The VITROS®CA 15-3 is an in vitro assay intended for the quantitative measurement of DF3 defined antigen in serum or plasma (EDTA or heparin) from patients previously treated for stage II or stage III breast cancer. Serial test results obtained with the VITROS CA 15-3 assay, in patients who are clinically free of disease, should be used in conjunction with all relevant information derived from diagnostic test, physical examination and full medical history in accordance with appropriate patient management procedures used for early detection of recurrence. The test is also intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring progression or response to treatment.

Device Description

The VITROS Immunodiagnostic System uses luminescence as the signal in the quantitative and semi-quantitative determination of selected analytes in human body fluids, commonly serum and plasma. Coated microwells are used as the solid phase separation system. The system is comprised of three main elements: 1. The VITROS Immunodiagnostic Products (in this case VITROS Immunodiagnostic Products CA 15-3 Reagent Pack, VITROS Immunodiagnostic Products CA 15-3 Calibrators, which are combined by the VITROS Immunodiagnostic System to perform the VITROS CA 15-3 assay). 2. The VITROS Immunodiagnostic System instrumentation, which provides automated use of the immunoassay kits. 3. Common reagents used by the VITROS System in each assay.

AI/ML Overview

The provided text does not contain acceptance criteria in the traditional sense of performance metrics (e.g., sensitivity, specificity, accuracy thresholds) for a diagnostic device.

Instead, the document focuses on demonstrating substantial equivalence to a previously cleared predicate device (Centocor CA 15-3 RIA) for regulatory approval (510(k)). This means the study aims to show that the new device performs similarly and is as safe and effective as the existing one, rather than meeting specific predefined performance targets set independently.

Here's an analysis based on the information provided, addressing as many of your points as possible:

1. Table of Acceptance Criteria and Reported Device Performance

As noted, explicit acceptance criteria (e.g., "sensitivity must be >X%") are not provided in the document. The primary criterion is demonstrating substantial equivalence to the predicate device.

Device Characteristic	Acceptance Criteria (Implied by Substantial Equivalence)	Reported Device Performance (VITROS CA 15-3 assay)
Calibration Range	Should be comparable to or improve upon the predicate device for clinical utility.	0 - 500 U/mL (Predicate: 0 - 200 U/mL, showing an expanded range)
Basic Principle	Similar immunoassay principle.	Solid phase immunoassay (Predicate: Solid phase radioimmunoassay - similar but different tracer)
Tracer	Functionally equivalent to quantify the analyte.	Enzyme labeled (Predicate: Radioactive tracer - different, but deemed equivalent in function)
Sample Type	Same or broader range of clinically relevant sample types.	Serum, plasma (heparin or EDTA) (Predicate: Serum, plasma - broader for plasma type)
Antibody	Should detect the same antigen (DF3) effectively.	1) Mouse monoclonal anti-DF3 antigen antibody in biotinylated antibody reagent; 2) Mouse monoclonal anti-DF3 antigen antibody in conjugate reagent (Predicate: 1) Mouse monoclonal 115D8 antibody coated onto beads; 2) Mouse monoclonal DF3 antibody labeled with I125 - different antibodies but target same antigen)
Sample Volume	Clinically reasonable and practical.	10 µL (Predicate: 20 µL - improvement in sample efficiency)
Incubation Time & Temp	Clinically reasonable and practical, ideally improving throughput.	First incubation 16 minutes at 37°C with shaking; Second incubation 16 minutes at 37°C with shaking (Predicate: First incubation 2 hours at room temperature; Second incubation 3 hours at room temperature - significant improvement in speed)
Correlation	Strong positive correlation (e.g., correlation coefficient > 0.9) with the predicate.	Bablock Passing regression: VITROS CA 15-3 assay = 0.945 x [Centocor CA 15-3 RIA] + 1.55 (U/mL); Correlation coefficient: 0.978
Clinical Utility	Expected to demonstrate similar clinical utility for monitoring recurrence and treatment response.	"The serial monitoring study demonstrated the clinical utility of the VITROS CA 15-3 assay for monitoring for recurrence of disease in patients previously treated for stage II or stage III breast cancer and for monitoring response to treatment of breast cancer patients with metastatic disease."

