K Number

Device Name

IMMULITE 2000 ANTI-CCP IGG ASSAY

Manufacturer

Siemens Healthcare Diagnostics Inc.

Date Cleared

2013-04-04

(309 days)

Product Code

NHX JIT

Regulation Number

866.5775

Intended Use

The IMMULITE 2000 Anti-CCP IgG assay is an in vitro diagnostic immunoassay for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum (including Serum Separator Tubes) or plasma (EDTA or lithium heparin) on the IMMULITE 2000 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. The IMMULITE 2000 Anti-CCP IgG Calibration Verification Material (CVM) is for in vitro diagnostic use, as a control for calibration verification of the IMMULITE 2000 Anti-CCP IgG assay on the IMMULITE 2000 system.

Device Description

The IMMULITE 2000 Anti-CCP IgG assay consists of the following components: - Anti-CCP IgG bead pack coated with cyclic citrullinated peptide . (CCP) antigen - Anti-CCP IgG reagent wedge containing bovine calf intestine . conjugated to a monoclonal murine anti-human IgG antibody - Anti-CCP IgG adjustors, low and high, containing lyophilized . human serum with IgG reactive to CCP - Anti-CCP IgG controls, negative and positive, containing human . serum - . Autoantibody sample diluent containing protein/buffer matrix The IMMULITE Anti-CCP IgG Calibration Verification Material consists of one set of four vials, containing low, intermediate and high levels of lyophilized human serum with IgG reactive to cyclic citrullinated peptide (CCP), in buffer with preservative, plus an anti-CCP-free sample.

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Device Name

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Class Advise Committee

SSP Indicator

Third Party Reviewed

Expedited Review

Predicate Devices

K023285, K091601

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a standard in vitro diagnostic immunoassay and does not mention any AI or ML components in the device description, intended use, or performance studies.

Therapeutic

No
The device is an in vitro diagnostic immunoassay used to aid in the diagnosis of Rheumatoid Arthritis by detecting anti-CCP antibodies. It provides diagnostic information rather than directly treating or preventing disease.

Diagnostic

Yes

The device is explicitly stated as an "in vitro diagnostic immunoassay" in the "Intended Use / Indications for Use" section, and its purpose is to aid in the diagnosis of Rheumatoid Arthritis.

SaMD (Software as a Medical Device)

The device description clearly lists physical components such as bead packs, reagent wedges, adjustors, and controls, indicating it is a hardware-based in vitro diagnostic assay system, not software-only.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The "Intended Use / Indications for Use" section explicitly states that the assay is an "in vitro diagnostic immunoassay" and the Calibration Verification Material is "for in vitro diagnostic use".
Purpose: The assay is designed to determine the presence of specific autoantibodies in human serum or plasma, which is a biological sample taken from the body. This analysis is performed in vitro (outside the body).
Clinical Application: The results are used as an "aid in the diagnosis of Rheumatoid Arthritis (RA)", indicating a clinical purpose for the test.
Device Description: The components described are typical of an immunoassay kit used for laboratory testing of biological samples.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The IMMULITE 2000 Anti-CCP IgG assay is an in vitro diagnostic immunoassay for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum (including Serum Separator Tubes) or plasma (EDTA or lithium heparin) on the IMMULITE® 2000 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 multicriteria diagnostic process, encompassing both clinical and laboratory-based assessments.

The IMMULITE 2000 Anti-CCP IgG Calibration Verification Material (CVM) is for in vitro diagnostic use, as a control for calibration verification of the IMMULITE 2000 Anti-CCP IgG assay on the IMMULITE 2000 system.

Product codes (comma separated list FDA assigned to the subject device)

NHX, JIT, JJX

Device Description

The IMMULITE 2000 Anti-CCP IgG assay consists of the following components:

Anti-CCP IgG bead pack coated with cyclic citrullinated peptide (CCP) antigen
Anti-CCP IgG reagent wedge containing bovine calf intestine conjugated to a monoclonal murine anti-human IgG antibody
Anti-CCP IgG adjustors, low and high, containing lyophilized human serum with IgG reactive to CCP
Anti-CCP IgG controls, negative and positive, containing human serum
Autoantibody sample diluent containing protein/buffer matrix

The IMMULITE Anti-CCP IgG Calibration Verification Material consists of one set of four vials, containing low, intermediate and high levels of lyophilized human serum with IgG reactive to cyclic citrullinated peptide (CCP), in buffer with preservative, plus an anti-CCP-free sample. Source materials derived from human blood were tested and found nonreactive for syphilis; for antibodies to HIV 1 and 2; for hepatitis B surface antigen; and for antibodies to hepatitis C.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

A total of 388 samples consisting of 212 apparently healthy samples, 106 RA positive samples, 70 anti-CCP positive samples, as determined by a 3rd party method, were tested with IMMULITE 2000 Anti-CCP Kit and the DIASTAT Anti-CCP ELISA. The cutoff of the IMMULITE® 2000 Anti-CCP IgG assay was determined with positive and negative patient samples by a ROC analysis, with a balanced consideration of sensitivity and specificity.

