For the quantitative measurement of 1116-NS-19-9 defined antigen in human serum and plasma (EDTA or heparin), using the VITROS 5600 Integrated System. The VITROS CA 19-9 test is to be used to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The VITROS CA 19-9 test can be used to monitor the disease status in patients with confirmed pancreatic cancer who show measurable CA 19-9 values over the course of their disease. Serial CA 19-9 test results should be used in conjunction with all other available clinical and laboratory data before a medical decision is determined.

Device Description

The VITROS Immunodiagnostic Products CA 19-9 assay (test) is performed using the VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack and VITROS CA 19-9 Calibrators on the VITROS 5600 System.

An immunometric immunoassay technique is used, which involves the simultaneous reaction of 1116-NS-19-9 defined antigen present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-1116-NS-19-9 defined antigen) bound to Streptavidin. In a second incubation a Horseradish Peroxidase (HRP)- labelled antibody conjugate (Mouse monoclonal anti-1116-NS-19-9 defined antigen) binds to the immobilized 1116-NS-19-9 defined antigen. Unbound materials are removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of conjugate bound is directly proportional to the concentration of 1116-NS-19-9 defined antigen present in the sample.

VITROS Immunodiagnostic Products CA 19-9™ Reagent Pack contains:
1 reagent pack containing:

100 coated wells (antibody, mouse monoclonal anti-1116-NS-19-9 defined antigen, binds >49 U 1116-NS-19-9 defined antigen/well)
13.4 mL assay reagent (buffer containing bovine gamma globulin and antimicrobial agent)
20.0 mL conjugate reagent (HRP-mouse monoclonal anti-1116-NS-19-9 defined antigen, binds ≥326 U 1116-NS-19-9 defined antigen/mL) in buffer with bovine serum albumin, bovine gamma globulin and antimicrobial agent.

VITROS CA 19-9 Calibrator contains:

1, 2, and 3 (OC 1116-NS-19-9 defined antigen in buffer with bovine serum albumin and antimicrobial agent, 1.75 mL); nominal values 15; 60 and 700 U 1116-NS-19-9 defined antigen/mL
24 calibrator bar code labels (8 for each calibrator)

AI/ML Overview

This document describes the non-clinical performance studies conducted for the VITROS CA 19-9 assay to demonstrate its safety and effectiveness. The information focuses on analytical performance characteristics rather than clinical diagnostic accuracy studies involving human experts for ground truth, which are typically found in studies for AI/ML-based medical devices or imaging diagnostics.

Since this device is an in-vitro diagnostic (IVD) assay for measuring a tumor-associated antigen (CA 19-9) in human serum and plasma, the "acceptance criteria" and "study that proves the device meets the acceptance criteria" are primarily based on established analytical performance parameters, not on human-expert-validated diagnostic accuracy. Therefore, several points from your request (e.g., number of experts, adjudication methods, MRMC studies, human-in-the-loop performance) are not directly applicable or reported in this type of submission.

Here's the breakdown of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document presents validation studies against established guidelines (e.g., CLSI documents) and compares the modified device's performance to its predicate. The nature of these acceptance criteria is based on quantitative analytical performance characteristics.

