ADVIA Centaur CEA Assay

K200215 · Siemens Healthcare Disgnostics, Inc. · DHX · Apr 13, 2020 · Immunology

Device Facts

• Record ID: K200215
• Device Name: ADVIA Centaur CEA Assay
• Applicant: Siemens Healthcare Disgnostics, Inc.
• Product Code: DHX · Immunology
• Decision Date: Apr 13, 2020
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.6010
• Device Class: Class 2

Indications for Use

For in vitro diagnostic use in the quantitative measurement of carcinoembryonic antigen (CEA) in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems.

Device Story

ADVIA Centaur CEA assay is an in vitro diagnostic test for quantitative measurement of carcinoembryonic antigen (CEA) in serum and plasma; used to aid management of cancer patients by monitoring changing CEA concentrations. Device utilizes sandwich immunoassay principle with direct chemiluminescent technology; reagents include polyclonal rabbit anti-CEA antibody labeled with acridinium ester and monoclonal mouse anti-CEA antibody coupled to paramagnetic particles. Performed on ADVIA Centaur XP and XPT systems; requires 50 µL sample volume and 7.5-minute incubation at 37°C. Healthcare providers use quantitative results to track disease progression or treatment response in cancer patients. Submission adds plasma (EDTA and lithium heparin) sample claims to existing serum-based assay.

Clinical Evidence

No new clinical studies performed. Analytical performance (precision, linearity, specificity) was established in the predicate (K981478). Matrix comparison study (n=64 for K2-EDTA, n=46 for Li-Heparin) demonstrated equivalence to serum with correlation coefficients (r) of 1.00 and slopes near 1.0. Interference testing confirmed no significant assay interference from K2-EDTA or lithium heparin at 3x and 5x nominal concentrations.

Technological Characteristics

Single-wash sandwich immunoassay; direct chemiluminescent detection. Reagents: polyclonal rabbit anti-CEA (acridinium ester labeled), monoclonal mouse anti-CEA (paramagnetic particles). Dimensions/form factor: ReadyPack reagent packs. Connectivity: Integrated with ADVIA Centaur XP/XPT systems. Standards: CLSI EP05-A3, EP06-A, EP07, EP17-A2.

Indications for Use

Indicated for quantitative measurement of CEA in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed.

Regulatory Classification

Identification

A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.

Special Controls

*Classification.* Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.

Predicate Devices

• ADVIA Centaur® CEA assay (K981478)

Submission Summary (Full Text)

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FDA

U.S. FOOD & DRUG

ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

## I Background Information:

A 510(k) Number

K200215

B Applicant

Siemens Healthcare Diagnostics, Inc.

C Proprietary and Established Names

ADVIA Centaur CEA Assay

D Regulatory Information

| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| DHX | Class II | 21 CFR 866.6010 - Tumor-Associated Antigen Immunological Test System | IM - Immunology |

## II Submission/Device Overview:

A Purpose for Submission:

Modification of a previously cleared device: addition of Li-Heparin and K2-EDTA plasma matrices.

B Measurand:

Carcinoembryonic antigen 125 (CEA)

C Type of Test:

Quantitative, Chemiluminescent

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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## III Intended Use/Indications for Use:

### A Intended Use(s):

See Indications for Use below.

### B Indication(s) for Use:

For in vitro diagnostic use in the quantitative measurement of carcinoembryonic antigen (CEA) in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur XP and ADVIA Centaur XPT systems.

### C Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

### D Special Instrument Requirements:

For use on the ADVIA Centaur XP and ADVIA Centaur XPT

## IV Device/System Characteristics:

### A Device Description:

The ADVIA Centaur CEA Assay kit contains the following:

- ReadyPack primary reagent packs for 100 or 500 tests
- ADVIA Centaur CEA Master Curve card

The ReadyPack for ADVIA Centaur CEA consists of the following:

- CEA Lite Reagent: 5.0 mL polyclonal rabbit anti-CEA antibody (~400 ng/mL) labeled with acridinium ester in phosphate buffered saline with protein stabilizers, sodium azide (0.12%), and preservatives.
- CEA Solid Phase Reagent: 25.0 mL monoclonal mouse anti-CEA antibody (~120 µg/mL) covalently coupled to paramagnetic particles in phosphate buffered saline with protein stabilizers, sodium azide (0.11%), and preservatives.
- CEA diluent: 5.0 mL bicine buffer, gelatin, and BSA with preservatives and sodium azide (0.1%)

Materials Required but not provided:

- ADVIA Centaur Calibrator D

Optional Reagents:

- ADVIA Centaur CEA Master Curve Material
- ADVIA Centaur CEA Diluent

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B Principle of Operation:

The ADVIA Centaur CEA Assay is a fully automated, single-wash sandwich immunoassay using direct, chemiluminescent technology. The Lite Reagent is composed of the polyclonal rabbit anti-CEA antibody labeled with acridinium ester. The Solid Phase Reagent is composed of monoclonal mouse anti-CEA antibody covalently coupled to paramagnetic particles. The sample is incubated with the Lite Reagent and Solid Phase Reagent for 7.5 minutes at 37 °C to allow formed immune complexes to be captured by the particles. After incubation, the particles are washed before addition of the Acid Reagent and Base Reagent to initiate the chemiluminescent reaction. The measured chemiluminescence is directly proportional to the quantity of CEA antigen in the sample.