Method Comparison: For reagent lot 1, 255 unaltered patient serum samples were tested, 229 of which were determined to be reactive and 26 nonreactive using the DIASTATTM assay. For reagent lot 2, 256 unaltered patient serum samples were tested, 230 of which were determined to be reactive and 26 nonreactive using the DIASTAT™ assay.

Clinical Performance Study: A total of 1512 patient serum samples were collected for the study. 1048 samples were rheumatoid arthritis (RA) positive and the remaining 464 samples were from not-RA patients with potentially cross-reactive diseases. RA positive patients were classified according to the ACR criteria.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Precision/Reproducibility:
Precision was evaluated using a protocol based on CLSI document EP05-A2. Eleven samples were tested over a period of 20 days, using 2 IMMULITE® 2000 instruments with 2 reagent lots each, 2 runs per day and 2 replicates per sample (Total N=320 per sample type).
Reproducibility was evaluated using two different reagent lots at three external testing sites, using serum donor panels from the precision study. The protocol was run over 10 days, 2 runs per day, with 4 replicates per run for the sample pools and control material. (Total N=240-246 per sample per lot tested)
Results are presented in tables showing Mean U/mL, SD, and %CV for various factors (Between Lot, Between Day, Between Run, Within Run, Total for precision; Within Run, Between Run, Between Day, Between Site, Total Within-Device, Total Within-Lot for reproducibility).

Linearity/assay Reportable Range:
Performed according to CLSI document EP6-A. A dilution series was prepared by combining a reactive serum pool and a non-reactive serum pool in different ratios to produce 11 dilutions covering the assay measuring range (1.50 U/mL to 200 U/mL). The dilutions were run in triplicate on one IMMULITE® 2000 instrument. Results showed % recovery relative to linear fitted dose.

Detection Limit:
Limit of Blank (LoB): An Anti-CCP nonreactive donor sample was used and analyzed on three IMMULITE® 2000 instruments over 5 days, tested twice daily using two lots of reagent with two replicates per run. LoB was determined to be 0.26 U/mL.
Limit of Detection (LoD): Five Anti-CCP serum samples were assayed in replicates of 6 using 2 reagent kit lots run for 5 days with 2 runs per day. Two instruments and 2 operators generated 960 observations. LoD was determined to be 1.46 U/mL.

Analytical Specificity:
A study was conducted to assess the effect of several endogenous interferents (human serum albumin, triglycerides, hemoglobin, bilirubin (conjugated and unconjugated), and rheumatoid factor). One control sample and five different sample pools with differing Anti-CCP concentrations (range 2.0 U/mL to 205 U/mL) were used. Each potentially interfering substance was spiked separately into the sample pools. Less than 10% mean interference was found with all endogenous interfering substances at specified concentrations.

Method Comparison with predicate device:
The IMMULITE® 2000 Anti-CCP IgG assay was compared to the predicate Axis-Shield DIASTAT™ Anti-CCP assay using two lots of reagents. Each sample was tested in singlicate using 3 IMMULITE® 2000 instruments.
Reagent lot 1: 255 unaltered patient serum samples. Percent Positive Agreement 86.9%, Percent Negative Agreement 46.2%, Total Agreement 82.2%.
Reagent lot 2: 256 unaltered patient serum samples. Percent Positive Agreement 86.1%, Percent Negative Agreement 42.3%, Total Agreement 81.6%.

Matrix Comparison:
Thirty-nine matched serum and plasma samples were collected in scrum clot tube, Lithium Heparin plasma tube, serum separator tube (SST), and EDTA plasma tube. Data was analyzed using Deming regression plots. Correlation coefficients were 1.000 for Lithium Heparin, SST Serum, and EDTA Plasma compared to Serum, with slopes close to 1 and small intercepts.