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

Sample Size: The document states that comparisons were performed with "samples from a variety of clinical categories" and "patient specimens from patients who are normal, undergoing therapeutic and/or undergoing diagnostic evaluation." However, specific sample sizes for the test set are not provided in the excerpt.
Data Provenance: The document does not specify the country of origin of the data. The data appears to be retrospective as it involves "patient specimens" and "clinical studies of apparently healthy individuals, patients with cancer and patients with a variety of non-malignant diseases," indicating samples collected prior to the study for the VITROS assay.

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

There is no mention of experts being used to establish ground truth in the context of this diagnostic assay. For an in vitro diagnostic test that measures a biomarker (CA 15-3 antigen), the "ground truth" is typically the quantitative value obtained from the reference method (the predicate device) or from established analytical assays. The study aims to correlate the new device's measurements with those of the predicate.

4. Adjudication Method for the Test Set

Not applicable. As described above, this is a quantitative in vitro diagnostic assay comparing its results to a predicate device, not a qualitative assessment requiring expert adjudication.

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

Not applicable. This is an in vitro diagnostic device, not an AI or imaging device involving human readers/interpreters.

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

This device is a standalone diagnostic kit/system. Its performance is evaluated directly through its quantitative measurements, rather than as an assistant to a human. The "standalone" performance is essentially what the comparability study demonstrates.

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

The primary ground truth/reference standard used for comparison is the results obtained from the legally marketed predicate device, the Centocor CA 15-3 RIA. This is implicitly considered the "truth" for establishing substantial equivalence. Additionally, "clinical utility" was demonstrated via a "serial monitoring study" for recurrence and response to treatment, which would likely involve outcomes data (e.g., disease recurrence, treatment response status) but the methodology for determining these outcomes is not detailed.

8. The Sample Size for the Training Set

Not applicable. This document describes a traditional in vitro diagnostic assay, not a machine learning or AI-based device that typically has a distinct "training set." The development of such assays often involves optimization and calibration using various samples, but these are not usually referred to as a "training set" in the context of AI.

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

Not applicable, as there is no mention of a "training set" for an AI or machine learning model. The assay's development would involve establishing accurate measurements against known standards and optimizing chemical/biological parameters, but this is a different process than establishing "ground truth" for machine learning training.

Summary

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ADMINISTRATIVE l

1.1 510(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: J

1. Submitter name, address, contact

Ortho-Clinical Diagnostics, Inc. 100 Indigo Creek Drive Rochester, New York 14626-5101 (716) 453-3607

Contact Person: Anne Zavertnik

Date 510(k) prepared: October 19, 1998

2. Device Name

Trade or Proprietary Name: VITROS Immunodiagnostic Products CA 15-3 Calibrators VITROS Immunodiagnostic Products CA 15-3 Reagent Pack

Common Name: CA 15-3 assay

Classification Name: test for the in vitro quantitative determination of DF3-defined antigen in serum or plasma.

3. Comparitor Device

The VITROS Immunodiagnostic Products CA 15-3 assay is substantially equivalent to the Centocor CA 15-3 RIA (K963803).

4. Device Description

The system is comprised of three main elements:

1. The VITROS Immunodiagnostic Products (in this case VITROS Immunodiagnostic Products CA 15-3 Reagent Pack, VITROS Immunodiagnostic Products CA 15-3 Calibrators, which are combined by the VITROS Immunodiagnostic System to perform the VITROS CA 15-3 assay).
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1. The VITROS Immunodiagnostic System instrumentation, which provides automated use of the immunoassay kits. The VITROS Immunodiagnostic System was cleared for market by a separate 510(k) pre-market notification (K962919).
1. Common reagents used by the VITROS System in each assay. The VITROS Immunodiagnostic Products Signal Reagent and VITROS Immunodiagnostic Products Universal Wash Reagent were cleared as part of the VITROS Immunodiagnostic Products Total T3 510(k) pre-market notification (K984310).

The VITROS System and common reagents are dedicated specifically only for use with the VITROS Immunodiagnostic Products range of immunoassay products.

5. Device Intended Use

6. Comparison to Comparitor Device

The VITROS Immunodiagnostic Products CA 15-3 assay is substantially equivalent to Centocor CA 15-3 RIA (comparitor device), which was approved by FDA (K963803) for IVD use.

