For the quantitative measurement of carcinoembryonic antigen (CEA) concentration in human serum and plasma (EDTA or heparin) using the VITROS 5600 Integrated System, to aid in the prognosis and management of cancer patients in whom changing concentrations of CEA are observed.

Device Description

The VITROS Immunodiagnostic Products CEA Reagent Pack (test) is performed using the VITROS CEA Reagent Pack and VITROS CEA Calibrators on the VITROS 5600 System.

An immunometric immunoassay technique is used, which involves the reaction of CEA present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-CEA) bound to Streptavidin, and a Horseradish Peroxidase (HRP)-labelled antibody conjugate (Mouse monoclonal anti- CEA). Unbound (HRP)-labeled anti-CEA antibody conjugate is 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 HRP conjugate bound is directly proportional to the concentration of CEA present in the sample.

VITROS CEA Reagent Pack contains:
1 reagent pack containing:

100 coated wells (antibody, mouse monoclonal anti-CEA, binds ≥8ng CEA/well); ●
9.7 mL assay reagent (buffer containing bovine serum albumin, bovine gamma globulin and . antimicrobial agent).
9.7 mL conjugate reagent (HRP-mouse monoclonal anti-CEA, binds ≥123ng CEA/mL). ●

VITROS CEA Calibrator contains:

1 set of VITROS CEA Calibrators 1 and 2 (human CEA in bovine serum with ● antimicrobial agent, 2 mL); nominal values 3 and 250 ng/mL (us/L)
16 calibrator bar code labels (8 for each calibrator) ●

AI/ML Overview

The provided document describes the safety and effectiveness information for the VITROS Immunodiagnostic Products CEA Reagent Pack (K231517), which is intended for the quantitative measurement of carcinoembryonic antigen (CEA) in human serum and plasma to aid in the prognosis and management of cancer patients. The document primarily focuses on nonclinical performance studies to demonstrate substantial equivalence to a predicate device.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a singular table alongside performance for all aspects. However, it implicitly defines acceptance by stating that certain studies were performed "consistent with CLSI document" guidelines and that "all results were acceptable" or "met the acceptance criteria." For linearity, it specifies "Allowable nonlinearity." For matrix comparison, it states "The results met the acceptance criteria."

Here's an attempt to synthesize the acceptance criteria and performance from the text for key analytical characteristics:

Performance Characteristic	Acceptance Criteria (Implicit/Explicit)	Reported Device Performance
Stability (Shelf-life)	"supports a 52 week shelf-life" (implies acceptance of data over this period)	"Four runs have been performed on each time-point, monthly intervals, supports a 52 week shelf-life."
Stability (On-board)	"support the current claim of 8 weeks on-board stability" (implies acceptance of data over this period)	"Four runs were performed on each Lot at each time-point for fresh and open, all results were acceptable and support the current claim of 8 weeks on-board stability."
Precision (Repeatability)	Not explicitly stated as a separate acceptance criterion, but data is provided consistent with CLSI EP05-A3.	Repeatability (%CV) for 6.55 ng/mL: 1.7%; 41.4 ng/mL: 1.4%; 228 ng/mL: 1.9%; 390 ng/mL: 1.2%. Additional precision table shows within-run %CV ranging from 1.5% to 1.9%.
Precision (Within-Lab)	Not explicitly stated as a separate acceptance criterion, but data is provided consistent with CLSI EP05-A3.	Within-Lab (%CV) for 6.55 ng/mL: 2.7%; 41.4 ng/mL: 2.5%; 228 ng/mL: 2.7%; 390 ng/mL: 2.9%. Additional precision table shows within-laboratory %CV ranging from 3.1% to 3.6%.
Detection Capability (LoD)	"This supports the claimed LOD of 0.31ng/ml." (Implies the observed LoD must be ≤ 0.31 ng/mL)	Observed LoD: 0.15 ng/mL (ug/L)
Detection Capability (LoQ)	"designed to be less than or equal to currently claimed low end of the measuring range of 0.31 ng/mL (ug/L) at 20% CV." (Implies observed LoQ must be ≤ 0.31 ng/mL at 20% CV)	Observed LoQ at 20% CV: 0.15 ng/mL (ug/L). Claimed LoQ: 0.31 ng/mL (ug/L).
Linearity	"Allowable nonlinearity: ±14.3%"	Linearity demonstrated from 0.22 ng/mL to 500 ng/mL (ug/L) with deviations from linearity within +/- 14.3%. All individual data points in the table are within ±14.3% deviation.
Matrix Comparison	"The results met the acceptance criteria for the comparison between serum and plasma (Li-Hep and EDTA) specimens spanning the expected measuring interval." (Specific criteria not provided, but statistical metrics like slope, intercept CIs, and correlation coefficient are presented).	The table shows for Li-Hep: Slope 0.998 (95% CI 0.9765-1.019), Intercept -0.1177 (95% CI -0.8353 to -0.5999), r=0.999. For EDTA: Slope 0.995 (95% CI 0.9459-1.044), Intercept -0.8768 (95% CI -3.056 to 1.302), r=0.998. Both passed.
Analytical Specificity (Interferents)	"Of the compounds tested, none were found to cause bias of >10%." (Implicit acceptance criterion for "Substances that do not Interfere").	None of the numerous tested substances (e.g., Acetaminophen, Bilirubin, Biotin, Hemoglobin up to specified concentrations) caused bias >10% at CEA concentrations of 3.00 ng/mL and 15.0 ng/mL.
High Dose Hook	"The updated VITROS CEA assay has a high dose hook claim of up to 80,000ng/mL." (Implies the testing confirmed no hook effect below or at this concentration). The study assesses consistency with CLSI EP34.	High dose hook panel tested from 273 to 546,000 ng/mL to support the claim of up to 80,000 ng/mL. (No specific performance data presented, but implies successful demonstration).
Method Comparison (Accuracy)	Allowable difference of ±10% (as shown in the regression plot).	Passing-Bablok regression: y = 0.1059 + 1.006x, with 95% CI for slope (0.9972 to 1.012) and intercept (-0.01602 to -0.3729). Correlation coefficient (r): 0.999. The plot includes dashed lines indicating an allowable difference of ±10%, implying performance within this range.