Clinical Sensitivity and Specificity:
The assay was performed on the IMMULITE® 2000 using 1512 patient serum samples (1048 RA positive, 464 non-RA with potentially cross-reactive diseases).
Sensitivity: 63.6%
Specificity: 97.0%

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Method Comparison (IMMULITE 2000 Anti-CCP IgG vs DIASTAT):
Reagent lot 1: Percent Positive Agreement = 86.9%, Percent Negative Agreement = 46.2%, Total Agreement = 82.2%
Reagent lot 2: Percent Positive Agreement = 86.1%, Percent Negative Agreement = 42.3%, Total Agreement = 81.6%

Clinical Performance Study:
Sensitivity = 63.6%
Specificity = 97.0%

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

K023285, K091601

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 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).

Summary

IMMULITE® 2000 Anti-CCP IgG Assay

APR 0 4 2013

510(k) Summary as Required by 21 CFR 807.92

A. 510(k) Number	K121576
B. Purpose for Submission	New device
C. Measurand	Anti-cyclic citrullinated peptide (CCP) antibodies
D. Type of test	Semi-quantitative chemiluminescent immunometric assay
E. Applicant:	Siemens Healthcare Diagnostics Inc.
511 Benedict Avenue
Tarrytown, NY 10591
F. Proprietary and Established
Names:	IMMULITE® 2000 Anti-CCP IgG Assay
G. Regulatory
Information:

Regulation 21 CFR 866.5775 1

section:

Classification: Class II

1. Products Codes: NHX - Antibodies, Anti-Cyclic Citrullinated Peptide (CCP) JIT- Calibrators JJX – Single Analyte Control

Panel: Immunology (82)

The IMMULITE 2000 Anti-CCP IgG assay is an in vitro diagnostic H. Intended Use: immunoassay for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum (including Serum Separator Tubes) or plasma (EDTA or lithium heparin) on the IMMULITE® 2000 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 multicriteria diagnostic process, encompassing both clinical and laboratorybased assessments.
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I. Device Description: The IMMULITE 2000 Anti-CCP IgG assay consists of the following components:

Anti-CCP IgG bead pack coated with cyclic citrullinated peptide . (CCP) antigen
Anti-CCP IgG reagent wedge containing bovine calf intestine . conjugated to a monoclonal murine anti-human IgG antibody
Anti-CCP IgG adjustors, low and high, containing lyophilized . human serum with IgG reactive to CCP
Anti-CCP IgG controls, negative and positive, containing human . serum
. Autoantibody sample diluent containing protein/buffer matrix

Predicate device name: DIASTATTM Anti-Cyclic Citrullinated Peptide (anti-CCP) ELISA

510(k) number: K023285

Comparison with predicate:

A comparison of the device features, intended use, laboratory data and other information demonstrates that the IMMULITE ® 2000 Anti-CCP IgG assay is substantially equivalent to the predicate device, DIASTATTM Anti-Cyclic Citrullinated Peptide (anti-CCP) ELISA, as summarized in the following tables.

J. Substantial Equivalence Information:

	SIMILARITIES
Item	Device	Predicate
	IMMULITE 2000 Anti-CCP IgG
Assay	DIASTATT™ Anti-Cyclic
Citrullinated Peptide (anti-CCP)
ELISA
Intended Use	The IMMULITE® 2000 Anti-CCP
IgG assay is an in vitro diagnostic
immunoassay for the semi-
quantitative determination of the
IgG class of autoantibodies
specific to cyclic citrullinated
peptide (CCP) in human serum or
plasma on the IMMULITE®2000
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.	The DIASTATT™ Anti-CCP test is a
semi-quantitative/qualitative
enzyme-linked immunosorbent assay
(ELISA) for the detection of the IgG
class of autoantibodies specific to
cyclic citrullinated peptide (CCP) in
human serum or plasma. The test is
intended to aid in the diagnosis of
Rheumatoid Arthritis (RA) and is not
definitive in isolation.
Autoantibody levels represent one
parameter in a multi-criterion
diagnostic process, encompassing
both clinical and laboratory-based
assessments.
Antigen Used
on the Solid
Phase	Synthetic cyclic citrullinated
peptide, second generation	Same
Detecting
Antibody	Murine monoclonal antibody
conjugated to Alkaline
Phosphatase	Same
Controls	Negative and positive kit controls	Same
Interference	Rheumatoid factor (up to 200
IU/mL does not interfere with anti-
CCP antibody results.	Same
DIFFERENCES
Item	Device	Predicate
	IMMULITE® 2000 Anti-CCP
IgG Assay	DIASTATT™ Anti-Cyclic
Citrullinated Peptide (anti-CCP)
ELISA
Assay format	Solid-phase, two-cycle sequential
chemiluminescent immunometric
assay	Enzyme-linked immunosorbent
assay (ELISA)
Substrate	Chemiluminescent	Mg2+, phenolphthalein
monophosphate (PMP)
Sample size	5 µL
(20 µL of the prediluted sample)	10 µL
(100 µL of the prediluted sample)
Sample
Dilution	1:40	1:100
Sample Types	Serum or plasma (EDTA, lithium
heparin)	Serum or plasma (EDTA, lithium
heparin, sodium citrate)
Incubation	30 minutes, 30 minutes, 5 minutes	60 minutes, 30 minutes, 30 minutes
LoD	1.50 U/mL	0.05 U/mL
Expected
Values
(apparently
healthy
donors)	Median: 5 U/mL = Positive
Interference	Bilirubin (up to 0.2 mg/L),
hemoglobin (up to 500 mg/dL),
and triglycerides (up to 1.5 g/dL)
do not interfere with anti-CCP
antibody results.
Total protein not assessed.	Bilirubin (up to 0.2 mg/L),
hemoglobin (up to 400 mg/dL), and
intralipid (up to 15 mg/mL) do not
interfere with anti-CCP antibody
results.
Total Protein up to 120 mg/mL does
not interfere with anti-CCP antibody
results.

