The ADVIA Centaur® BR assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 27.29 in human serum and plasma (EDTA) using the ADVIA Centaur XP, and ADVIA Centaur XPT systems. The test is intended for use as an aid in monitoring patients previously treated for Stage III breast cancer. Serial testing for CA 27.29 in the serum and plasma of patients who are clinically free of disease should be used in conjunction with other clinical methods used for the early detection of cancer recurrence. The test is also intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment.

Device Description

The ADVIA Centaur BR assay is a fully automated, competitive immunoassay using direct, chemiluminescent technology. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve with the reagent bar code. The ADVIA Centaur BR assay is intended for use on the ADVIA Centaur family of analyzers. The ADVIA Centaur Calibrator G is a set of 2 level calibrators for the assay. Siemens recommends the use of commercially available quality control materials with at least two levels (low and high).

The ADVIA Centaur BR reagent kit contains the following:

ADVIA Centaur BR ReadyPack primary reagent pack contains Lite Reagent and Solid Phase ● Reagent.
Materials Required but Not provided:
ADVIA Centaur Calibrator G: consists of 2 levels (low and high) of CA 27.29 calibrators in equine serum with sodium azide (0.1%) and preservatives; lyophilized.
ADVIA Centaur BR Pretreatment Reagent: consists of sodium hydroxide (0.24 N) Optional Reagents:
ADVIA Centaur Multi-Diluent 1: consists of equine serum with sodium azide (0.1%) and preservatives.
. ADVIA Centaur BR Master Curve Material: consists of a set of 7 levels of CA 27.29 (MCM1-7) spiked in lyophilized equine serum with sodium azide (0.1% after reconstitution) and preservatives.

AI/ML Overview

The Siemens Healthcare Diagnostics Inc. ADVIA Centaur BR assay, with updated claims for plasma (EDTA) sample and detection capability (LoB, LoD, and LoQ), was determined to be substantially equivalent to the predicate device (K982680). The purpose of this submission was to add the plasma (EDTA) sample claim and update the detection capability claims.

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria (Predicate)	Reported Device Performance (New Claims)
Detection Capability (LoB)	Analytical Sensitivity: 3.5 U/mL (Serum)	3.5 U/mL (Serum and Plasma)
Detection Capability (LoD)	Not explicitly stated as LoD	7.0 U/mL (Serum and Plasma)
Detection Capability (LoQ)	Not explicitly stated as LoQ	9.0 U/mL (Serum and Plasma)
Assay Range (Serum)	3.5 - 450 U/mL	9.0 - 450 U/mL
Assay Range (Plasma)	Not applicable (Serum only)	9.0 - 450 U/mL
Sample Type	Serum	Serum, Plasma (EDTA)
Measurement	Quantitative	Quantitative
Operating Principle	Competitive immunoassay	Competitive immunoassay
Technology	Direct chemiluminescent	Direct chemiluminescent
Sample Volume	20 µL (serum)	20 µL (serum and plasma)
Traceability/Standardization	Traceable to internal standard	Same
Calibration	2-point	Same
Calibrator/Levels	Calibrator G/2 levels	Same
Controls/Levels	Commercial Controls/2 levels	Same
Master Curve Materials	Seven levels (MCM1-7)	Same
Detection Antibody	Monoclonal mouse anti-CA 27.29 antibody (~1.2 µg/mL) labeled with acridinium ester	Same
Capture Antibody	Human CA 27.29 (~0.72 U/mL) covalently coupled to paramagnetic particles	Same

Comparisons of Candidate and Predicate Device for Specimen Equivalence (Dipotassium EDTA Plasma vs. Serum):

Measurement	N	Sample Interval	Slope (95% CI)	Intercept (95% CI)	Correlation Coefficient (r)
Performance	101	10.80 - 444.42 U/mL	0.97 (0.955 – 0.993)	2.21 U/mL (1.376 – 3.040)	1.00

Interference Testing (Dipotassium EDTA):

Interferent	Interferent Concentration	Analyte Concentration (U/mL)	Bias (%)
Dipotassium EDTA	5.4 mg/mL	20.46	1.8
		318.39	3.7