Performance Characteristic	Acceptance Criteria (Implicit from CLSI Guidelines/Predicate Performance)	Reported Device Performance (VITROS CA 19-9 Assay)
Stability (Long Term)	Support 20-week shelf-life	Data supports a 20-week shelf-life
Stability (On-Board)	Support 8-week on-board stability	Data supports 8 weeks on-board stability
Precision (Repeatability SD)	Meets CLSI EP05-A3 guidelines for various concentrations	Ranges from 0.1 to 12.1 U/mL SD (1.7% to 2.2% CV)
Precision (Within Lab SD)	Meets CLSI EP05-A3 guidelines for various concentrations	Ranges from 0.3 to 27.6 U/mL SD (3.9% to 6.6% CV)
Limit of Blank (LoB)	Verified against existing claim	1.05 U/mL (Verified)
Limit of Detection (LoD)	Determined consistent with CLSI EP17-A2	1.4 U/mL (Determined)
Limit of Quantitation (LoQ)	Designed to be ≤ 1.4 U/mL at 20%CV	Achieved at 1.4 U/mL with <20%CV
Linearity Range	Performance within allowable deviation (e.g., ±15%)	0.9 to 1152 U/mL (Pass, deviations within ±15%)
Measuring (Reportable) Range	Defined based on linearity	1.4 – 1000 U/mL
Matrix Comparison (Serum vs. Plasma)	Equivalence demonstrated, meeting acceptance criteria for comparison	Slope (Li-Hep: 0.97, EDTA: 0.98), r (Li-Hep: 0.99, EDTA: 1.00). Pass.
Known Interferences (Bias)	Bias ≤ 10% for non-interfering substances; identified substances with >10% bias	Hemoglobin (1000 mg/dL): 190.1% bias at 7.1 U/mL Rheumatoid Factor (1035 U/mL): 27.4% bias at 5.0 U/mL
Dilution Recovery	Meet product requirements	Demonstrated on samples up to 10,000 U/mL
Expected Values (Reference Interval)	Verified, with no more than 10% of normal subjects falling outside	3/60 (5%) normal subjects outside ≤37 U/mL (2 in 37.1-70, 1 in >70). Pass.
Method Comparison (Slope)	Close to 1.0 (indicating good agreement with predicate)	0.97 (95% CI: 0.95-0.99)
Method Comparison (Intercept)	Close to 0.0 (indicating good agreement with predicate)	0.15 (95% CI: -0.03-0.32)
Method Comparison (R^2)	Close to 1.0 (indicating strong correlation)	0.989

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

The "test set" here refers to the samples used in the analytical validation studies. These are not human-interpreted images or clinical datasets in the AI/ML sense but rather biological samples.

Stability Studies: Four runs on each of 3 lots at monthly intervals for long-term; 3 lots up to 12 weeks for on-board stability. Number of samples not explicitly stated but implies sufficient runs to validate stability claims.
Precision: 6 precision fluids; 2 replicates, 2 runs/day for 20 days (total 80 data points per fluid).
Detection Capability (LoB): 4 endogenous fluids with no CA19-9; 2 replicates, 2 runs/day for 5 test days (20 reps/fluid) x 4 fluids = 80 replicates x 3 lots = 240 total replicates.
Detection Capability (LoD/LoQ): 5 samples; 6 replicates, 2 runs/day for 5 test days (60 reps/fluid) x 5 fluids = 300 replicates x 3 lots = 900 total replicates.
Linearity: 16 levels in the test panel; 5 replicates of each level run on 3 reagent lots over 2 days.
Matrix Comparison: 41 specimens for Li-Hep vs. Serum and 41 specimens for EDTA vs. Serum.
Analytical Specificity (Interferences): Tested at CA 19-9 concentrations of ~5.0 U/mL and ~50.0 U/mL. Specific sample numbers for this testing are not given but are implied to be within CLSI guidelines.
Expected Values (Reference Interval): 60 normal blood donors.
Method Comparison: 118 patient serum samples.

Data Provenance: The document does not explicitly state the country of origin for the samples or if they were retrospectively or prospectively collected. The studies appear to be laboratory-based analytical validation studies.

3. Number of Experts Used to Establish Ground Truth and Qualifications

This concept is not applicable to this type of IVD analytical device validation. The "ground truth" for the performance of a CA 19-9 assay is established by the known concentration of the analyte in control samples, reference materials, or by comparison to a well-validated predicate method, not by human expert interpretation of images or clinical outcomes.

4. Adjudication Method for the Test Set

This concept is not applicable to this type of IVD analytical device validation. Adjudication is typically used for reconciling disagreements among human experts in diagnostic imaging interpretation or clinical decision-making.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and its effect size

An MRMC study is not applicable to this device. This type of study assesses how human readers' diagnostic accuracy changes with or without AI assistance, which is for AI/ML-based diagnostic devices (e.g., imaging AI). This device is a quantitative immunoassay.

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

This concept is not applicable in the context of an IVD assay. The "algorithm" is the biochemical reaction and the instrument's measurement system. The device's "standalone" performance is what these non-clinical analytical studies demonstrate. The results are quantitative measurements of the CA 19-9 antigen, not classifications or detections that would then be presented to a human for interpretation.