K. Standard/Guidance Documents Referenced:

CLSI EP5-A2	Evaluation of Precision Performance of Quantitative Measurement Methods
CLSI EP6-A	Evaluation of the Linearity of Quantitative Measurement
CLSI EP17-A	Protocols for Determination of Limits of Detection and Limits of Quantitation
CEN 13640	Stability Testing of In Vitro Diagnostic Reagents

L. Test Principle:

The IMMULITE® 2000 Anti-CCP IgG assay is a solid phase, two-cycle sequential chemiluminescent immunometric assay. In the first cycle, the patient sample and the buffer are incubated together with the coated bead for 30 minutes. During this time, human IgG in the sample binds to CCP on the bead. Unbound sample is then removed by centrifugal washes. In the second cycle, the enzyme conjugated monoclonal murine antihuman IgG is added to the original reaction tube for additional 30 minutes incubation. The enzyme conjugated monoclonal wurine anti-human IgG antibody binds to immobilized anti-CCP IgG on the bead. The unbound enzyme conjugate is removed by centrifugal washes. Finally, chemiluminescent substrate is added to the reaction tube containing the bead and the signal is generated in proportion to the bound enzyme.

M. Performance Characteristics

1. Analytical Performance:
  a. Precision/Reproducibility:

Precision was evaluated using a protocol based on CLSI document EP05-A2, Evaluation of Precision Performance of Quantitative Measurement Methods. Eleven samples were tested over a period of 20 days, using 2 IMMULITE® 2000 instruments with 2 reagent lots each, 2 runs per day and 2 replicates per sample. The work list consisted of autisth control and 2 sets of six-member precision panels: one serum donor panel and one lithium heparin plasma donor panel. Precision panels were prepared by pooling the samples and spiking to the desired concentration with a stock Anti-CCP reactive sample. The sample concentrations are detailed in the table below:

Sample	Target Concentration (U/mL)
LPIC2.101 Positive control	46.0
SERP2 serum donor panel	2.96
SERP3 serum donor panel	4.8
SERP4 serum donor panel	9.0
SERP5 serum donor panel	37.4
SERP6 serum donor panel	135.5
PLASP2 Li Heparin donor panel	2.59
PLASP3 Li Heparin donor panel	4.9
PLASP4 Li Heparin donor panel	9.0
PLASP5 Li Heparin donor panel	37.4

Sample	Target Concentration (U/mL)
PLASP6 Li Heparin donor panel	135.5

Precision data is summarized in the table below:

| 20-Day
Imprecision

N=320		Between Lot		Between Day		Between Run		Within Run		Total
Sample	Mean
U/mL	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
LPIC2	47.4	0.18	0.4	0.00	0.0	0.90	1.9	1.84	3.9	2.05	4.3
SERP2	2.1	0.20	9.3	0.15	6.9	0.15	6.8	0.20	9.4	0.29	13.6
SERP3	4.3	0.08	1.8	0.13	3.1	0.17	3.9	0.28	6.5	0.35	8.2
SERP4	8.5	0.00	0.0	0.18	2.1	0.24	2.9	0.34	4.0	0.46	5.4
SERP5	37.6	0.66	1.8	0.96	2.6	1.12	3.0	1.54	4.1	2.13	5.7
SERP6	144.0	2.29	1.6	1.25	0.9	4.17	2.9	5.45	3.8	6.98	4.8
PLASP2	2.4	0.16	6.7	0.17	6.8	0.17	7.1	0.20	8.2	0.31	12.8
PLASP3	4.5	0.18	3.8	0.17	3.6	0.20	4.5	0.29	6.4	0.39	8.6
PLASP4	8.4	0.00	0.0	0.05	0.6	0.31	3.7	0.35	4.1	0.47	5.6
PLASP5	38.5	0.11	0.3	0.54	1.4	1.04	2.7	1.57	4.0	1.96	5.0
PLASP6	141.5	1.06	0.7	2.23	1.6	3.87	2.7	5.52	3.9	7.11	5.0

