The ADVIA Centaur® CA 19-9 Assay is an in vitro immunoassay for the quantitative measurement of the CA 19-9 tumor-associated antigen, in human serum, using the ADVIA Centaur System. This assay is indicated for the serial measurement of CA 19-9 to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The test is useful as an aid in monitoring of disease status in those patients having confirmed pancreatic cancer who have levels of serum CA 19-9 at some point in their disease process exceeding the median concentration determined for the apparently healthy cohort. CA 19-9 values must be interpreted in conjunction with all other clinical and laboratory data before a medical decision is determined. This assay is not intended for use on any other system.

Device Description

The ADVIA Centaur CA 19-9 assay is a fully automated, two-step sandwich immunoassay using direct, chemiluminescent technology. The method utilizes a single monoclonal antibody (Mab), 116-NS-19-9, for both the Solid Phase and the Lite Reagent. The Mab is both covalently coupled to paramagnetic particles in the Solid Phase as well as labeled with acridinium ester in the Lite Reagent.

The sample and Solid Phase are first incubated at 37℃ for 7.5 minutes. This step is followed by a wash step to remove excess unbound antigen. The Lite Reagent is then reacted with the Solid Phase that is bound to CA 19-9 antigen for an additional 20-minute incubation. This two-step protocol eliminates any high-dose hook effect in this assay.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Bayer HealthCare Diagnostics Division ADVIA Centaur® CA 19-9 Assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state "acceptance criteria" in a quantified format that one would typically find for a diagnostic test. Instead, it compares the performance characteristics of the new device (ADVIA Centaur CA 19-9 Immunoassay) to those of the predicate device (Fujirebio Diagnostics CA 19-9 RIA). The implication is that the new device's performance should be comparable or superior to the predicate for features where direct comparison is feasible. For clinical concordance, the new device's performance is presented on its own.

Feature	Acceptance Criteria (Implied by Predicate/Desired Performance)	Reported Device Performance (ADVIA Centaur CA 19-9 Immunoassay)
Precision	Values for duplicates should be within 15% of the mean (for predicate). New device should be comparable.	Within-run 4.3 – 11.3 %CV from 7.2 – 386.7 Units/mL. Total 5.5 – 14.5 %CV from 7.2 – 386.7 Units/mL. (Considered acceptable for substantial equivalence).
Hook Effect	None up to 1,250,000 Units/mL (for predicate). New device should be comparable or better.	No high dose effect up to 5,800,000 Units/mL. (Considered superior to predicate).
Analytical Sensitivity	0.9 Units/mL (for predicate). New device should be comparable.	1.2 Units/mL. (Slightly less sensitive than predicate, but considered substantially equivalent).
Clinical Concordance(with disease progression - Per-Visit Analysis)	Not explicitly stated as a concrete acceptance criterion, but demonstrated clinical agreement with disease status.	Concordance = (39+47)/131 = 65.7% (95% CI of 54.9% to 76.3%).Predictive Value (No Progression) = 47/74 = 63.5% (95% CI of 52.9% to 77.4%).Predictive Value (Progression) = 39/57 = 68.4% (95% CI of 56.6% to 80.1%).
Method Comparison (Correlation with Predicate)	Strong correlation (r) to the predicate device.	Relationship: ADVIA Centaur CA 19-9 = 0.97 (Fujirebio RIA) + 0.13 Units/mL.Correlation coefficient (r) = 0.88.

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

Clinical Concordance Test Set: 131 clinical samples (patients with pancreatic cancer, monitored serially for changes in disease status).
Method Comparison Test Set: 360 samples in the assay range of 1.2 - 700 Units/mL.
Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given the nature of a 510(k) submission, it's highly likely that these were prospective or a mix of prospective and retrospectively collected clinical samples, but this is not definitively stated.

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

The document states that the clinical concordance studies compare "changes in CA 19-9 value relative to disease progression." However, it does not provide details on:

The number of experts.
Their qualifications.
The specific method used to establish the "Change in Disease State" (i.e., "Progression" or "No Progression"). This clinical status would serve as the ground truth.

4. Adjudication Method for the Test Set

The document does not describe any adjudication method used to establish the ground truth ("Change in Disease State") for the clinical concordance study.

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, an MRMC comparative effectiveness study was not done.
This device is an in vitro diagnostic (IVD) immunoassay, not an AI-powered image analysis or interpretation tool that assists human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here. The study focuses on the performance of the assay itself and its correlation with clinical status and a predicate device.

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

Yes, a standalone study was done. This entire submission describes the standalone performance of the ADVIA Centaur CA 19-9 Assay, an automated in vitro diagnostic device, without human intervention in the result generation process once the sample is loaded. The "clinical concordance" section assesses the direct relationship between the assay's output and clinical disease progression.