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

Precision:
- 5600 System (Table 1): 4 precision fluids. 2 replicates per fluid, 2 occasions per day, for 20 days. Total 80 data points per fluid.
- Additional Precision Analysis (Table 2): 4 precision fluids (PP1-PP4). 240 observations per sample (likely 2 replicates per run, multiple runs, over multiple days/lots as per CLSI guideline EP05-A3).
Detection Capability (LoB): 4 endogenous fluids. 2 replicates per run, 2 runs per day, over 5 test days. Total 20 replicates per test fluid x 4 fluids = 80 replicates total for LoB. Tested on 3 lots, so 240 total replicates.
Detection Capability (LoD & LoQ): 5 samples. 6 replicates per run, 2 runs per day, over 5 test days. Total 60 replicates per fluid x 5 fluids = 300 replicates total for LoD/LoQ. Tested on 3 lots, so 900 total replicates.
Linearity: 13 levels, five replicates for each level.
Matrix Comparison: Not specified precisely, but samples were "spanning the expected measuring interval."
Analytical Specificity (Interferents): Not specified (e.g., number of replicates or distinct samples).
High Dose Hook: Panel of ten fluids. Tested in singleton.
Method Comparison (Accuracy): 110 human serum samples. Tested in singleton.

Data Provenance:
The document consistently refers to "human serum" or "patient samples." For the method comparison, it states "Human serum samples were obtained from certified vendors." For detection capability, it mentions "endogenous fluids" and "admixtures of serum samples containing endogenous CEA combined with CEA affinity stripped serum." For expected values, it refers to "healthy non-smokers (n=68)" and "healthy smokers (n=72)."
The country of origin is not specified but the submitter is Ortho-Clinical Diagnostics Inc. from the UK. The studies are nonclinical performance studies, often conducted in-house or by contract research organizations. These studies are prospective in nature, as they are designed experiments to evaluate specific performance characteristics.

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

Ground truth for these studies is analytically derived, not expert consensus interpretation. For in vitro diagnostic devices like the CEA assay, the "ground truth" for test sets in nonclinical studies typically refers to:

Reference values assigned by highly accurate reference methods or known concentrations of analytes (e.g., spiked samples) for linearity, detection, and accuracy studies.
The known physiological state of samples (e.g., healthy non-smokers, healthy smokers) for reference intervals.
The known presence/absence and concentration of interferents for specificity studies.