7. The Type of Ground Truth Used

Analyte Concentration: For precision, detection capability, linearity, known interferences, and dilution, the "ground truth" is based on the known or reference concentrations of CA 19-9 in control materials, spiked samples, or reference standards.
Comparative Method: For method comparison, the "ground truth" is established by the results from the legally marketed predicate device (VITROS CA 19-9 assay, K052889).
Normal Population Reference: For expected values, the "truth" is established by determining the range of values observed in a healthy, "normal" population.

8. The Sample Size for the Training Set

This document does not describe a "training set" in the context of machine learning. For an IVD assay, the development process involves reagent formulation, instrument calibration, and optimization using iterative testing and refinement, not a distinct "training set" of data in the AI/ML sense. The studies described are validation activities for the final device.

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

As there is no "training set" in the AI/ML sense for this IVD, this question is not applicable. The "ground truth" for developing and calibrating an IVD like this would be established through highly controlled laboratory preparations of samples with known concentrations of the target analyte, often traceable to international standards if available. Calibration itself establishes the relationship between the measured signal and the concentration of the analyte.

Summary

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August 9, 2023

Ortho Clinical Diagnostics Declan Hynes Senior Regulatory Affairs Manager Felindre Meadows Pencoed Bridgend. CF35 5PZ United Kingdom

Re: K231525

Trade/Device Name: VITROS CA 19-9 Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: NIG Dated: May 26, 2023 Received: May 26, 2023

Dear Declan Hynes:

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

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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) 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 (QS) 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 medical devices and radiation-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,

Ying Mao -S

Ying Mao, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K231525

Device Name

VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack

Indications for Use (Describe) For in vitro diagnostic use only.

Type of Use (Select one or both, as applicable)X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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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: K231525

Submitter's Information

Ortho-Clinical Diagnostics Inc.

Felindre Meadows,

Pencoed,

UK CF35 5PZ Phone: +44 07505 370257

Fax: (585) 453-3368 Contact Person: Declan Hynes

Preparation Date

August 01, 2023

Device Proprietary Name(s)

VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack

Common Name(s) VITROS CA19-9 Assay

Classification Names

Product Code	Class	Regulation Section	Panel
NIG	II	21 CFR 866.6010Tumor-associated antigen immunological testsystem	Immunology

Predicate Device(s)

Predicate Device	FDA 510(k) Number
VITROS Immunodiagnostic Products CA 19-9 Assay	K052889

Device Description

The VITROS Immunodiagnostic Products CA 19-9 assay (test) is performed using the VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack and VITROS CA 19-9 Calibrators on the VITROS 5600 System.

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VITROS CA 19-9 Traditional 510(k)

HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of conjugate bound is directly proportional to the concentration of 1116-NS-19-9 defined antigen present in the sample.

VITROS Immunodiagnostic Products CA 19-9™ Reagent Pack contains:

1 reagent pack containing:

100 coated wells (antibody, mouse monoclonal anti-1116-NS-19-9 defined antigen, binds >49 U 1116-NS-19-9 defined antigen/well)
13.4 mL assay reagent (buffer containing bovine gamma globulin and antimicrobial agent) ●
20.0 mL conjugate reagent (HRP-mouse monoclonal anti-1116-NS-19-9 defined antigen, binds ≥326 U ● 1116-NS-19-9 defined antigen/mL) in buffer with bovine serum albumin, bovine gamma globulin and antimicrobial agent.

VITROS CA 19-9 Calibrator contains:

1, 2, and 3 (OC 1116-NS-19-9 defined antigen in buffer with bovine serum albumin and ● antimicrobial agent, 1.75 mL); nominal values 15; 60 and 700 U 1116-NS-19-9 defined antigen/mL
24 calibrator bar code labels (8 for each calibrator) ●

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Intended Use Statement(s):

Rx ONLY

For in vitro diagnostic use only.

Comparison to Predicate Devices

The following tables provide a summary of the key features of the new device assessed against the predicate.