V Substantial Equivalence Information:

A Predicate Device Name(s):

ACS:Centaur CEA

B Predicate 510(k) Number(s):

K981478

C Comparison with Predicate(s):

| Device & Predicate Device(s): | K200199 Device | K981478 Predicate |
| --- | --- | --- |
| Device Trade Name | ADVIA Centaur CEA Assay | ACS:Centaur CEA |
| General Device Characteristic Similarities | | |
| Intended Use/Indications for Use | For in vitro diagnostic use in the quantitative measurement of carcinoembryonic antigen (CEA) in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur XP and ADVIA Centaur XPT systems. | For in vitro diagnostic use in the quantitative measurement of carcinoembryonic antigen (CEA) in serum to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur®, ADVIA Centaur XP, and ADVIA Centaur XPT systems. |
| Operating Principle | Single wash sandwich immunoassay | Same |
| Assay Technology | Direct chemiluminescent | Same |
| Measurement | Quantitative | Same |
| Sample Volume | 50 μL | Same |
| Reagent Volume | 50 μL of Lite Reagent and 250 μL | Same |

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| | of Solid Phase | |
| --- | --- | --- |
| Detection Antibody | Polyclonal rabbit anti-CEA antibody labeled with acridinium ester | Same |
| Capture Antibody | Monoclonal mouse anti-CEA antibody covalently coupled to paramagnetic particles | Same |
| Traceability | The ADVIA Centaur CEA assay is traceable to an internal standard manufactured using highly purified material. Assigned values for calibrators are traceable to this standardization | Same |
| Calibrators | ADVIA Centaur Calibrator D/ Two levels | Same |
| Calibration | Two-point | Same |
| Controls | Commercial Controls /Two levels | Same |
| General Device Characteristic Differences | | |
| Sample Type | Serum, plasma (EDTA and lithium heparin) | Serum |
| Detection Capability | LoB: 0.5 ng/mL
LoD: 1.0 ng/mL
LoQ: 2.0 ng/mL | Analytical Sensitivity: 0.5 ng/mL |
| Assay Range | 2.0–100 ng/mL | 0.5–100 ng/mL |

VI Standards/Guidance Documents Referenced:

CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition

CLSI EP06-A, Evaluation of Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline

CLSI EP07, 3rd Edition, Interference Testing in Clinical Chemistry

CLSI EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline—Second Edition

VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:

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The precision and reproducibility of the ADVIA Centaur CEA Assay were demonstrated in K981478.

## 2. Linearity:

The linearity of the ADVIA Centaur CEA Assay was demonstrated in K981478.

## 3. Analytical Specificity/Interference:

The analytical specificity was demonstrated in K981478. Interference was evaluated with hemoglobin, triglycerides, bilirubin and chemotherapeutic agents. The potential interference of NCA (normal cross-reacting antigen) and NCA2 was also evaluated.

To evaluate the performance of the ADVIA Centaur CEA Assay in samples collected with K2-EDTA and lithium heparin tubes, one sample at low level and one at high level of CEA for each matrix were used to titrate the EDTA and heparin anticoagulants. The nominal K2-EDTA and lithium heparin concentrations are 1.8 mg/mL and 15.0 U/mL in blood collection tubes, respectively. Both K2-EDTA and lithium heparin samples were spiked at three times and five times the nominal additive concentration for testing. Testing was performed in three replicates per sample on one ADVIA Centaur XP instrument using one lot of reagent. The recovery was calculated as the difference between the means of the test samples spiked with the interferent and control samples spiked with the same volume of the interferent vehicle. Results summarized in the table below show that no significant assay interference was demonstrated with K2-EDTA and lithium heparin at the indicated test concentrations.

| Interferent | Interferent Test concentration | Low level CEA sample | | High level CEA sample | |
| --- | --- | --- | --- | --- | --- |
| | | Mean (ng/mL) | Recovery (%) | Mean (ng/mL) | Recovery (%) |
| K2-EDTA | 5.4 mg/mL | 5.55 | 96.2 | 58.34 | 104.9 |
| | 9.0 mg/mL | 5.76 | 99.7 | 58.20 | 104.6 |
| Lithium heparin | 45 U/mL | 5.82 | 99.8 | 62.17 | 101.5 |
| | 75 U/mL | 5.80 | 99.4 | 61.77 | 100.1 |

## 4. Assay Reportable Range:

The claimed measuring range is from 2.0 ng/mL to 100 ng/mL.

