The Access BR Monitor assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of CA 15-3 antigen levels in human serum and plasma using the Access Immunoassay Systems. This device is indicated for use in the measurement of CA 15-3 antigen to aid in the management of breast cancer patients. Serial testing for patient CA 15-3 antigen concentrations should be used in conjunction with other clinical methods for monitoring breast cancer.

Device Description

The Access BR Monitor reagents, calibrators, and the Access Immunoassay Analyzers (Access, Access 2, Synchron LXi 725, and UniCel Dxl 800) comprise the Access Immunoassay Systems for the quantitative determination of CA 15-3 antigen in human serum and plasma.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Beckman Coulter Access BR Monitor, based on the provided document:

Acceptance Criteria and Device Performance

Acceptance Criteria Category	Specific Criteria/Metric	Reported Device Performance/Result
Imprecision (Analytical)	Within-run imprecision (CV)	Ranged from 1.4% CV to 2.2% CV for concentrations from ~15 to 662 U/mL.
	Between-run imprecision (CV)	Ranged from 1.6% CV to 4.1% CV.
	Total imprecision (CV)	Ranged from 2.1% CV to 4.6% CV.
Analytical Sensitivity	Lowest detectable level of CA 15-3 antigen	< 0.5 U/mL.
Dilution Recovery (Linearity)	Average recovery	101%
	Individual recoveries range	89% to 113%
Methods Comparison	Agreement with predicate device (linear regression)	y = 0.8234x + 1.9212, r = 0.91
Analytical Specificity	Interference from therapeutic drugs/similar compounds	No significant interference.
	Interference from potential sample interferents	No significant interference from total protein, bilirubin, hemoglobin, and triglycerides.
Stability	Reagent stability after opening	56 days.
	Calibrator stability after opening	90 days.
	Calibration curve stability	56 days.
Clinical Performance (Relative to Predicate)	Percent positive agreement (relative sensitivity)	83.8% (based on URL of 31.3 U/mL).
	Percent negative agreement (relative specificity)	98.5% (based on URL of 31.3 U/mL).
	Total agreement (between the two assays)	90.7%.
Clinical Sensitivity (Progression)	Access BR Monitor clinical sensitivity	70.5% (using 31.3 U/mL URL).
	Predicate device clinical sensitivity	75.0% (using 31.3 U/mL URL).
Clinical Specificity (No Evidence of Disease)	Access BR Monitor clinical specificity	90.0% (using 31.3 U/mL URL).
	Predicate device clinical specificity	85.0% (using 31.3 U/mL URL).
LS % Change Analysis	Percent positive agreement (relative to predicate)	92.5% (95% CI 80.1% to 97.4%).
	Percent negative agreement (relative to predicate)	77.8% (95% CI 54.8% to 91.0%).
	Total agreement (relative to predicate)	87.4% (95% CI 79.6% to 92.5%).
	Positive concordance (relative to clinical status)	52.9% (95% CI 36.7% to 68.6%).
	Negative concordance (relative to clinical status)	63.8% (95% CI 52.0% to 74.1%).
	Total concordance (relative to clinical status)	60.2% (95% CI 50.5% to 69.1%).

Study Information

2. Sample sizes used for the test set and the data provenance:

Methods Comparison (Analytical):
- Sample Size: 435 samples
- Data Provenance: Human serum samples. No country of origin is explicitly stated, but clinical studies often involve multi-site collection, implicitly from the country of the submitting company (USA) or collaborating regions. The sample type (serum) is mentioned, indicating laboratory-based retrospective analysis.
Clinical Studies (Serial Monitoring):
- Sample Size: The document refers to "subjects" and "samples" from a serial monitoring study. The exact number of subjects or individual samples (visit pairs) used for the clinical agreement and concordance calculations (e.g., 83.8% positive agreement, 52.9% positive concordance) is not explicitly stated as a single number for each metric, but it refers to the "serial monitoring study."
- Data Provenance: Samples from subjects diagnosed with breast cancer, monitored over the course of disease management. This indicates prospective collection relative to the disease course, but the analysis described would be retrospective with respect to the study endpoint. Country of origin not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

The document does not explicitly state the number or qualifications of experts used to establish ground truth for the test set. For cancer management studies, clinical ground truth would typically be established by oncologists, pathologists, and other medical specialists, but this information is not provided.
The "Least Significant %Change (LS %Change)" analysis compared the device's performance against "clinical status" (classified as "Progression" or "No Progression"), which would implicitly rely on expert clinical assessment, but the details are absent.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

The document does not describe any explicit adjudication method for establishing ground truth, such as a consensus process among multiple experts. The reliance is generally placed on the "predicate device" for comparative agreement or "clinical status" for concordance, which would have had their own "ground truth" methods in their original context.

