Immunological in vitro assay for quantitative determination of CA 15-3 in human serum, Li-heparin and EDTA plasma to aid in the management of breast cancer patients. In conjunction with other clinical and diagnostic procedures, serial testing with this assay is an aid

· in the early detection of recurrence in previously treated stage II and III breast cancer patients
· for monitoring response to therapy in metastatic breast cancer patients
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Device Description

The Elecsys CA 15-3 II Test System is a two-step sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection for the quantitative determination of CA 15-3 in human serum, Li-heparin plasma and EDTA plasma. It is intended for use on the cobas e 801 immunoassay analyzer. The cobas e family of analyzers employs the electrochemiluminescence "ECLIA" technology. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve provided via the cobas link.

AI/ML Overview

The provided text describes a 510(k) premarket notification for the Elecsys CA 15-3 II device, which is an immunological in vitro assay for the quantitative determination of CA 15-3. The primary purpose of this specific submission (K181492) is to extend the allowable sample type to include K2-EDTA plasma, in addition to serum and Li-heparin plasma already cleared under a previous submission (K171605).

Therefore, the acceptance criteria and study specifically relate to demonstrating the comparability of K2-EDTA plasma samples to serum samples for this assay. Most other performance characteristics (precision, analytical sensitivity, hook effect, linearity, endogenous interferences, method comparison to another analyzer, and stability) were demonstrated in the prior K171605 submission and are simply referenced, not re-evaluated in detail here, as the core assay technology remains the same.

Here's the breakdown of the information requested, focusing on the K2-EDTA plasma extension:

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria (from context of K171605 and typical IVD validation)	Reported Device Performance (for K2-EDTA Plasma)
Comparability of K2-EDTA Plasma to Serum	Passing/Bablok regression analysis coefficients to represent comparable results (e.g., slope close to 1, intercept close to 0, high correlation coefficient).	Slope (95% CI): 0.985 (0.955–1.036)
		Intercept (95% CI): -0.279 (-1.143–0.288)
		Correlation Coefficient: 0.997
		Conclusion: The 44 serum/plasma pairs fulfilled the acceptance criteria for Passing Bablok Analysis. The data supports the addition of K2-EDTA plasma type.

Note: The exact numerical acceptance criteria (e.g., specific ranges for slope and intercept) for Passing/Bablok regression are not explicitly stated in this document but are implied by the "fulfilled the acceptance criteria" statement. Typically, these would be pre-defined limits for non-inferiority or equivalence.

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

Sample Size: 44 serum/plasma paired samples.
Data Provenance: The document does not explicitly state the country of origin for the samples. It is a retrospective study using existing samples, as they were "tested in singleton" for this specific comparison.

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

This study does not involve expert human readers or ground truth established by subjective expert consensus (like in imaging studies). Instead, it's a quantitative immunoassay comparing instrument measurements from different sample types.
The "ground truth" for this type of test is the measured value of the analyte (CA 15-3) in the serum sample, which is the established and currently accepted sample type. The study aims to show that the K2-EDTA plasma sample provides a comparable measurement.

4. Adjudication Method for the Test Set

None. Adjudication methods (like 2+1, 3+1) are typically used in clinical or imaging studies where subjective interpretation is involved and consensus among multiple experts is needed to establish a definitive ground truth. This is a quantitative analytical performance study.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done

No. This is an analytical performance study of an in vitro diagnostic (IVD) device, not a multi-reader, multi-case clinical effectiveness study. It assesses the device's ability to measure an analyte accurately and comparably across different sample types, not how it impacts human reader performance or diagnostic accuracy in a clinical setting.

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

Yes, this is a standalone analytical performance study. The Elecsys CA 15-3 II assay itself provides a quantitative result. The study evaluated the direct output of the assay on the cobas e 801 analyzer for different sample types. There is no "human-in-the-loop" component in the direct measurement or comparison being assessed here.

7. The Type of Ground Truth Used

The "ground truth" for comparison in this study is the measured CA 15-3 value in human serum, which is the currently accepted and validated sample matrix for this assay. The K2-EDTA plasma samples are being compared against these serum measurements to determine if they yield equivalent results. This implicitly relies on the established analytical accuracy of the device when using serum.

8. The Sample Size for the Training Set

Not applicable / Not explicitly specified for this K2-EDTA plasma validation. This is an analytical validation study of a reagent/instrument system, not a machine learning model that requires a "training set" in the conventional sense. The "training" of the assay system itself comes from its development and standardization processes (e.g., against reference methods, master curves), which would have used numerous samples but are not detailed as a distinct "training set" in this context. The K171605 submission would have contained more foundational validation data.