Therefore, the concept of "experts establishing ground truth" in the sense of clinical interpretation (like radiologists for imaging) is not applicable here. The ground truth is established by the design of the analytical experiment and the reference materials/methods used.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used in clinical studies where human interpretation of data (e.g., images) forms the ground truth, and discrepancies need to be resolved. This is not relevant for the analytical performance studies of a laboratory immunoassay described in this document.

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

No. An MRMC study is relevant for devices involving human interpretation (e.g., medical imaging) to assess how the device impacts human reader performance. This document describes the analytical performance of an in vitro diagnostic immunoassay.

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

Yes, this entire submission describes the standalone performance of the VITROS Immunodiagnostic Products CEA Reagent Pack and the VITROS 5600 Integrated System. The data presented are purely analytical measurements performed by the device, without human interpretive input or assistance being part of its core function.

7. The Type of Ground Truth Used

Stability: Time points with known age of reagents/calibrators/samples.
Precision: Control materials or patient samples where inherent variability is being measured. No "ground truth" in the sense of an absolute true value is typically assigned for precision, but rather the repeatability and reproducibility of the measurements around a mean.
Detection Capability: Samples confirmed to contain no measurable CEA (for LoB) or samples with targeted, known low concentrations of CEA (for LoD and LoQ), often prepared by spiking.
Linearity: Samples covering a wide range of concentrations, often prepared by dilution of a high-concentration sample with known low-concentration diluent, such that the "expected value" is calculable.
Matrix Comparison: Patient samples (serum vs. various plasma types) where a comparison between matrices is the objective, not an absolute ground truth value.
Analytical Specificity: Samples spiked with known concentrations of potential interfering substances, with the expectation that the CEA measurement should not be significantly biased.
High Dose Hook: Samples with extremely high, known CEA concentrations to ensure the device correctly reports high values and doesn't "hook" and report falsely low.
Method Comparison (Accuracy): Patient samples compared against a legally marketed predicate device (VITROS CEA assay K041322) on the same system. The predicate device's results serve as the comparative measure, assumed to be accurate for the purpose of demonstrating equivalence.
Expected Values: Clinically healthy subjects (non-smokers and smokers) categorized by their CEA levels.

In summary, the ground truth is primarily based on analytical reference materials, known spiked concentrations, and comparative measurements against a predicate device, all within the domain of quantitative laboratory measurements.

8. The Sample Size for the Training Set

This document describes nonclinical performance testing for an in vitro diagnostic device, not a machine learning or AI algorithm in the typical sense that would involve a "training set." The device is a chemical reagent pack used on an automated immunoassay system. While there were certainly development and validation phases during the device's creation (which might involve analogous processes to "training"), the document provided does not detail a "training set" in the context of an AI/ML algorithm. The studies described are validation studies of the finalized product.

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

As noted in point 8, the concept of a "training set" with established ground truth as typically understood for AI/ML is not applicable to this kind of device and its regulatory submission. The document focuses on demonstrating the analytical performance of a developed immunoassay kit.

Summary

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August 23, 2023

Ortho Clinical Diagnostics Rebecca Lewis Senior Regulatory Affairs Associate Felindre Meadows Pencoed Bridgend, CF35 5PZ United Kingdom

Re: K231517

Trade/Device Name: VITROS Immunodiagnostic Products CEA Reagent Pack Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: DHX Dated: May 23, 2023 Received: May 25, 2023

Dear Rebecca Lewis:

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.

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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) 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

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Indications for Use

510(k) Number (if known) K231517

Device Name

VITROS Immunodiagnostic Products CEA Reagent Pack

Indications for Use (Describe) For In Vitro Diagnostic Use Only

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)

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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: K231517.

Submitter's Information

Ortho-Clinical Diagnostics Inc.

Felindre Meadows,

Pencoed.

UK CF35 5PZ Phone: +44 (0) 7971 427649

Fax: (585) 453-3368 Contact Person: Rebecca Lewis

Preparation Date

Aug 23, 2023

Device Proprietary Name(s)

VITROS® Immunodiagnostic Products CEA Reagent Pack

Common Name(s) VITROS Immunodiagnostic Products CEA

Reagent Pack

Classification Names

Product Code	Class	Regulation Section	Panel
DHX	II	21 CFR 866.6010	Immunology

Predicate Device(s)

Predicate Device	FDA 510(k) Number
VITROS Immunodiagnostic Products CEA Reagent Pack	K041322

Device Description

The VITROS Immunodiagnostic Products CEA Reagent Pack (test) is performed using the VITROS CEA Reagent Pack and VITROS CEA Calibrators on the VITROS 5600 System.