2. Sample Size Used for the Test Set and Data Provenance

Specimen Equivalence by Method Comparison:
- Sample Size: 101 samples (N=101)
- Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). The study used patient samples.
Detection Capability (LoB, LoD, LoQ): The specific sample sizes for LoB, LoD, and LoQ determination are not provided in this summary, but the determination was performed in accordance with CLSI Document EP17-A2.
Interferences: EDTA: The specific number of samples tested for interference is not provided, but tests were performed at two analyte concentrations.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This type of immunoassay (measuring tumor-associated antigen CA 27.29) does not typically involve expert review of images or clinical data for establishing ground truth in the same way imaging devices do. The ground truth for analytical performance studies is established by the known concentration of the analyte in the samples, or by comparison to a reference method, rather than through expert consensus.

4. Adjudication Method for the Test Set

Not applicable for this type of analytical performance study. Adjudication methods (e.g., 2+1) are typically used in studies involving subjective interpretation of data, such as medical images, where discrepancies between readers need to be resolved. This study involves quantitative measurements.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

No MRMC comparative effectiveness study was conducted as this device is an in vitro diagnostic test for quantitative serial determination of a cancer antigen, not an AI-based imaging or diagnostic tool requiring human reader interpretation in that context.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

This is a standalone in vitro diagnostic assay. Its performance is evaluated based on its ability to accurately measure the target analyte (CA 27.29) in patient samples. Human intervention is limited to sample handling, loading, and interpreting the quantitative results per clinical guidelines, not in generating the test result itself.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the performance characteristics was established by:

Detection Capability: Defined statistically based on measured values from blank and low-concentration samples (in accordance with CLSI EP17-A2).
Specimen Equivalence: Comparison of results from plasma (EDTA) samples to serum samples using Deming linear regression, implying serum results (from the predicate device/established method) serve as the reference.
Interferences: Known concentrations of interferents and analyte spiked into samples.

8. The Sample Size for the Training Set

No training set information is provided in the summary. Immunoassays are generally optimized and validated during development, and the performance studies presented reflect the validation of the finalized assay.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as no training set information is provided as per point 8.

Summary

{0}------------------------------------------------

Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the FDA name and title on the right. The symbol on the left is a stylized representation of a human figure, while the text on the right reads "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue letters.

February 13, 2020

Siemens Healthcare Diagnostics Inc. Ian Thompson Regulatory Clinical Affairs Specialist 511 Benedict Avenue Tarrytown, New York 10591

Re: K193489

Trade/Device Name: ADVIA Centaur BR Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: MOI Dated: December 16, 2019 Received: December 17, 2019

Dear Ian Thompson:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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

{1}------------------------------------------------

requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Carolina Kagan Acting Chief Immunology and Flow Cytometry Branch Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

{2}------------------------------------------------

Indications for Use

510(k) Number (if known) K193489

Device Name ADVIA Centaur® BR

Indications for Use (Describe)

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)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

{3}------------------------------------------------

This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.

The assigned 510(k) Number is: K193489

Date Prepared 1.

December 13, 2019

Applicant Information 2.

Contact: lan Thompson Regulatory Clinical Affairs Specialist
Address: Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue Tarrytown, NY 10591 914-524-2296 Phone:

Fax: 914-524-2101

Email ian thompson@siemens-healthineers.com

Regulatory Information 3.

Table 1. Regulatory Information for ADVIA Centaur® BR

Trade Name	ADVIA Centaur® BR
Device	System, Test, Immunological, Antigen, Tumor
Regulation Description	Tumor-associated antigen immunological test system
FDA Classification	Class II
Review Panel	Immunology
Product Code	MOI
Regulation Number	21 CFR 866.6010

4. Predicate Device Information

Predicate Device Name: ADVIA Centaur® BR

510(k) Number: K982680

The ADVIA Centaur BR assay with the addition of the plasma (EDTA) sample and detection capability [Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ)] claims in the Instructions for Use (Package Inserts) is substantially equivalent to the ADVIA Centaur BR assay that was cleared under 510(k) K982680, as shown below in the Substantial Equivalence Information section.