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:

This device is an immunoassay system (a laboratory diagnostic test for measuring a biomarker, CA 15-3), not an imaging or pathology device that typically involves "human readers" or AI assistance in interpretation in the MRMC sense. Therefore, an MRMC study related to human readers improving with AI assistance is not applicable to this type of device and was not performed or reported.

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

Yes, the performance presented in the "Summary of Analytical Studies" and "Summary of Clinical Studies" pages all represent standalone (algorithm only) performance of the Access BR Monitor assay. This is an automated immunoassay system that quantitatively measures CA 15-3 levels. Its output is the CA 15-3 concentration, which is then used by clinicians for patient management. There is no human "reading" of an image or pattern that is then assisted by an AI.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

Analytical Studies:
- For imprecision, sensitivity, and dilution recovery, the ground truth is based on reference materials, spiked samples, and controlled dilutions, which are standard laboratory validation methods.
- For methods comparison, the ground truth for comparison was the predicate device's measurements (Abbott AxSYM® CA 15-3™).
Clinical Studies:
- For relative sensitivity/specificity and agreement, the ground truth was the predicate device's classification (based on its URL).
- For clinical sensitivity/specificity related to disease status, the ground truth was clinical status ("Progression" or "No Evidence of Disease"), which would be determined by a combination of clinical assessment, imaging, and possibly pathology, though not detailed in this document.

8. The sample size for the training set:

The document does not provide information on a "training set" for the Access BR Monitor assay, as it is a quantitative immunoassay with established biochemical principles, not a machine learning or AI algorithm in the contemporary sense that requires explicit data training. The "development" of such assays involves reagent formulation, calibration, and optimization rather than machine learning on a dataset.

9. How the ground truth for the training set was established:

As explained above, the concept of a "training set" in the context of machine learning and its corresponding ground truth establishment is not applicable to this immunoassay device as described in the provided 510(k) summary. The development process would have involved internal R&D and validation using known samples and established analytical methods.

Summary

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FEB - 3 2004

510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is:

Submitter's Name and Address

Beckman Coulter, Inc. 1000 Lake Hazeltine Drive Chaska, MN 55318 Telephone: (952) 368-1323 Fax: (952) 368-7610 Contact: Brent Taber

Date Prepared: January 23, 2004

Device Names

Proprietary Name:	BR Monitor and BR Monitor Calibrators on theAccess® Immunoassay Systems
Common Name:	Immunological test for CA 15-3 antigen
Classification Name:	System, Test, Immunological, Antigen, Tumor

Predicate Device

Abbott AxSYM® CA 15-3 TM Abbott Laboratories, Diagnostics Division Abbott Park, IL 60064

510(k) Number: K963926

Device Description

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Intended Use

Attribute	AxSYM CA 15-3	Access BR Monitor
IntendedUse	For the measurement ofCA 15-3 antigen in humanserum and plasma	For the measurement ofCA 15-3 antigen in humanserum and plasma
AssayPrinciples	Utilizes the binding of CA 15-3to a specific monoclonalantibody in a two site"sandwich" immunoassay;Utilizes alkaline phosphataseenzyme conjugated tomonoclonal antibody	Utilizes the binding of CA 15-3to a specific monoclonalantibody in a two site"sandwich" immunoassay;Utilizes alkaline phosphataseenzyme conjugated tomonoclonal antibody
SolidSupport	Latex particles	Paramagnetic particles
DetectionSystem	Utilizes 4-MethylumbelliferylPhosphate substrate;Measures fluorescentMethylumbelliferone from afluorescent reaction	Utilizes dioxetane-basedchemiluminescent substrate;Measures light production froma chemiluminescent reaction
Calibrators	Liquid calibrators preparedfrom buffered bovine serumalbumin matrix with CA 15-3antigen at specified levels	Liquid calibrators preparedfrom buffered bovine serumalbumin matrix with CA 15-3antigen at specified levels

Comparison of Technological Characteristics

Beckman Coulter, Inc. 1000 Lake Hazeltine Drive Chaska, MN 55318-1084

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Image /page/2/Picture/0 description: The image shows the logo for Beckman Coulter. The logo consists of a circular symbol on the left and the company name on the right. The symbol is a black circle with a white, wave-like design inside. The company name, "BECKMAN COULTER," is written in bold, black letters, with "BECKMAN" on the top line and "COULTER" on the bottom line.

Summary of Analytical Studies

Imprecision: Within-run assay imprecision was tested for concentrations from approximately 15 to 662 U/mL. The within-run imprecision ranged from 1.4% CV to 2.2% CV. Between-run assav imprecision ranged from 1.6% CV to 4.1% CV. Total imprecision ranged from 2.1% CV to 4.6% CV.

Analytical Sensitivity: The lowest detectable level of CA 15-3 antigen distinquishable from zero (Access BR Monitor Calibrator $0) is < 0.5 U/mL.

Dilution Recovery (Linearity): Linearity studies performed by diluting 6 human serum samples at various levels with Access Sample Diluent A provided an average recovery of 101%, with individual recoveries ranging from 89% to 113%.