QuidelOrtho

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VITROS CEA Reagent Traditional 510(k) 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 HRP conjugate bound is directly proportional to the concentration of CEA present in the sample.

VITROS CEA Reagent Pack contains:

1 reagent pack containing:

100 coated wells (antibody, mouse monoclonal anti-CEA, binds ≥8ng CEA/well); ●
9.7 mL assay reagent (buffer containing bovine serum albumin, bovine gamma globulin and . antimicrobial agent).
9.7 mL conjugate reagent (HRP-mouse monoclonal anti-CEA, binds ≥123ng CEA/mL). ●

VITROS CEA Calibrator contains:

1 set of VITROS CEA Calibrators 1 and 2 (human CEA in bovine serum with ● antimicrobial agent, 2 mL); nominal values 3 and 250 ng/mL (us/L)
16 calibrator bar code labels (8 for each calibrator) ●

Intended Use Statement(s):

Rx ONLY

For in vitro diagnostic use only.

Comparison to Predicate Devices

The following table provides a summary of the key features of the new device assessed against the predicate.

DeviceCharacteristic	Predicate Device	Modified Device
DeviceCharacteristic	VITROS Immunodiagnostic ProductsCEA Reagent Pack, K041322, cleared 17June 2004	VITROS Immunodiagnostic Products CEAReagent Pack
Intended Use	Rx ONLYFor in vitro diagnostic use only.For the quantitative measurement ofcarcinoembryonic antigen (CEA)concentration in human serum andplasma (EDTA or heparin) using theVITROS ECi/ECiQ/3600Immunodiagnostic Systems and theVITROS 5600/XT 7600 IntegratedSystems, to aid in the prognosis andmanagement of cancer patients inwhom changing concentrations ofCEA are observed.	Rx ONLYFor in vitro diagnostic use only.For the quantitative measurement ofcarcinoembryonic antigen (CEA) concentration inhuman serum and plasma (EDTA or heparin)using the VITROS 5600 Integrated System, to aidin the prognosis and management of cancerpatients in whom changing concentrations of CEAare observed.
Antibody	Mouse Monoclonal anti-CEA antibody.	Same.
Sample Type	Serum and Plasma.	Same.

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VITROS CEA Reagent

Traditional 510(k)

Traditional 510(k)Sample Volume	20 µL.	Same.
Traceability	Traceable to in-house referencecalibrators which have been valueassigned tocorrelate to another commerciallyavailable test with reference to the1st International Preparation73/601.	Same.
Measuring Range	Analytical Measuring Interval:0.31-400 ng/mL (µg/L)	Analytical Measuring Interval:0.31-400 ng/mL (µg/L)Extended Measuring Interval:400 - 40,000 ng/mL (µg/L)Reportable Measuring Interval:0.31-40,000 ng/mL (µg/L)
Detect on Limit	LOB: 0.06 ng/mL (µg/L)LOD: 0.31 ng/mL (µg/L)	LOB: 0.08 ng/mL (µg/L)LOD: Same.LOQ: 0.31 ng/mL (µg/L)
Calibrator Levels	2.	Same.
Instrumentation	VITROS 5600 Integrated System	Same.

Differences:

Assay Principle	Sandwich immunoassay	Sandwich immunoassay. In the modified CEA assay, themouse anti- CEA antibody has been removed from theBiotin Reagent and coated directly onto the well. Themodification toallow the biotinylated antibody capture conjugate tobe pre- bound to the well, eliminates the risk ofbiotin interference.
Assay Reagent	0.5% BSA, no Tween 20 or EDTA.	The modified product utilizes the same capture anddetection antibodies. The modified product includes theaddition of 0.6% Tween 20, 25 mM EDTA and an increasein BSA concentration from 0.5% to 3% in the CEA assayreagent.These modifications have improved the CEA assay:The purpose of BSA in the assay reagentformulation is to minimize matrix effects, reducenon-specific binding (NSB) and improve thestability of the biotin conjugate. Hemoglobin insamples may adsorb to the wells and introduce anadditional peroxidase activity, resulting inelevated signals and therefore a positive bias.Increase in BSA concentration of the assayreagent reduces the NSB, and therefore addressesthe hemoglobin interference with the currentassay.Improvement to the serum/plasma equivalence whichpreviously required a limitation on bias for EDTA in thepreviously cleared product IFU.