## 5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

The traceability and reagent stability were established in K981478.

## 6. Detection Limit:

The Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation for the ADVIA Centaur CEA Assay were determined in accordance with the CLSI guideline EP17-A2.

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The LoB was determined using two lots of reagents and one ADVIA Centaur XP instrument. Five analyte-free human serum pools were tested in five replicates per run, two runs per day for five days, to obtain a total of 250 replicates per lot. The LoB was estimated as the 95th percentile of the measurements and determined to be 0.15 ng/mL and 0.36 ng/mL for the two lots of reagents. The claimed LoB is 0.5 ng/mL.

The LoD was determined using 10 serum pools with low analyte levels on one ADVIA Centaur XP instrument using two lots of reagents. All samples were tested in five replicates per sample for ten runs over a period of five days yielding a total of 500 replicates per reagent lot. The LoD was determined as 0.46 ng/mL and 0.48 ng/mL for the two lots of reagents. The claimed LoD is 1.0 ng/mL.

The LoQ was determined using 10 serum pools with low analyte levels on one ADVIA Centaur XP instrument using two lots of reagents. All samples were tested in five replicates per sample for ten runs over a period of five days yielding a total of 500 replicates per reagent lot. The LoQ defined as the mean value of the sample which fulfills the specification for the total within-laboratory imprecision ≤ 20% CV is 0.29 ng/mL and 0.43 ng/mL for the two lots of reagents. The claimed LoQ is 2.0 ng/mL which is the lower limit of the measuring range claimed for the assay.

7. Assay Cut-Off:

The assay cut-off was demonstrated in K981478.

B Comparison Studies:

1. Method Comparison with Predicate Device:

The method comparison with predicate device was presented in K981478. Results from this study were re-analyzed to determine the relationship of the ADVIA Centaur CEA assay to the ACS:180 CEA assay. A total of 284 samples with CEA concentrations ranging from 0.5 to 78.5 ng/mL were tested. Because the lower limit of the measuring range was raised from 0.5 ng/mL to 2.0 ng/mL, 83 samples with CEA concentrations below 2.0 ng/mL were removed from the analysis. A Deming regression analysis was performed for the remaining 201 samples and the results are summarized in the following table:

| Comparison | N | Sample Range (ng/mL) | Slope (95% CI) | Intercept (95% CI) | Correlation Coefficient (r) |
| --- | --- | --- | --- | --- | --- |
| ADVIA Centaur CEA vs. ACS:180 CEA | 201 | 2.0 – 78.9 | 0.97 (0.96 – 0.98) | 0.11 (-0.26 – 0.48) | 1.00 |
| N = Number of samples tested | | | | | |

2. Matrix Comparison:

To demonstrate that Li-Heparin plasma and K2-EDTA plasma samples yield results comparable with serum samples by the ADVIA Centaur CEA Assay, a study was performed by using 64 serum/K2-EDTA plasma paired samples (59 native samples and five pooled

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samples) and 46 serum/Li-heparin plasma paired samples (41 native samples and five pooled samples). The pooled sample pairs were prepared by mixing high CEA and low CEA native human matched pairs. Paired samples were each tested in singleton using five reagent lots on three ADVIA Centaur XP instruments. The Deming regression analysis was performed, and the results are summarized in the following table:

| Comparison | N | Sample Range (ng/mL) | Slope (95% CI) | Intercept (95% CI) | Correlation Coefficient (r) |
| --- | --- | --- | --- | --- | --- |
| K2-EDTA plasma vs. serum | 64 | 2.1 – 97.1 | 0.95 (0.91 – 0.99) | 0.20 (-0.45 – 0.85) | 1.00 |
| Lithium Heparin plasma vs. serum | 46 | 2.1 – 97.1 | 0.99 (0.95 – 1.04) | 0.19 (-0.27 – 0.64) | 1.00 |
| N = Number of samples tested | | | | | |

The data support the addition of K2-EDTA plasma and Li-heparin plasma sample types to the ADVIA Centaur CEA Assay.

## C Clinical Studies:

Clinical Sensitivity and Specificity:

The clinical sensitivity and specificity of the assay was demonstrated in K981478.

## D Clinical Cut-Off:

The clinical cut-off was demonstrated in K981478.

## E Expected Values/Reference Range:

The expected values were established in K981478.

## VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

## IX Conclusion:

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

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