Reproducibility was evaluated using two different reagent lots at three external testing sites, using serum donor panels from the precision study. The protocol was run over 10 days, 2 runs per day, with 4 replicates per run for the sample pools and control material r

The results for reproducibility, pooled across 3 sites, are presented in the table below.

| Sample ID | N | Mean
(U/mL) | Within Run | | Between Run | | Between Day | | Between Site | | Total Within-Device | | Total Within-Lot | |
|-----------------|-----|----------------|-------------|-----------|-------------|-----------|-------------|-----------|--------------|-----------|---------------------|-----------|------------------|-----------|
| | | | SD
Index | CV
(%) | SD
Index | CV
(%) | SD
Index | CV
(%) | SD
Index | CV
(%) | SD
Index | CV
(%) | SD
Index | CV
(%) |
| Reagent Lot 201 | | | | | | | | | | | | | | |
| SERP2 | 244 | 1.94 | 0.20 | 10.1 | 0.06 | 3.2 | 0.11 | 6.0 | 0.17 | 8.7 | 0.23 | 12.0 | 0.29 | 14.8 |
| SERP3 | 244 | 3.98 | 0.22 | 5.6 | 0.12 | 2.9 | 0.11 | 3.0 | 0.14 | 3.6 | 0.27 | 6.9 | 0.31 | 7.8 |
| SERP4 | 244 | 8.08 | 0.37 | 4.5 | 0.07 | 0.8 | 0.17 | 2.0 | 0.18 | 2.3 | 0.41 | 5.1 | 0.45 | 5.6 |
| SERP5 | 243 | 36.07 | 1.48 | 4.1 | 0.50 | 1.4 | 0.61 | 2.0 | 0.84 | 2.3 | 1.68 | 4.6 | 1.88 | 5.2 |
| SERP6 | 244 | 139.18 | 5.11 | 3.7 | 2.84 | 2.0 | 1.25 | 1.0 | 3.79 | 2.7 | 5.98 | 4.3 | 7.08 | 5.1 |

| Sample ID | N | Mean
(U/mL) | Within Run | | Between Run | | Between Day | | Between Site | | Total Within-Device | | Total Within-Lot | |
|-----------------|-----|----------------|------------|--------|-------------|--------|-------------|--------|--------------|--------|---------------------|--------|------------------|--------|
| | | | SD Index | CV (%) | SD Index | CV (%) | SD Index | CV (%) | SD Index | CV (%) | SD Index | CV (%) | SD Index | CV (%) |
| LPIC2 | 246 | 45.66 | 1.97 | 4.3 | 0.56 | 1.2 | 0.83 | 2.0 | 1.55 | 3.4 | 2.21 | 4.8 | 2.70 | 5.9 |
| Reagent Lot 202 | | | | | | | | | | | | | | |
| SERP2 | 228 | 1.61 | 0.19 | 11.7 | 0.04 | 2.2 | 0.13 | 8.0 | 0.16 | 10 | 0.23 | 14.4 | 0.28 | 17.6 |
| SERP3 | 240 | 3.72 | 0.25 | 6.7 | 0.09 | 2.4 | 0.21 | 6.0 | 0.15 | 4.1 | 0.34 | 9.1 | 0.37 | 10 |
| SERP4 | 240 | 8.02 | 0.41 | 5.2 | 0.22 | 2.7 | 0.16 | 2.0 | 0.27 | 3.4 | 0.50 | 6.2 | 0.56 | 7.0 |
| SERP5 | 240 | 36.79 | 1.36 | 3.7 | 0.86 | 2.3 | 0.89 | 2.0 | 1.10 | 3.0 | 1.84 | 5.0 | 2.14 | 5.8 |
| SERP6 | 240 | 139.61 | 6.27 | 4.5 | 2.46 | 1.8 | 4.81 | 3.0 | 4.81 | 3.4 | 8.28 | 5.9 | 9.58 | 6.9 |
| LPIC2 | 240 | 43.54 | 2.49 | 5.7 | 0 | 0 | 1.61 | 4.0 | 1.65 | 3.8 | 2.97 | 6.8 | 3.39 | 7.8 |

b. Linearity/assay Reportable Range: The Anti-CCP Linearity study was performed according to the CLSI document EP6-A; Evaluation of the Linearity of Quantitative Measurement Methods. A dilution series was prepared by combining a reactive serum pool and a non-reactive serum pool in different ratios to produce 11 dilutions covering the assay measuring range (1.50 U/mL to 200 U/mL). The dilutions were run in triplicate on one IMMULITE® 2000 instrument. Results are shown below. Since this assay has no reference material or method and is traceable to internal standard, the recovery is defined as the difference between the observed dose and the fitted values of the linear equation.