7. The Type of Ground Truth Used

Clinical Outcomes/Disease State: For the clinical concordance study, the ground truth was "Change in Disease State" (Progression or No Progression), which is derived from a patient's overall clinical presentation and likely involves various clinical and diagnostic assessments over time. The document does not specify the exact methods or criteria used to define "Progression" or "No Progression."
Predicate Device Measurements: For the method comparison study, the ground truth for measuring CA 19-9 values was essentially the measurement obtained from the Fujirebio Diagnostics CA 19-9 RIA predicate device.

8. The Sample Size for the Training Set

The document does not specify a separate training set size for the development of the ADVIA Centaur CA 19-9 Assay. This is common for traditional immunoassays, where the "training" involves optimizing reagents, chemistry, and instrument parameters rather than iterative machine learning on a distinct dataset. Clinical and analytical performance studies are typically conducted on independent samples after the assay development is complete.

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

As there's no explicitly defined "training set" in the context of machine learning, the question of its ground truth establishment is not applicable in the same way. The development of an immunoassay involves extensive biochemical research, optimization of antibody performance, fluorogenic labels, reaction kinetics, and calibration curves using known standards, rather than establishing a ground truth for a dataset to "train" an algorithm.

Summary

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K 031393

JUN 2 4 2003

Section 4 Premarket Notification – 510(k)

Bayer HealthCare Diagnostics Division ADVIA Centaur® CA 19-9 Assay

Summary of Safety and Effectiveness

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Bayer HealthCare, Diagnostics Division ADVIA Centaur CA 19-9 Assay

Summary of Safety and Effectiveness

This Summary of Safety and Effectiveness has been prepared in accordance with the requirements of 21 CFR 807.92, to provide sufficient information to understand the basis for a determination of substantial equivalence.

1. Submitter Information Kenneth T. Edds, Ph.D. Contact Person: Baver HealthCare Address: Diagnostics Division 511 Benedict Ave. Tarrytown, NY 10591 Phone: (914) 524 2446 Fax: (914) 524 2500 e-mail: ken.edds.b@bayer.com Date Summary Prepared: April 25, 2003 2. Device Information Propriety Name: ADVIA Centaur® CA 19-9 Assav Common Name: Immunological test for CA 19-9 Antigen (1116NS19-9 Antibody Defined Antigen) Classification Name: Tumor Associated Antigen Immunological Test System: Calibrator Class: = CFR: 21 CFR 866.6010; 21 CFR 862.1150 Product Code: NIG, JIT

3. Predicate Device Information

Name:	Fujirebio Diagnostics CA 19-9 RIA
Manufacturer:Manufactured by:	Fujirebio Diagnostics, Inc.201 Great Valley ParkwayMalvern, PA 19355
510(k) Number:	K020566

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4. Device Description

5. Statement of Intended Use

6. Substantial Equivalence

The ADVIA Centaur CA 19-9 Assay is substantially equivalent to the Fujirebio Diagnostics CA 19-9 RIA predicate device cleared under K020566. Both products are based on the use of the same monoclonal antibody (Mab), 1116NS19-9, which is intended for use in the quantitative determination of the CA 19-9 tumorassociated antigen.

(a) Technological Characteristics

The following table compares the technology features of the ADVIA Centaur CA 19-9 Assay with the Fujirebio Diagnostics CA 19-9 RIA predicate device:

Feature	ADVIA Centaur® CA19-9Immunoassay	Fujirebio Diagnostics CA 19-9RIA (Predicate Device)
Intended Use	Quantitative determination of CA19-9 tumor-associated antigen	Quantitative determination of CA19-9 tumor-associated antigen
Indication for Use	An aid in the management ofpatients diagnosed with cancersof the exocrine pancreas	An aid in the management ofpatients diagnosed with cancersof the exocrine pancreas
Assay Principle	Chemiluminescenceimmunoassay	Radioimmunoassay
Sample Type	Human serum	Human serum or plasma
Sample Volume	75 µL	100 µL

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Feature	ADVIA Centaur® CA19-9Immunoassay	Fujirebio Diagnostics CA 19-9RIA (Predicate Device)
Calibrator	CA 19-9 Calibrator set (2 levels)	CA 19-9 Standard set (6 levelsincluding 0)
Controls	Tumor Marker Plus 1, 2 Controlset	Defibrinated human plasmacontaining 2 levels of CA 19-9
Instrument	ADVIA Centaur System, a fullyautomated, random-accessimmunoassay analyzer	Manual method or semi-automated with commerciallyavailable rinsing/aspirationsystems
Measuring Range	1.2 - 700 Units/mL	0.9 - 240 Units/mL

(b) Performance Characteristics

The following table compares the performance characteristics of the ADVIA Centaur CA 19-9 assay with the Fujirebio Diagnostics CA 19-9 RIA predicate device:

