr Virus (EBV), Lyme disease, osteoarthritis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, reactive arthritis/Reiter's syndrome, scleroderma, Sjogrens syndrome, systemic lupus erythematosus (SLE) and ulcerative colitis. Using a 5.0 U/mL cut-off, the ARCHITECT Anti-CCP % clinical specificity calculations for total non-RA, non-RA asymptomatic, and non-RA other disease specimens is summarized in the table below:
| Specimen Category | Total (n) | Anti-CCP Positive (n) | % Specificity |
| --- | --- | --- | --- |
| Non-RA (Normals) | 200 | 1 | 99.5 |
| Non-RA other diseases | 299 | 8 | 97.3 |
| Total Non-RA | 499 | 9 | 98.2 |
c. Other clinical supportive data (when a. and b. are not applicable):
{11}
12
Not applicable
4. Clinical cut-off:
Not applicable.
5. Expected values/Reference range:
Reference interval was established by testing 199 asymptomatic apparently healthy males (n=126) and females (n=73), 19 to 67 years old. Specimen values ranged from < 0.5 U/mL to 2.5 U/mL. No differences attributed to gender or age was observed.
N. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.
O. Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