The relationship between the VITROS CA 15-3 assay and the comparitor device, determined by Bablock Passing regression, is:

VITROS CA 15-3 assay = 0.945 x [Centocor CA 15-3 RIA] + 1.55 (U/mL). with a correlation coefficient of 0.978.

Comparisons of the VITROS CA 15-3 assay and the comparitor device were performed with samples from a variety of clinical categories.

In addition to the studies mentioned above, tests were performed to obtain analytical sensitivity, specificity, precision, dilution and expected values. Refer to the VITROS CA 15-3 assay package insert for VITROS CA 15-3 assay results.

Table 1 lists the similarities and differences of the device characteristics between the VITROS CA 15-3 assay with the comparitor device, Centocor CA 15-3 RIA assay:

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Table 1 List of the assay characteristics

DeviceCharacteristic	VITROS CA 15-3 assay	ComparitorDevice
Calibration range	0 - 500 U/mL	0 - 200 U/mL
Basic principle	Solid phase immunoassay	Solid phaseradioimmunoassay
Tracer	Enzyme labeled	Radioactive tracer
Sample type	Serum, plasma (heparin orEDTA)	Serum, plasma
Antibody	1) Mouse monoclonal anti-DF3 antigen antibody inbiotinylated antibodyreagent2) Mouse monoclonal anti-DF3 antigen antibody inconjugate reagent	1) Mouse monoclonal115D8 antibody coatedonto beads2) Mouse monoclonalDF3 antibody labeledwith I125
Sample volume	10 µL	20 µL
Incubation time andtemperature	First incubation 16minutes at 37°C withshakingSecond incubation 16minutes at 37°C withshaking	First incubation 2 hours atroom temperatureSecond incubation 3hours at room temperature

7. Conclusions

The data presented in the premarket notification demonstrate that the VITROS CA 15-3 assay performs substantially equivalent to the cleared comparitor device.

Equivalence was demonstrated using currently commercially available reagents along with patient specimens from patients who are normal, undergoing therapeutic and/or undergoing diagnostic evaluation. In clinical studies of apparently healthy individuals, patients with cancer and patients with a variety of non-malignant diseases, the VITROS CA 15-3 assay exhibited distribution results that parallel expected distributions for these patient types.

The serial monitoring study demonstrated the clinical utility of the VITROS CA 15-3 assay for monitoring for recurrence of disease in patients previously treated for stage II or stage III breast cancer and for monitoring response to treatment of breast cancer patients with metastatic disease.

The data presented in the premarket notification provide a reasonable assurance that the VITROS CA 15-3 assay is safe and effective for the stated intended use.

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Image /page/3/Picture/2 description: The image shows a partial view of a logo or emblem, featuring a stylized design of three curved lines stacked on top of each other. The lines appear to be thicker at the top and taper slightly as they descend. To the left of the design, a portion of text is visible, oriented vertically. The text is partially cut off, but the visible letters suggest it is part of a larger phrase or title.

FEB 2 1999

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Anne Zavertnik Regulatory Affairs Associate Ortho-Clinical Diagnostics, Inc. 100 Indigo Creek Drive Rochester, New York 14626-5101

Re: K983690 Trade Name: VITROS Immunodiagnostic Products CA 15-3 Calibrators VITROS Immunodiagnostic Products CA 15-3 Reagent Pack Regulatory Class: II Product Code: MOI December 14, 1998 Dated: Received: December 16, 1998

Dear Ms. Zavertnik:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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 (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in In addition, FDA may publish further requlatory action. announcements concerning your device in the Federal Register. this response to your premarket notification Please note: submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or requlations.

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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655.

This letter will allow you to begin marketing your device as described in your 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.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification"(21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers 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 Putman

Steven I. Gutman, M.D. M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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1.3 Indications For Use Statement

K 9431,90

510(k) Number (if known):

Device Name:

VITROS Immunodiagnostic Products CA 15-3 Reagent Pack VITROS Immunodiagnostic Products CA 15-3 Calibrators

Indications for Use:

Petu G. Moir

Division Sign-Off)
Division of Clinical Laboratory Devices K983698
510(k) Number

(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)

…

Over-The-Counter Use _

(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.