Feature	Bayer ADVIA Centaur® CA 19-9Immunoassay	Fujirebio Diagnostics CA 19-9RIA (Predicate Device)
Precision	Within-run 4.3 – 11.3 %CV from 7.2 – 386.7 Units/mL Total 5.5 – 14.5 %CV from 7.2 – 386.7 Units/mL	Values for duplicates should be within 15% of the mean (except for 0 standard0)
Hook Effect	No high dose effect up to 5,800,000 Units/mL	None up to 1,250,000 Units/mL
Analytical Sensitivity	1.2 Units/mL	0.9 Units/mL
Limitations/Warning/Precautions	This test has been evaluated with serum. No interference from hemoglobin up to 1200 mg/dL No interference from triglycerides up to 3500 mg/dL No interference from bilirubin up to 60 mg/dL No interference from human serum albumin up to 14 g/dL No interference from commonly used pharmaceutical drugs. Patients known to be genotypically negative for the Lewis blood group antigen will be unable to produce the CA 19-9 antigen even in the presence of malignant tissue. Results should always be assessed in conjunction with the patient's medical history, clinical evaluation and other diagnostic procedures.	This test has been evaluated with serum and plasma (using different anticoagulants). However, it is recommended that if the specimen type is changed during patient monitoring, the patient should be re-baselined to negate any potential biases due to specimen type. The assay should not be performed on clotted, icteric hemolyzed or lipemic samples. No interference from commonly used pharmaceutical drugs. Patients known to be genotypically negative for the Lewis blood group antigen will be unable to produce the CA 19-9 antigen even in the presence of malignant tissue. Results should always be assessed in conjunction with the patient's medical history, clinical evaluation and other diagnostic procedures.

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(c) Clinical Concordance

The following two 2x2 tables compare the clinical concordance of the ADVIA Centaur CA 19-9 Assay (test device) and the Fujirebio Diagnostics CA 19-9 RIA (predicate device) with a change in a patient's CA 19-9 value relative to disease progression.

Monitoring of Pancreatic Cancer Patients for Changes in Disease Status: Correspondence of Serial CA 19-9 Changes as Measured by the ADVIA Centaur CA 19-9 Assay (Test Device) and Clinical Status (Per-Visit Analysis).

Change in CA 19-9		Change in Disease State
	Progression	No Progression	Total
> 15% increase	39	27	66
≤ 15% increase	18	47	65
Total	57	74	131

Concordance = (39+47)/ 131 = 65.7% (95% CI of 54.9% to 76.3%) Predictive Value (No Progression) = 47/74 = 63.5% (95% CI of 52.9% to 77.4%) Predictive Value (Progression) = 39/57 = 68.4% (95% CI of 56.6% to 80.1%)

Monitoring of Pancreatic Cancer Patients for Changes in Disease Status: Correspondence of Serial CA 19-9 Changes as Measured by the Fujirebio Diagnostics CA 19-9 RIA (Predicate Device) and Clinical Status (Per-Visit Analysis),

Change in CA 19-9	Progression	No Progression	Total
> 20% increase	37	19	57
< 20% increase	20	55	74
Total	55	74	131

Concordance = (37+55)/ 131 = 70.2% (95%CI of 59.5% to 80.9%)

Predictive Value (No Progression) = 55/74 = 74.3% (95% CI of 64.3% to 83.8%)

Predictive Value (Progression) = 37/57 = 64.9% (95% CI of 52.9% to 77.1%)

For 360 samples in the assay range of 1.2 - 700 Units/mL, the relationship of the ADVIA Centaur CA 19-9 Assay to the Fujirebio Diagnostics CA 19-9 RIA is described by the following equation (as determined with a Passing-Bablock Regression):

ADVIA Centaur CA 19-9 = 0.97 (Fujirebio RIA) + 0.13 Units/mL

The correlation coefficient (r) is 0.88.

	Coefficient	95% CI
Intercept	0.127	-1.234 to 1.970
Slope	0.972	0.914 to 1.032

The non-clinical and clinical data presented herein demonstrate substantial equivalence of the ADVIA Centaur CA 19-9 Assay to the FDA-cleared Fujirebio Diagnostics CA 19-9 RIA.

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Kenneth T. Edds, Ph.D. Manager Regulatory Affairs Bayer HealthCare Diagnostics Division 511 Benedict Avenue Tarrytown, New York 10591-5097

Re: K031393 Trade/Device Name: ADVIA Centaur® CA 19-9 Assay Regulation Number: 21 CFR § 866.6010 Regulation Name: Tumor Associated Antigen Immunological Test System; Calibrator Regulatory Class: II Product Code: NIG, JIT Dated: May 2, 2003 Received: May 5, 2003

JUN 2 4 2003

Dear Dr. Edds:

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.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

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Page 2 -

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). 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) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.

Sincerely yours,

steven Sutman

Steven I. Gutman, M.D., M.B.A. Director Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Page

510(k) Number (if known):

Device Name: ADVIA Centaur® CA 19-9 Assay

Indications for Use:

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use(Per 21 CFR 801.109)	✓
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Division Sign-Off	JP Reves for S.Banton
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	Over-The-Counter Use (Optional Format 1-2-96)
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Office of In Vitro Diagnostic Device Evaluation and Safety

510(k)	K031393
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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.