Methods Comparison: A comparison of CA 15-3 antigen values from 435 samples, ranging from approximately 0 to 250 U/mL, run with both the Access BR Monitor assay and the AxSYM CA 15-3 assay demonstrated acceptable agreement with the following statistical data: y = 0.8234x + 1.9212, r = 0.91.

Analytical Specificity: There was no significant interference from therapeutic drugs or similar compounds in the Access BR Monitor assay. In addition, there was no significant interference from potential sample interferents (total protein, bilirubin, hemoglobin, and triglvcerides).

Stability: Access BR Monitor reagents are stable for 56 days after opening and calibrators are stable for 90 days after opening. The calibration curve is stable for 56 days.

Summary of Clinical Studies

A value of 31.3 U/mL CA 15-3 for apparently healthy female subjects was set as the upper reference limit (URL) for the Access BR Monitor assay. The distribution of Access BR Monitor values for apparently healthy female subjects and for female subjects with non-malignant and malignant conditions are comparable with results provided in the predicate device labeling.

Results from a serial monitoring study of subjects who were diagnosed with breast cancer and who were monitored over the course of disease management demonstrate that CA 15-3 concentrations obtained with the Access BR Monitor assay paralleled results obtained with the predicate device.

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Summary of Clinical Studies, continued

Results from samples in a serial monitoring study show percent positive agreement (relative sensitivity) and percent negative agreement (relative specificity), based on the URLs for the Access BR Monitor and the predicate device (URL = 31.3 U/mL), were 83.8% and 98.5%, respectively. The % agreement between the two assays was 90.7%.

Based on samples from the serial monitoring study categorized as "Progression", the clinical sensitivity, using the 31.3 U/mL URLs, for the Access BR Monitor and for the predicate device were 70.5% and 75.0%. respectively. Based on samples from the serial monitoring study categorized as "No Evidence of Disease", the clinical specificity, using the 31.3 U/mL URLs, for the Access BR Monitor and for the predicate device were 90.0% and 85.0%, respectively.

A 25% Least Significant %Change (LS %Change) was selected to cover the imprecision across the range of Access BR Monitor concentrations. The LS %Change represents the minimum magnitude change between two serial CA 15-3 antigen measurements that could not be attributed to assay variation or noise. The effectiveness of CA 15-3 antigen measurements to aid in the management of breast cancer subjects was also further determined by assessing changes in CA 15-3 antigen levels in serial sets (sequential visit pairs) with changes in disease status. Samples from subjects from the serial monitoring study were further analyzed for %Change in CA 15-3 antigen concentrations across serial sets (sequential visit pairs) and disease status. In this evaluation disease status, between consecutive serial draws, was classified as "Progression" or "No Progression".

The LS %Change analysis resulted in a percent positive agreement of 92.5% (95% CI 80.1% to 97.4%), a percent negative agreement of 77.8% (95% CI 54.8% to 91.0%), and a percent total agreement of 87.4% (95% Cl 79.6% to 92.5%) relative to the predicate device. The LS %Change analysis resulted in positive concordance of 52.9% (95% Cl 36.7% to 68.6%), negative concordance of 63.8% (95% Cl 52.0% to 74.1%), and total concordance of 60.2% (95% Cl 50.5% to 69.1%) relative to clinical status for the Access BR Monitor assay.

Conclusion

Access BR Monitor and BR Monitor Calibrators on the Access Immunoassay Systems is substantially equivalent to Abbott AxSYM CA 15-3 for the measurement of CA 15-3 antigen in human serum and plasma.

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. Brent Taber Senior Regulatory Specialist Beckman Coulter. Inc. 1000 Lake Hazeltinc Drive Chaska, Minnesota 55318-1084

FEB - 3 2004

Re: K033036 Trade/Device Name: BR Monitor and BR Monitor Calibrators on the Access Immunoassay Systems Regulation Number: 21 CFR § 866.6010 Regulation Name: Tumor Associated Antigen (Immunological System) Regulatory Class: II Product Code: MOI, JIT Dated: January 26, 2004 Received: January 28, 2004

Dear Mr. Taber:

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,

Joseph L. Arnholt

Joseph L. Hackett, Ph.D. Acting Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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INDICATIONS FOR USE STATEMENT

Page 1 of 1

Ko33036 510(k) Number (if known):

Device Name: BR Monitor and BR Monitor Calibrators on the Access Immunoassay Systems

Indications For Use:

(PLEASE DO NOT WRITE BELOW THIS LINE--CONTINUE ON ANOTHER PAGE ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Concurrence of CDRH, Office of Device Evaluation (ODE)

Mana M Chan

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k)________________________________________________________________________________________________________________________________________________________________________ Prescription Use OR Over-The Counter Use (Per 21 CFR 801.109)

(Optional Format 1-2-96)

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.