DeviceCharacteristic	Predicate DeviceVITROS Immunodiagnostic ProductsCA 19-9 Assay, K052889, cleared 20December 2005	Modified DeviceVITROS Immunodiagnostic ProductsCA 19-9TM Reagent Pack
Intended Use	Rx ONLYFor in vitro diagnostic use only.	Rx ONLYFor in vitro diagnostic use only.
	For the quantitative measurement of 1116-NS-19-9 defined antigen concentration in humanserum and plasma (EDTA or heparin) usingthe VITROS ECi/ECiQ/3600Immunodiagnostic Systems and the VITROS5600/XT 7600 Integrated Systems. TheVITROS CA 19-9 assay is to be used as an aidin management of patients diagnosed with canersof the exocrine pancreas. The VITROS CA 19-9test can be used to monitor disease status inpatients with confirmed pancreatic cancer whoshow measurable CA 19-9 values over thecourse of their disease. Serial CA 19-9 testresults should be used in conjunction withother clinical and laboratory data before amedical decision is determined.	For the quantitative measurement of 1116-NS-19-9 defined antigen concentration in humanserum and plasma (EDTA or heparin) usingthe VITROS 5600 Integrated System. TheVITROS CA 19-9 test is to be used to aid in themanagement of patients diagnosed with cancersof the exocrine pancreas. The VITROS CA19-9 test can be used to monitor the diseasestatus in patients with confirmed pancreaticcancer who show measurable CA 19-9 valuesover the course of their disease. Serial CA 19-9test results should be used in conjunction withall other available clinical and laboratory databefore a medical decision is determined.
Assay Principle	Immunometric.	Same.
Antibody	Mouse Monoclonal anti-1116-NS-19-9antigen.	Same.
Sample Type	Serum and Plasma.	Same.
Sample Volume	35 µL.	Same.

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VITROS CA 19-9 AssayTraditional 510(k)

Traceability	Calibration of the VITROS CA 19-9 test istraceable to in-house reference calibratorswhich have been value assigned to correlateto another commercially available test.	Same.
Measuring Range	1.4-1000 (U/mL)	Same.
Detect on Limit	LOB: 1.05 (U/mL)LOD: 1.4 (U/mL)LOQ: 1.4 (U/mL)	LOB: Same.LOD: Same.LOQ: Same
Calibrator Levels	3.	Same.

Differences:

Basic Principle	Sandwich immunoassay	Sandwich immunoassay.In the modified CA 19-9assay, the mouse anti-1116-NS-19-9 has beenremoved from the BiotinReagent and coateddirectly onto the well.The modification to allowthe biotinylated antibodycapture conjugate to bepre- bound to the well,eliminates the risk ofbiotin interference.
Instrumentation	VITROS 5600 Integrated SystemVITROS XT7600 Integrated SystemVITROS 3600 Immunodiagnostic SystemVITROS ECi/ECiQ Immunodiagnostic System	VITROS 5600 Integrated System

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Nonclinical Performance

Several nonclinical tests were performed.

Stability Studies

Long term stability and on-board storage performance was evaluated consistent with methods based on CLSI EP25-A.

Long Term Stability: Four runs have been performed on each of 3 Lots at each time-point, monthly intervals, data supports a 20 week shelf-life.

On-board Stability: Three Lots of the VITROS CA19-9 assay were stored opened refrigerated for up to 12 weeks. Four runs were performed on the each Lot at each time-point for fresh and open, all result were acceptable and support the current claim of 8 weeks on-board stability.

Precision

Precision was evaluated on the VITROS 5600 Integrated System consistent with CLSI document EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. Six (6) precision fluids, covering the analytical measuring interval, were evaluated for performance. For one reagent lot, two (2) replicates of each precision fluid were run on two (2) occasions per day for twenty (20) days, for a total of 80 data points per fluid.

The data presented are a representation of test performance and are provided as a guideline. Variables such as sample handling and storage, reagent handling and storage, laboratory environment, and system maintenance can affect reproducibility of test results.

VITROSSystem	Units = U/mL					No. ofObs.	No. ofDays
	MeanCA 19-9Conc.	Repeatability*		Within Lab**
		SD	%CV	SD	%CV
5600	29.0	0.5	1.8%	1.9	6.6%	80	20
	107	2.0	1.9%	6.3	5.9%	80	20
	223	4.4	2.0%	9.2	4.1%	80	20
	301	5.8	1.9%	14.0	4.6%	80	20
	708	12.1	1.7%	27.6	3.9%	80	20
	6.7	0.1	2.2%	0.3	4.2%	80	20

*Repeatability (formerly called within-run precision) was determined using two replicates per run.