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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 time-point, monthly intervals, supports a 52 week shelf-life. data

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

Precision

Precision was evaluated consistent with CLSI document EP05-A3. Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. Four (4) 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.

System	MeanCEAConc.	Repeatability*		Within Lab**		No. ofObs.	No. ofDays
		SD	%CV	SD	%CV
5600	6.55	0.114	1.7%	0.175	2.7%	80	20
	41.4	0.58	1.4%	1.02	2.5%	80	20
	228	4.4	1.9%	6.2	2.7%	80	20
	390	4.6	1.2%	11.4	2.9%	80	20

				Product Claim

*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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			Units = ng/mL (µg/L)
Sample	N	Mean	Within-run(Repeatability)		Between-Run		Between-Day		Between-Lot		Within-Laboratory*
			SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
PP1	240	6.44	0.107	1.7%	0.096	1.5%	0.095	1.5%	0.132	2.1%	0.217	3.4%
PP2	240	40.8	0.59	1.5%	0.84	2.1%	0.62	1.5%	0.45	1.1%	1.28	3.1%
PP3	240	223	4.3	1.9%	3.4	1.5%	3.2	1.4%	4.5	2.0%	7.8	3.5%
PP4	240	381	5.6	1.5%	6.6	2.1%	6.0	1.6%	8.7	2.3%	13.7	3.6%

Additional Precision Analysis Summarv

*Within-laboratory precision includes following components:

repeatability, between-run, between-day and between-lot was determined using three reagent lots.

Detection Capability

Detection studies for the VITROS CEA Reagent were evaluated 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 carcinoembryonic antigen (CEA) 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 CEA combined with CEA affinity stripped serum to achieve the approximate target CEA 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 observed Limit of Detection (LoD) for the VITROS CEA test is 0.15 ng/mL (ug/L), determined consistent with CLSI document EP17. This supports the claimed LOD of 0.31ng/ml. The Limit of Quantitation (LoQ) for the VITROS CEA test was designed to be less than or equal to currently claimed low end of the measuring range of 0.31 ng/mL (ug/L) at 20% CV. The observed LoO at 20% CV was determined to be 0.15 ng/mL (ug/L), consistent with CLSI document EP17. The claimed LQ is set at 0.31 ng/mL (ug/L). The representative LoB is 0.08 ng/mL.

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VITROS CEA Reagent Traditional 510(k) Linearity

Linearity studies were performed according to CLSI document EP06 2ªd edition. In a study with 13 levels and five replicates for each level on 1 reagent lot on one VITROS 5600 Integrated System, linearity was demonstrated from 0.22 ng/mL (ug/L) to 500 ng/mL (ug/L) with deviations from linearity within +/- 14.3%.

			Slope		Intercept
DilutionRange	% Recovery	Estimate	95% CI	Estimate	95% CI	R2
0.22 to 500	82.1% to 109%	1.04275	1.025 to1.061	-0.06678	-0.085 to -0.049	0.999

Sample ID	% HP	Expectedvalue(ng/mL)	MeasuredValue(ng/mL)	PredictedValue(ng/mL)	Deviation(ng/mL)	% Deviation	Allowablenonlinearity	WithinAllowablenonlinearity
Lin-2	0.04	0.267	0.219	0.212	0.008	3.6%	±14.3%	Yes
Lin-3	0.05	0.317	0.262	0.264	-0.002	-0.8%	±14.3%	Yes
Lin-4	0.50	2.565	2.632	2.608	0.024	0.9%	±14.3%	Yes
Lin-5	1.01	5.11	5.26	5.26	-0.006	-0.1%	±14.3%	Yes
Lin-6	5.00	25.0	26.2	26.0	0.19	0.7%	±14.3%	Yes
Lin-7	14.99	74.95	81.6	78.1	3.48	4.5%	±14.3%	Yes
Lin-8	34.98	175	186	182	4.2	2.3%	±14.3%	Yes
Lin-9	50.00	250	266	260	5.4	2.1%	±14.3%	Yes
Lin-10	69.99	350	351	365	-13.6	-3.7%	±14.3%	Yes
Lin-11	80.00	400	398	417	-18.3	-4.4%	±14.3%	Yes
Lin-12	89.96	449	455	469	-13.4	-2.9%	±14.3%	Yes
Lin-13	100.00	500	500	521	-21.3	-4.1%	±14.3%	Yes