Dose Recovery:
Sample	Expected
Dose
(U/mL)	Mean
Observed
Dose
(U/mL)	Linear
Fitted
Dose
(U/mL)	Mean
% Recovery
P3	181.51	182.93	183.00	100.0%
P4	151.38	158.52	152.70	103.8%
P5	121.26	127.68	122.40	104.3%
P6	91.13	93.00	92.09	101.0%
P7	61.00	61.91	61.79	100.2%
P8	30.87	28.32	31.49	89.9%
P9	15.80	17.01	16.34	104.1%
P10	12.07	11.89	12.58	94.5%
P11	8.33	8.58	8.82	97.3%
P12	4.43	4.48	4.89	91.5%
P13	2.64	2.40	3.10	77.4%

c. Traceability, Stability, Expected Values (controls, calibrators, methods):

Traceability - There is no recognized standard reference material for Anti-CCP. The IMMULITE® 2000 Anti-CCP IgG assay is traceable to an internal standard and manufactured using qualified materials and measurement procedures.

Stability - Freshly opened and prepared IMMULITE® 2000 Anti-CCP IgG adjustors and controls showed 30 days open vial stability when stored at 2-8°C, or 6 months (aliquotted) when stored at -20°C. The IMMULITE® 2000 Anți-CCP IgG reagent wedge is stable at 2-8°C until the expiration date on the label.

Adjustors and Controls are prepared in house and arbitrary units are assigned during the development process. Calibrator and Control values are summarized in the tables below. The listed values are approximate values, as the values are lot specific.

Adjustor	Dose Range U/mL
Low	2.0 - 5.0
High	40 - 60

Control	Target* U/mL
Low	± 10% interference.

Hook Effect: Not applicable. The IMMULITE® 2000 Anti-CCP assay is a 2-cycle assay with sample containing anti-CCP antibodies first binding to the CCP pertide immobilized on the polystyrene capture bead. Excess unbound antibody is pephued by washing prior to the second cycle reagent incubation. During the second chive, an anti-human IgG alkaline phosphatase conjugate binds in turn to the anti-CCP antibody bound to the bead.

Assay response is positively related to the amount of anti-CCP antibody bound to the capture bead up to the point where the CCP determinants are saturated with antibody, at which point the response plateaus. Any unbound anti-CCP beyond the reportable range of the assay and in excess of saturation is removed by washing prior to contact with the reagent conjugate and there is no risk that a hook effect will be observed.

f. Assay cut-off:

A high Anti-CCP IgG positive defibrinated plasma unit was arbitrarily assigned with a value of 1000 U/mL. A lot of reference calibrators was prepared by diluting the positive unit with negative normal human serum. The reference calibrators were value-assigned by the dilution factor in relationship to the neat values of 1000 U/mL.

The cutoff of the IMMULITE® 2000 Anti-CCP IgG assay was determined with positive and negative patient samples by a ROC analysis, with a balanced consideration of sensitivity and specificity. A result greater than or equal to 4U/mL indicates that anti-CCP IgG antibodies were detected in the sample. A result of less than 4U/mL indicates that anti-CCP IgG antibodies were not detected in the sample.

2. Comparison Studies

a. Method Comparison with predicate device:

Method Comparison: The IMMULITE® 2000 Anti-CCP IgG assay was compared to the predicate Axis-Shield DIASTAT™ Anti-CCP assay using two lots of reagents. Each sample was tested in singlicate using 3 IMMULITE® 2000 instruments. For reagent lot 1, 255 unaltered patient serum samples were tested, 229 of which were determined to be reactive and 26 nonreactive using the DIASTATTM assay. For reagent lot 2, 256 unaltered patient serum samples were tested, 230 of which were determined to be reactive and 26 nonreactive using the DIASTAT™ assay. Results are shown in the tables below.