5. Intended Use / Indications for Use

{4}------------------------------------------------

510(k) Summary of Safety and Effectiveness

cancer. Serial testing for CA 27.29 in the serum and plasma of patients who are clinically free of disease should be used in conjunction with other clinical methods used for the early detection of cancer recurrence. The test is also intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment.

Special Conditions for Use Statement(s): For prescription use only

6. Device Description

The ADVIA Centaur BR reagent kit contains the following:

ADVIA Centaur BR ReadyPack primary reagent pack contains Lite Reagent and Solid Phase ● Reagent.
Materials Required but Not provided:
ADVIA Centaur Calibrator G: consists of 2 levels (low and high) of CA 27.29 calibrators in equine serum with sodium azide (0.1%) and preservatives; lyophilized.
ADVIA Centaur BR Pretreatment Reagent: consists of sodium hydroxide (0.24 N) Optional Reagents:
ADVIA Centaur Multi-Diluent 1: consists of equine serum with sodium azide (0.1%) and preservatives.
. ADVIA Centaur BR Master Curve Material: consists of a set of 7 levels of CA 27.29 (MCM1-7) spiked in lyophilized equine serum with sodium azide (0.1% after reconstitution) and preservatives.

7. Purpose of the Submission

The purpose of this submission is for the addition of plasma (EDTA) sample claim and updating the detection capability claim for the ADVIA Centaur BR assay.

8. Substantial Equivalence Information - Comparison of Candidate Device and Predicate Device

The following table demonstrates substantial equivalence between the ADVIA Centaur BR assay (Candidate Device) that has modified Instructions for Use (Package Inserts) with the addition of plasma (EDTA) sample and detection capability (LoB, LoD, and LoQ) claims and the currently marketed ADVIA Centaur BR assay (Predicate Device) that was cleared under 510(k) K982680.

{5}------------------------------------------------

Trade Name	Candidate Device	Predicate Device
	ADVIA Centaur BR	ADVIA Centaur BR
	(Modified Labeling)	(Unmodified Labeling)
Intended Use	The ADVIA Centaur® BR assay is an invitro diagnostic test for the quantitativeserial determination of cancer antigenCA 27.29 in human serum and plasma(EDTA) using the ADVIA Centaur®,ADVIA Centaur XP, and ADVIA CentaurXPT systems.	The ADVIA Centaur® BR assay is an invitro diagnostic test for the quantitativeserial determination of cancer antigenCA 27.29 in human serum using theADVIA Centaur, ADVIA Centaur XP,and ADVIA Centaur XPT systems.
Indications for Use	The test is intended for use as an aid inmonitoring patients previously treated forStage II or Stage III breast cancer. Serialtesting for CA 27.29 in the serum andplasma of patients who are clinically freeof disease should be used in conjunctionwith other clinical methods used for theearly detection of cancer recurrence. Thetest is also intended for use as an aid inthe management of breast cancerpatients with metastatic disease bymonitoring the progression or regressionof disease in response to treatment.	The test is intended for use as an aidin monitoring patients previouslytreated for Stage II or Stage III breastcancer. Serial testing for CA 27.2G inthe serum of patients who are clinicallyfree of disease should be used inconjunction with other clinicalmethods used for the early detection ofcancer recurrence. The test is alsointended for use as an aid in themanagement of breast cancer patientswith metastatic disease by monitoringthe progression or regression ofdisease in response to treatment.
Measurement	Quantitative	Same
Detection Capability	LoB: 3.5 U/mLLoD: 7.0 U/mLLoQ: 9.0 U/mL	Analytical Sensitivity: 3.5 U/mL
		NA
		NA
Assay Range	Serum and Plasma: 9.0-450 U/mL	Serum: 3.5—450 U/mL
Operating Principle	Competitive immunoassay	Same
Technology	Direct chemiluminescent	Same
Sample Type	Serum, Plasma (EDTA)	Serum
Sample Volume	20 µL (serum and plasma)	20 µL (serum)
Traceability/Standardization	Traceable to an internal standardmanufactured using highly purified CA27.29	Same
Calibration	2-point	Same
Calibrator/Levels	Calibrator G/2 levels	Same
Controls/Levels	Commercial Controls/2 levels	Same
Master CurveMaterials	Seven levels (MCM1-7)	Same
Detection Antibody	Monoclonal mouse anti-CA 27.29antibody (~1.2 µg/mL) labeled withacridinium ester	Same
Capture Antibody	Human CA 27.29 (~0.72 U/mL)covalently coupled to paramagnetic	Same
	particles
Limit of Blank (LoB)	3.5 U/mL
Limit of Detection (LoD)	7.0 U/mL
Limit of Quantitation (LoQ)	9.0 U/mL