** Within Lab precision was determined using a single reagent lot and a single calibration.

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Detection Capability

Detection studies for the VITROS CA 19-9 Assay were evaluated on the VITROS 5600 Integrated System consistent with CLSI document EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition. Four endogenous fluids containing no measurable 1116-NS-19-9 defined antigens (CA19-9) were used for determining the LoB. The study design was 2 replicates per run, 2 runs per day over 5 test days = 20 reps per test fluid x 4 fluids = 80 replicates x 3 lots = 240 total replicates

Five samples were used for establishing the LoD, which were targeted at 1 to 5 times the LoB

concentration. The LoD samples were admixtures of serum samples containing endogenous CA 19-9 to achieve the approximate target CA 19-9 concentrations. The LoD fluids were used to determine the LoQ. All samples were run using three reagent lots on one VITROS 5600 System,

6 replicates per run, 2 runs per day over 5 test days = 60 reps per fluid x 5 fluids = 300 replicates x 3 lots = 900 total replicates.

The Limit of Detection (LoD) for the VITROS CA 19-9 test is 1.4 U/mL, determined consistent with CLSI document EP17-A2 . The Limit of Quantification (LoQ) for the VITROS CA19-9 test was designed to be less than or equal to 1.4 U/mL at 20%CV. The existing LoB product claim of 1.05 U/mL has been verified.

Linearity

Linearity was established in accordance with the CLSI document EP06 2nd Edition. The linearity test panel was comprised of 16 levels, five replicates of each linearity level were run on three reagent lots on one VITROS 5600 Integrated System over 2 days.

		Slope		Intercept
Lot	DilutionRange	% Recovery	Estimate	95% CI	Estimate	95% CI	R
તે તે તે તે તે તે તે તે તે તે તે તે તે આ ગામમાં પ્રાથમિક શાળા, આંગણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં પ્રાથમિક શાળા, આંગણવાડી તેમ જ દૂધની ડેરી જેવી	0.9 to 1152	93.0% to125%	0.973	0.957 to0.989	0.145	0.103 to0.186	0.999

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Weighted Least Squares Regression
Level	%HP	MeasuredResult(U/mL)	PredictedResult(U/mL)	DeviationfromLinearity	AllowableDeviationfromLinearity(±)	Pass /Fail
1	0.00	0.861	0.981	-12.3%	15.0%	Pass
2	0.03	1.516	1.328	14.1%	15.0%	Pass
3	0.05	1.59	1.52	5.0%	15.0%	Pass
4	0.10	2.35	2.08	13.0%	15.0%	Pass
5	0.50	6.81	6.60	3.1%	15.0%	Pass
6	1.00	12.2	12.1	0.3%	15.0%	Pass
7	2.99	33.5	34.5	-2.8%	15.0%	Pass
8	5.01	54.6	57	-4.3%	15.0%	Pass
9	10	108	113	-4.5%	15.0%	Pass
10	30	332	337	-1.5%	15.0%	Pass
11	40	441	449	-1.7%	15.0%	Pass
12	50	557	561	-0.6%	15.0%	Pass
13	60	668	672	-0.6%	15.0%	Pass
14	80	904	896	0.8%	15.0%	Pass
15	95	1074	1064	0.9%	15.0%	Pass
16	100	1152	1121	2.8%	15.0%	Pass
Linearity Interval 0.9 to 1152 U/mL

Linearity/Measuring Range

VITROS System	Measuring (Reportable) Range
5600	1.4–1000 U/mL

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VITROS CA 19-9 AssayTraditional 510(k) Matrix Comparison

Serum and plasma (Li-Hep and EDTA) specimen matrices was determined to be equivalent. The results met the acceptance criteria for the comparison between serum and plasma (Li-Hep and EDTA) specimens spanning the expected measuring interval. Based on the analysis serum and plasma (Li-Hep and EDTA) are suitable specimen matrices for use with the VITROS CA 19-9 assay.