Linearity/Measuring Range

VITROS System	Measuring (Reportable) Range
5600	0.31-400 ng/mL( µg/L)

The extended measuring interval is 400-40,000 ng/mL (ug/L). Results with concentrations greater than 40,000 ng/mL (ug/L) will be reported as >40,000 ng/ mL(ug/L).

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 CEA assay.

Specimens Recommended

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

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VITROS 5600System
	Li-Hep	EDTA
OrdinaryDemingSlope	0.998	0.995
95% CI (Slope)	0.9765 to 1.019	0.9459 to 1.044
Intercept	-0.1177	-0.8768
95% CI(Intercept)	-0.8353 to -0.5999	-3.056 to 1.302
CorrelationCoefficient (r)	0.999	0.998
n	40	40
Pass/Fail Status	Pass	Pass

Analytical Specificity

Known Interferents

The VITROS CEA assay was screened for interfering substances at CEA concentrations of approximately 3.00 ng/mL(ug/L) and 15.0 ng/mL(ug/L) following EP07 3rd ed – Interference Testing in Clinical Chemistry and EP37 1st ed - Supplemental Tables for Interference Testing in Clinical Chemistry. Commonly encountered substances were tested. Of the compounds tested, none were found to cause bias of >10%.

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

Substances that do not Interfere

The substances listed in the table below were tested with the VITROS CEA test following CLSI EP07and EP37 and found not to cause bias > 10% at CEA concentrations of approximately 3.00 ng/mL(ug/L) and 15.0 ng/mL(ug/L) at the test concentrations shown.

Substance	Concentration
Acetaminophen	20.3 mg/dL
N-Acetylcysteine	15.0 mg/dL
Acetylsalicylic acid	50 mg/dL
Alpha-tocopherol	6.45 mg/dL
Aminoglutethimide	39.8 mg/dL
Amoxicillin	5.40 mg/dL
Ascorbic acid	6.00 mg/dL
Bilirubin, conjugated	100 mg/dL
Bilirubin, unconjugated	100 mg/dL
Biotin	0.351 mg/dL
Bleomycin	300 mg/dL
onal 510(k)
Carbamazepine	4.50 mg/dL
Cefoxitin sodium	695 mg/dL
Cholecalciferol (D3)	19.2 µg/dL
Cholesterol	400 mg/dL
Cisplatin	1.3 mg/dL
Codeine	0.141 mg/dL
Cotinine	0. 24 mg/dL
Cyclophosphamide	54.9 mg/dL
Dextran 40	1200 mg/dL
Dextromethorphan	0.00156 mg/dL
Doxorubicin hydrochloride	5.2 mg/dL
Enoxaparin	360 U/dL
Ethanol	600 mg/dL
Etoposide	83 mg/dL
5-Fluorouracil	34.8 mg/dL
Furosemide	1.59 mg/dL
Gamma globulin	6 g/dL
HAMA (Human Anti-Mouse Antibodies)	800 µg/L
Hemoglobin	1000 mg/dL
Hydralazine	1.44 mg/dL
Hydrocodone	0.0072 mg/dL
Ibuprofen	71.0 mg/dL
Intralipid	2000 mg/dL
Levothyroxine	0.0429 mg/dL
Loratadine	0.0087 mg/dL
Methotrexate	136 mg/dL
Mitomycin C	5.52 mg/dL
Morphine	0.78 mg/dL
Naproxen	36.0 mg/dL
Omeprazole	0.840 mg/dL
Phenytoin	6.00 mg/dL
Prednisone	0.010 mg/dL
Rheumatoid Factor	900 IU/mL
Tamoxifen	4.8 mg/dL
Theophylline	6.0 mg/dL
Total protein	15.0 g/dL
Triglycerides	1500 mg/dL
Vancomycin hydrochloride	12.3 mg/dL
Vinblastine	138 mg/dL
Vincristine	140 mg/dL

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VITROS CEA Reagent

Traditional 510(k)

Cross-Reactivity

The cross-reactivity of the VITROS CEA test was evaluated by adding the following substance to a sample containing no CEA.