Standard/Guidance Document References 9.

The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:

Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved . Guideline-Third Edition (CLSI EP09-A3).

{6}------------------------------------------------

. Interference Testing in Clinical Chemistry; Approved Guideline-Third Edition (CLSI EP07ed3).
Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved . Guideline-Second Edition (EP17-A2).

Test Principle 10.

The ADVIA Centaur BR assay is a fully automated, competitive immunoassay using direct, chemiluminescent technology. The Lite Reagent is composed of a monoclonal mouse antibody specific for CA 27.29, labeled with acridinium ester. The antibody used in the assay, MAb B27.29, binds to a peptide epitope in the tandem repeat region of the MUC-1 gene product. The Solid Phase is composed of purified CA 27.29, which is covalently coupled to paramagnetic particles. After onboard pretreatment, the sample is incubated with both Lite Reagent and Solid Phase simultaneously for 7.5 minutes.

11. Performance Characteristics

The addition of the plasma (EDTA) sample and detection capability (LoB, LoD, LoQ) claims in the Instructions for Use (Package Inserts) for the ADVIA Centaur BR assay was demonstrated by testing the performance characteristics with the following studies:

Detection Capability (LoB, LoD, LoQ) ●
Specimen Equivalence by Method Comparison ●
. Interferences: EDTA

The plasma (EDTA) sample and detection capability (LoB, LoQ) claims for the ADVIA Centaur BR assay do not require the collection of additional analytical performance data. Therefore, all analytical performance data previously reviewed for the ADVIA Centaur BR assay continues to apply to this assay, because the assay was not modified.

Detection Capability 11.1

The Detection capability was determined in accordance with CLSI Document EP17-A2.

The LoB corresponds to the highest measurement likely to be observed for a blank sample with a probability of 95%.

The LoD corresponds to the lowest concentration of cancer antigen CA 27.29 that can be detected with a probability of 95%.

The LoQ corresponds to the lowest amount of cancer antigen CA 27.29 in a sample at which the within laboratory CV is ≤ 20%. CV is ≤ 20%.

Specimen Equivalence by Method Comparison 11.2

Specimen equivalency was determined with the Deming linear regression model in accordance with CLSI Document EP09-A3. The following results were obtained:

{7}------------------------------------------------

510(k) Summary of Safety and Effectiveness

Comparison	N*	Sample Interval	Slope(95%CI)	Intercept(95%CI)	CorrelationCoefficient (r)
Dipotassium EDTA Plasmavs. Serum	101	10.80-444.42 U/mL	0.97(0.955 – 0.993)	2.21 U/mL(1.376 – 3.040)	1.00

N = Number of samples tested.

Interferences: EDTA 11.3

Interference testing was performed in accordance with CLSI Document EP07-ed3. The following results were obtained:

Interferent	InterferentConcentration	Analyte Concentration(U/mL)	Bias (%)
Dipotassium EDTA	5.4 mg/mL	20.46	1.8
		318.39	3.7

11.4 Clinical Studies

Not applicable.

11.5 Clinical Cut-off

Not applicable.

Conclusion 12.

The ADVIA Centaur BR assay with the addition of the plasma (EDTA) sample and detection capability (LoB, LoQ) claims in the Instructions for Use (package insert) is substantially equivalent to the currently marketed ADVIA Centaur BR assay (K982680).

Regulation Number and Section

§ 866.6010 Tumor-associated antigen immunological test system.

(a)
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.(b)
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.