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

Not applicable in the context of machine learning training data. For an IVD assay like this, the "ground truth" for its development and standardization (analogous to "training") is established through:
- Traceability to international standards or reference methods: The document states the method has been standardized against other established CA 15-3 methods (Enzymun-Test CA 15-3, CA 15-3 RIA from Fujirebio Diagnostics), indicating a chain of traceability to agreed-upon CA 15-3 values.
- Analytical precision and accuracy studies: Extensive studies are performed during development to ensure the assay consistently and accurately measures the target analyte over its dynamic range using known concentrations and reference materials.
- Clinical correlation: While not the focus of this specific K181492 submission, initial device development and validation (e.g., for K171605) would have involved clinical studies to correlate CA 15-3 levels with patient outcomes, disease status, and therapy response.

In summary, this 510(k) submission (K181492) is a targeted analytical validation to expand the Indications for Use for an existing immunoassay by demonstrating the analytical equivalence of an additional sample matrix (K2-EDTA plasma) to the previously cleared serum samples. The validation relies on quantitative comparisons rather than subjective human interpretation.

Summary

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

Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which consists of the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG" in blue, and then the word "ADMINISTRATION" in a smaller font size below that.

June 22, 2018

Roche Diagnostics Adennis Cora Regulatory Affairs Consultant 9115 Hague Road Indianapolis, Indiana 46250

Re: K181492

Trade/Device Name: Elecsys CA 15-3 II Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-associated antigen immunological test system Regulatory Class: Class II Product Code: MOI Dated: June 5, 2018 Received: June 6, 2018

Dear Adennis Cora:

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 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device 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

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

Part 820); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Kelly Oliner-S

For Lea Carrington Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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

Indications for Use

510(k) Number (if known) K181492

Device Name Elecsys CA 15-3 II

Indications for Use (Describe)

· in the early detection of recurrence in previously treated stage II and III breast cancer patients
· for monitoring response to therapy in metastatic breast cancer patients

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

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}------------------------------------------------

510(k) Summary

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

The assigned 510(k) number is ___________K181492

Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457
Contact	Adennis CoraPhone: (317) 521-3915FAX: (317) 521-2324Email: adennis.cora_gress@roche.com
Date Prepared	May 10, 2018
Proprietary Name	Elecsys CA 15-3 II
Common Name	Elecsys Cancer Antigen 15-3 II
Classification Name	System, Test, Immunological, Antigen, Tumor
Product Codes,Regulation Numbers	MOI, 866.6010
Predicate Devices	Elecsys CA 15-3 II (K171605)
Establishment Registration	For the Elecsys CA 15-3 II, the establishment registration number for RocheDiagnostics GmbH manufacturing in Penzberg, Germany is 9610529, and forRoche Diagnostics GmbH packaging in Mannheim, Germany is 9610126. Theestablishment registration number for Roche Diagnostics in the United States is1823260.

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

1. DEVICE DESCRIPTION

Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve provided via the cobas link.

1.1. Reagents

The cobas e pack includes:

. Streptavidin-coated microparticles
. Reagent 1 (Biotinylated monoclonal antibody (115D8; mouse) 1.75 mg/L)
. Reagent 2 (Monoclonal anti-CA 15-3 antibody (DF3; mouse) labeled with ruthenium complex 10 mg/L)

1.2. Calibration

Traceability: This method has been standardized against the Elecsys CA 15-3 assay. This in turn has been standardized against the Enzymun Test CA 15-3 method and CA 15-3 RIA by Fujirebio Diagnostics. The predefined master curve is adapted to the analyzer using the relevant CalSet. Calibration frequency: Calibration must be performed once per reagent lot using fresh reagent (i.e. not more than 24 hours since the cobas e pack was registered on the analyzer). Calibration interval may be extended based on acceptable verification of calibration by the laboratory.

Control 1.3.

PreciControl Tumor Marker is used for the quality control verification of the performance of the assay on the cobas e analyzers.

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

2. INDICATIONS FOR USE

Immunological in vitro assay for quantitative determination of CA 15 3 in human serum.

Li-heparin and EDTA plasma to aid in the management of breast cancer patients. In conjunction with other clinical and diagnostic procedures, serial testing with this assay is an aid

in the early detection of recurrence in previously treated stage II and III breast cancer patients .
for monitoring response to therapy in metastatic breast cancer patients .

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

TECHNOLOGICAL CHARACTERISTICS 3.

The following table compares the Elecsys CA 15-3 II with its predicate device, CA 15-3 (K171605). In summary, the Elecsys CA15-3 II described in this submission is substantially equivalent to the predicate device.