Specimens Recommended

Serum and Plasma ●
Specimens Not Recommended
Do not use turbid specimens. Turbidity in specimens may affect test results. ●

VITROS 5600 System
OrdinaryDeming	Li-Hep	EDTA
Slope	0.97	0.98
CorrelationCoefficient (r)	0.99	1.00
n	41	41
Pass/FailStatus	Pass	Pass

Analytical Specificity

Known Interferences

The VITROS CA 19-9 assay was screened for interfering substances at CA 19-9 concentrations of approximately 5.0 U/mL and 50.0 U/mL following CLSI EP07+ and EP37.2 The substances listed in the table demonstrated observed bias of ≥ 10% when tested at the concentrations shown.

For substances that were tested and did not interfere, refer to "Substances that do not Interfere."

Interferent	Interferent Concentration		Analyte Conc.* (U/mL)	Bias %**
Hemoglobin	1000 mg/dL	0.155 mmol/L	7.1	190.1
	125 mg/dL	0.0194 mmol/L	45.2	30.5
	125 mg/dL	0.0194 mmol/L	47.5	0.8
	100 mg/dL	0.0155 mmol/L	6.1	2.0
Rheumatoid Factor	1035 U/mL	N/A	5.0	27.4
	981 U/mL		43.4	2.8
	900 U/mL		32.5	5.2
	199 U/mL		5.0	5.2

Average test concentration of replicate determinations using 3 different lots of reagent, on the VITROS 5600 platform

**Estimate of the average difference observed

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Substances that do not Interfere

The substances listed in the table below were tested with the VITROS CA 19-9 assay following CLSI EP07 and EP372 and found not to cause bias > 10% at CA 19-9 concentrations of approximately 5.0 U/mL at the test concentrations shown.

Substance	Concentration
	Conventional Units	SI Units
Acetaminophen	50 mg/dL	3.3 mmol/L
N-Acetylcysteine	15.0 mg/dL	0.919 mmol/L
Acetylsalicylic acid	50 mg/dL	2.78 mmol/L
Alpha-tocopherol	6.45 mg/dL	0.150 mmol/L
Amoxicillin	5.40 mg/dL	0.148 mmol/L
Ascorbic acid	300 mg/dL	17.0 mmol/L
Bilirubin, conjugated	40 mg/dL	0.475 mmol/L
Bilirubin, unconjugated	40 mg/dL	0.684 mmol/L
Biotin	0.351 mg/dL	0.014 mmol/L
Cefoxitin sodium	695 mg/dL	15.5 mmol/L
Cetuximab	70.5 mg/dL	0.00464 mmol/L
Cholecalciferol (D3)	19.2 $ μg $ /dL	0.499 $ μmol $ /L
Cholesterol, total	400 mg/dL	10.3 mmol/L
Cisplatin	5.7 mg/dL	0.19 mmol/L
Codeine	0.141 mg/dL	0.005 mmol/L
Cotinine	0.24 mg/dL	0.014 mmol/L
Coumadin	1.4 mg/dL	0.042 mmol/L
Cyclophosphamide	54.9 mg/dL	1.97 mmol/L
Cytarabine	3 mg/dL	0.123 mmol/L
Dextran 40	2400 mg/dL	0.600 mmol/L
Dextromethorphan	0.00156 mg/dL	0.057 $ μmol $ /L
Doxorubicin hydrochloride	4 mg/dL	0.053 mmol/L
Enoxaparin - Low molecular weight Heparin	360 U/dL	N/A
Ethanol	600 mg/dL	130 mmol/L
Eribulin	1.12 $ μg $ /mL	0.00136 mmol/L
5-Fluorouracil	39 mg/dL	3.0 mmol/L
Furosemide	1.59 mg/dL	0.048 mmol/L
Gemcitabine	38.2 mg/dL	1.28 mmol/L
HAMA (Human Anti-Mouse Antibodies)	800 $ μg $ /L	0.053 $ μmol $ /L
Hydralazine	1.44 mg/dL	0.073 mmol/L
Substance	Concentration
	Conventional Units	SI Units
Hydrocodone	0.0072 mg/dL	0.241 µmol/L
Ibuprofen	40 mg/dL	1.94 mmol/L
Intralipid	2000mg/dL	0.0192 mol/L
Leucovorin	11.4 mg/dL	0.386 mmol/L
Levothyroxine	0.0429 mg/dL	0.552 µmol/L
Loratadine	0.0087 mg/dL	0.227 µmol/L
Megestrol Acetate	2.26 µg/mL	0.0058 mmol/L
Methotrexate	136 mg/dL	3.0 mmol/L
Mitomycin C	300 µg/dL	0.009 mmol/L
Morphine	0.780 mg/dL	0.010 mmol/L
Naproxen	36.0 mg/dL	1.56 mmol/L
Omeprazole	0.840 mg/dL	0.024 mmol/L
Paclitaxel	6.7 mg/dL	0.080 mmol/L
Phenytoin	6.00 mg/dL	0.238 mmol/L
Prednisone	0.010 mg/dL	0.280 µmol/L
Salicylic acid	2.86 mg/dL	0.207 mmol/L
Streptozocin	114 mg/dL	4.30 mmol/L
Tamoxifen	51.9 ug/dL	1.40 µmol/L
Theophylline	6.0 mg/dL	0.333 mmol/L
Total Protein	15 g/dL	N/A
Triglycerides, total	3000 mg/dL	33.8 mmol/L
Vancomycin hydrochloride	12.3 mg/dL	0.083 mmol/L
Vinblastine	0.0084 mg/dL	0.092 µmol/L
Vincristine	0.00162 mg/dL	0.0176 µmol/L
Vinorelbine	0.19 mg/dL	0.002 mmol/L