Reagent lot 1:

IMMULITE 2000 Anti-CCP IgG

| DIASTAT | Reactive | Non-Reactive | Percent Positive
Agreement | Percent Negative
Agreement |
|----------|----------|--------------|-------------------------------|-------------------------------|
| Positive | 199 | 30 | 86.9% | |
| Negative | 14 | 12 | | 46.2% |

Total Agreement: 82.2%

Reagent lot 2:

IMMULITE 2000 Anti-CCP IgG

| DIASTAT | Reactive | Non-Reactive | Percent Positive
Agreement | Percent Negative
Agreement |
|----------|----------|--------------|-------------------------------|-------------------------------|
| Positive | 198 | 32 | 86.1% | |
| Negative | 15 | 11 | | 42.3% |

Total Agreement: 81.6%

b. Matrix Comparison:

Thirty-nine matched serum and plasma samples were collected in the following anticoagulant tubes: serum clot tube, Lithium Heparin plasma tube, serum separator tube (SST), and EDTA plasma tube. Twenty-one of the 39 samples were spiked to achieve Anti-CCP levels across the assay measuring range. Data was analyzed using Deming regression plots.

| SERUM vs. | Correlation
Coefficient | Slope | Intercept | Means |
|-----------------|----------------------------|-------|-----------|------------------|
| Lithium Heparin | 1.000 | 1.020 | -0.46 | 52.9 U/mL |
| SST Serum | 1.000 | 1.020 | -0.52 | 53.0 U/mL |
| EDTA Plasma | 1.000 | 1.010 | -0.31 | 52.2 U/mL |
| | | | | Serum: 52.3 U/mL |

3. Clinical Studies:

a. Clinical Sensitivity and Specificity

Clinical Performance Study: The assay was performed on the IMMULITE® 2000 to assess the clinical sensitivity and specificity of well-characterized samples.

A total of 1512 patient serum samples were collected for the study. 1048 samples were rheumatoid arthritis (RA) positive and the remaining 464 samples were from not-RA patients with potentially cross-reactive diseases. RA positive patients were classified according to the ACR criteria.

IMMULITE 2000 Anti-CCP IgG

Clinical Status	Reactive	Non-Reactive	Sensitivity	Specificity
Positive	667	381
Negative	14	450	63.6%	97.0%

b. Other clinical supportive data (when a. and b. are not applicable): Not applicable.
1. Clinical Cut-off: Same as assay cut-off.
1. Expected Values/Reference Range:

A total of 200 serum samples from presumed healthy male and female donors were analyzed using the IMMULITE® 2000 Anti-CCP IgG assay. The results from this study suggest a median of in vitro diagnostic use, as a control for calibration
verification of the IMMULITE® 2000 Anti-CCP IgG assay on the
IMMULITE 2000 system. |
| I. Device Description: | The IMMULITE Anti-CCP IgG Calibration Verification Material
consists of one set of four vials, containing low, intermediate and high
levels of lyophilized human serum with IgG reactive to cyclic
citrullinated peptide (CCP), in buffer with preservative, plus an
anti-CCP-free sample. |
| | Source materials derived from human blood were tested and found
nonreactive for syphilis; for antibodies to HIV 1 and 2; for hepatitis B
surface antigen; and for antibodies to hepatitis C. |
| J. Substantial
Equivalence
Information: | Predicate device name: Elecsys Anti-CCP CalCheck
510(k) number: K091601 |

Comparison with predicate:

A comparison of the device features, intended use, and other information demonstrates that the IMMULITE ® 2000 Anti-CCP IgG Calibration Verification Material is substantially equivalent to the predicate device, Roche Elecsys Anti-CCP CalCheck, as summarized in the following tables.

SIMILARITIES
Item	Device	Predicate
	IMMULITE Anti-CCP IgG CVM	Elecsys Anti-CCP CalCheck
Intended Use	For in vitro diagnostic use, as a control for calibration verification of Anti-CCP IgG assay.	Same
Format	Lyophilized	Same
Matrix	Human serum	Same
Handling	Reconstitute with distilled or deionized water	Same

DIFFERENCES
Item	Device	Predicate
	IMMULITE Anti-CCP IgG
CVM	Elecsys Anti-CCP CalCheck
Analyzer	For use on IMMULITE 2000
analyzer	For use on Elecsys 2010,
MODULAR ANALYTICS E170,
cobas e411 and cobas e601
analyzers
CVM Levels	4	3

K. Standard/Guidance Documents Referenced:

Guidance for Industry and FDA Staff Assayed and Unassayed Quality Control Material .