Feature	Predicate	Candidate
Assay	CA 15-3 II(Cleared K171605)	Elecsys CA 15-3 II(K181492)
Intended use	Immunological in vitro assay forquantitative determination of CA15-3 in human serum and Li-heparin plasma to aid in themanagement of breast cancerpatients. In conjunction withother clinical and diagnosticprocedures, serial testing withthis assay is an aid• in the early detection ofrecurrence in previously treatedstage II and III breast cancerpatients• for monitoring response totherapy in metastatic breastcancer patientsThe electrochemiluminescenceimmunoassay “ECLIA” isintended for use on cobas e	Immunological in vitro assayfor quantitative determination ofCA 15-3 in human serum, Li-heparin and EDTA plasma toaid in the management of breastcancer patients. In conjunctionwith other clinical anddiagnostic procedures, serialtesting with this assay is an aid• in the early detection ofrecurrence in previouslytreated stage II and III breastcancer patients• for monitoring response totherapy in metastatic breastcancer patientsThe electrochemiluminescenceimmunoassay “ECLIA” isintended for use on cobas e

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

Feature	Predicate	Candidate
Sample Type	Human serum and Li-heparinplasma	Human serum, Li-heparin andK2-EDTA plasma
Analytical Specificity	Based on monoclonal 115D8 andDF3 antibodies available fromFujirebio Diagnostics, itslicensees and its representatives	Same
Instrument Platform	cobas e 801	Same
Measuring Range	3 – 300 U/mLDetermined by LOQ (Per EP17-A2)	Same
Calibrator	CA 15-3 II CalSet	Same
Control	PreciControl Tumor Marker	Same
Traceability	The method has beenstandardized against theEnzymun-Test CA 15-3 method.This in turn has beenstandardized against the CA 15-3RIA from Fujirebio Diagnostics.	Same
Prewash	Prewash needed	Same

NON-CLINICAL PERFORMANCE EVALUATION 4.

Non-clinical performance evaluation for the Elecsys CA 15-3 II are briefly summarized below:

4.1. Precision

Precision and reproducibility of the Elecsys CA 15-3 II were demonstrated under K171605.

Analytical Sensitivity 4.2.

Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) of the Elecsys CA 15-3 II were demonstrated under K171605.

High-Dose Hook Effect 4.3.

High-Dose Hook Effect of the Elecsys CA 15-3 II was demonstrated under K171605.

4.4. Linearity/Assay Reportable Range

Linearity/Assay Reportable Range of the Elecsys CA 15-3 II was demonstrated under K171605.

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

Endogenous Interferences 4.5.

Endogenous Interferences of the Elecsys CA 15-3 II was demonstrated under K171605.

Exogenous Interferences – Anticoagulants 4.6.

4.6.1 Serum/Li-Heparin Plasma Comparison

The performance of the Elecsys CA 15-3 II using Li-heparin plasmas sample comparing to serum sample on the cobas e 801 analyzer was demonstrated under K171605.

4.6.2 Serum/K2-EDTA Plasma Comparison

A study was performed to demonstrate that K2-EDTA plasma samples vield comparable values as serum samples by the Elecsys CA 15-3 II assay on the cobas e 801 analyzer. 44 serum/plasma paired samples were tested in singleton with one reagent lot on one cobas e 801 Immunoassav Analyzer. Potential effects were assessed by Passing/Bablok regression analysis. The data are summarized in the following table:

	N	Range(U/mL)	Slope(95% CI)	Intercept(95% CI)	CorrelationCoefficient
Serum vs.K2-EDTA Plasma	44	8.37–298	0.985(0.955–1.036)	-0.279(-1.143–0.288)	0.997

Conclusion:

The 44 serum/plasma pairs fulfilled the acceptance criteria for Passing Bablock Analysis. The data supports the addition of K2-EDTA plasma type.

Method Comparison to cobas e 601 Immunoassay Analyzer 4.7.

Method Comparison of the Elecsys CA 15-3 II on the cobas e 801 to the cobas e 601 immunoassay analyzer was demonstrated under K171605.

Stability (Reagent, Sample, Calibration) 4.8.

Stability (Reagent, Sample, Calibration) of the Elecsys CA 15-3 II was demonstrated under K171605.

{8}------------------------------------------------

5. CONCLUSIONS

The information provided in this 510(k) Premarket Notification will support extending the sample type to include K2-EDTA plasma for the Elecsys CA 15-3 II test system on cobas e 801. The data supports a safe, effective device which performs as well as the predicate device.

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.