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VITROS CA 19-9 AssayTraditional 510(k)

N/A = Not applicable, alternate units not available

Dilution

The dilution recovery and dilution imprecision product requirements were met for the VITROS Immunodiagnostic Products CA 19-9 Reagent. Serum or plasma (EDTA or heparin) samples with concentrations greater than the measuring range may be automatically diluted on the system up to 20-fold (1 partsample with 19 parts diluent) by the VITROS 5600 Integrated System with the VITROS High Sample Diluent B Reagent Pack prior to test. Refer to the VITROS High Sample Diluent B Reagent Pack instructions for use. The 20-fold dilution has been demonstrated on samples with a concentration up to 10,000 U/mL.

Expected Values

Adult Reference Interval

The adult reference interval was verified following CLSI document EP28-A3c Defining,

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VITROS CA 19-9 AssayTraditional 510(k) Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.

Unit (U/L)
$\u2264$ 37 U/mL

The number of test results from 60 normal blood donors that fell outside the reference limit of >37 UlmL are shown in Table 1, for each reagent lot and instrument combination. As no more than 10% of the test results were outside the limit, the expected values claim of the current VITROS CA 19-9 will be transferred to the updated VITROS CA 19-9 assay.

Table 1: Test results for the modified VITROS CA 19-9 assay

Normal Subjects	N	≤37 U/mL	37.1-70 U/mL	>70 U/mL
VITROS 5600	60	57	2	1

Traceability of Calibration

Calibration of the VITROS CA 19-9 assay is traceable to in-house reference calibrators which have been value assigned to correlate to another commercially available test.

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Method Comparison

Accuracy was evaluated consistent with CLSI document EP09. The plot and table show the results of a method comparison study using patient serum samples analyzed on the VITROS 5600 Integrated System compared with those analyzed using the VITROS CA 19-9 assay. The relationship between the 2 methods was determined by Weighted Deming regression.

Image /page/14/Figure/3 description: This image is a regression plot comparing two methods of measuring CA19-9 levels. The x-axis represents the Comparative Method CA19-9 (Current) in U/mL, ranging from 0 to 1000. The y-axis represents the VITROS CA19-9 Modified in U/mL, also ranging from 0 to 1000. A red regression line is plotted through the data points, with gray dashed lines indicating the confidence interval.

Single Lot Analyses	n	Sample Range(U/mL)	Slope 95%(Confidence Interval)	Intercept 95%(ConfidenceInterval)	R2
VITROS 5600 ModifiedCA19-9 vs ComparativeMethod VITROS CA19-9	118	2.8934	0.97 (0.95-0.99)	0.15 (-0.03-0.32)	0.989

Conclusion

The conclusions drawn from the nonclinical tests (discussed above) demonstrate the VITROS Immunodiagnostic Products CA 19-9 Assay is as safe, effective, and performs as well as the cleared predicate device. The information submitted in the premarket notification is complete and supports a substantial equivalence decision.

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.