L. Test Principle:

. Not Applicable

M. Performance Characteristics

6. Analytical Performance:

a. Precision/Reproducibility: Not Applicable
b. Linearity/assay reportable range: Not Applicable
c. Traceability, Stability, Expected values:

Traceability - Since there is no recognized standard reference material for Anti-CCP, the IMMULITE 2000 Anti-CCP IgG assay is traceable to an internal standard and manufactured using qualified materials and measurement procedures. The IMMULITE Anti-CCP Calibration Verification Material (CVM) is traceable to this standard.

Stability - Open vial stability - Freshly opened and reconstituted IMMULITE 2000 Anti-CCP CVMs showed 30 days open vial stability when stored at 2-8°C. Unopened stability is indicated by expiration date on the label when stored at 2-8°C.

Value Assignment: The Anti-CCP reference calibrator values were assigned by using an approved internal standard. This reference standard lot is used to assign Anti-CCP IgG CVMs. Quality control is then performed by calculating the recovery of controls using the reference calibration verification material.

Each CVM level below was run in duplicate on 3 different reagent kit lots (Lot 201, 202 and 211) and 14-15 runs per lot for a total of 86 replicates. Five instruments were used to carry out all the runs. The analyte values were calculated based on the recovered values for each run independently. The average analyte recovered for each CVM level determined the value assigned to the Target Mean.

The Guideline Range (95% confidence interval) for each CVM level was established based on the Target Mean and ± 2 Standard Deviations (SD).

| Level | Catalog and
Lot number | Target Mean
(U/mL)* | SD | Guideline
Range
(U/mL) | Total
CV% | Spec
CV% |
|-------|---------------------------|------------------------|-------|------------------------------|--------------|-------------|
| 1 | L2PICVM1 Dxxx | 0.00 | | ≤ 1.50 | NA** | NA |
| 2 | L2PICVM2 Dxxx | 6.19 | 0.41 | 5.37
7.00 | 6.6% | 10% |
| 3 | L2PICVM3 Dxxx | 103 | 8.85 | 85.3
121 | 8.6% | 10% |
| 4 | L2PICVM4 Dxxx | 209 | 21.09 | 167
252 | 10% | 10% |

note that CVM value assignment is lot-specific

** NA = Not Applicable

d. Detection limit: Not Applicable
e. Analytical Specificity: Not Applicable
Assay cut-off: Not Applicable · f.

7. Comparison Studies

Method Comparison with predicate device: Not Applicable a.
Matrix Comparison: Not Applicable b.

8. Clinical Studies:

a. Clinical Sensitivity and Specificity: Not Applicable
b. Other clinical supportive data (when a. and b. are not applicable): Not Applicable
1. Clinical Cut-off. Not Applicable
1. Expected Values/Reference Range: See Value Assignment above.

Image /page/16/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" arranged around the perimeter. Inside the circle is a stylized design featuring a symbol that resembles a human figure embracing or protecting another figure, representing the department's mission of protecting the health of all Americans and providing essential human services.

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

April 4, 2013

Siemens Healthcare Diagnostics c/o Susan Brocchi Sr. Regulatory Affairs Specialist 511 Benedict Avenue Tarrytown, NY 10591

Re: K121576

Trade/Device Name: IMMULITE 2000 Anti-CCP IgG Assay and IMMULITE 2000 Anti-CCP IgG Calibration Verification Material Regulation Number: 21 §CFR 866.5775 Regulation Name: Rheumatoid factor immunological test system Regulatory Class: Class II Product Code: NHX, JIT Dated: March 29, 2013 Received: April 1, 2013

Dear Ms. Brocchi:

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

Page 2 - Ms. Susan Brocchi

CFR Part 807); labeling (21 CFR Part 801); medical device reporting (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 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 regulation (21 CFR Part 801), please contact the Division of Small Manufacturers, International and Consumer Assistance at its tollfree 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" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

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

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Maria M. Chan -S

Maria M. Chan, Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health (OIR) Center for Devices and Radiological Health

Enclosure

Indications for Use

510(k) Number (if known): kl21576

Device Name: IMMULITE® 2000 Anti-CCP IgG Assay and Calibration Verification Material

Indications for Use: The IMMULITE 2000 Anti-CCP IgG assay is an in vitro diagnostic immunoassay for the semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in human serum (including Serum Separator Tubes) or plasma (EDTA or lithium heparin) on the IMMULITE 2000 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.

Prescription Use X (21 CFR Part 801 Subpart D) Over the Counter Use (21 CFR Part 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostics and Radiological Health (OIR)

And/Or

Maria M. Chan -S

Division Sign-Off Office of In Vitro Diagnostics and Radiological Health

510(k) K121576