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Substance	TestedConcentration	VITROS 5600% Cross Reactivity
		MasterLot9991	MasterLot9992	MasterLot9993
Non- specific Cross- reactingAntigen 1(NCA 1)	500 ng/mL(µg/L)	ND	ND	ND

ND = Not Detectable; mean result is below the measuring interval of the assay

Other Limitations

· The VITROS CEA test is not recommended as a screening procedure for cancer detection.
· Patients with confirmed carcinoma frequently have CEA levels in the same range as normal patients. Elevated levels of CEA may be found in smokers or patients with nonmalignant conditions. Based on these observations, CEA levels in serum and plasma, regardless of level, should not be interpreted as absolute evidence of the presence or absence of malignant disease.
· Certain drugs and clinical conditions are known to alter CEA concentrations in vivo. For additional information, refer to one of the published summaries.
· The results from this test should be used and interpreted only in the context of the overall clinical picture.
· Heterophile, as well as human anti-animal antibodies (most common being human antimouse antibodies or HAMA) in serum or plasma of certain individuals are known to cause interference with immunoassays. The anti-animal antibodies may be present in blood samples from individuals regularly exposed to animals or who have received preparations of mouse monoclonal antibodies for diagnosis or therapy. Results inconsistent with clinical observations indicate the need for additional testing.

Dilution

The dilution recovery and dilution imprecision product requirements were met for the VITROS Immunodiagnostic Products CEA Reagent Pack. Serum or Plasma (EDTA or heparin) samples with concentrations greater than the measuring range will be reported as >400 ng/mL(ug/L) and may be automatically diluted on the system up to 100-fold (1 part sample with 99 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.

Expected Values

Adult Reference Interval

The adult reference interval was validated following CLSI document EP28-A3c Defining. Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.

The distribution of CEA values for healthy non-smokers (n=68) and healthy smokers (n=72) showed equivalency to the expected values claim published in the Instructions for Use of the current US VITROS CEA

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VITROS CEA Reagent Traditional 510(k) assay, therefore the current distribution of results for healthy subjects will be transferred to the updated VITROS CEA assay.

Product Claim:

		Percent (%)
Category	N	0-3.0 ng/mL (µg/L)	>3.0-5.0 ng/mL (µg/L)	>5.0-10.0 ng/mL (µg/L)	>10.0 ng/mL (µg/L)
Healthy Subjects
Nonsmokers	149	91.9	6.0	0.7	1.3
Smokers	101	67.3	22.8	8.9	1.0
Total	250	82.0	12.8	4.0	1.2

Distribution of Healthy Subjects Results for the updated VITROS CEA assay:

Category	n	Percent (%)
		0-3.0 ng/mL(µg/L)	>3.0-5.0 ng/mL(µg/L)	>5.0-10.0 ng/mL(µg/L)	>10.0 ng/mL(µg/L)
Healthy Subjects
Non-smokers	68	89.7	7.4	2.9	0
Smokers	72	72.2	22.2	5.6	0

High Dose Hook

The assessment was consistent with the high dose hook guidance found in CLSI document EP34. The high dose hook panel was prepared with VITROS High Sample Diluent B (HSDB), containing no measurable CEA, spiked with endogenous CEA antigen to produce a fluid with a concentration of approximately 546,000 ng/mL(ug/L). This fluid was diluted with VITROS HSDB to produce a set of ten fluids (the High Dose Hook Panel) with concentrations spanning between 273 and 546,000 ng/mL (ug/L). The high dose hook panel samples were tested in singleton using one reagent lot on one VITROS 5600 System.

The updated VITROS CEA assay has a high dose hook claim of up to 80,000ng/mL.

Traceability of Calibration

The Calibration of the VITROS CEA assay is traceable to in-house reference calibrators which have been value assigned to correlate to another commercially available test with reference to the 1st International Preparation 73/601.

Method Comparison

Accuracy was evaluated consistent with CLSI documents Measurement Procedure Comparison and Bias Estimation Using Patient Samples. 3rd ed. CLSI guideline EP09c; and Evaluation of Total Analytical Error for Quantitative medical laboratory Measurement Procedures. 2nd ed. CLSI guideline EP21. Human serum samples were obtained from certified vendors and tested neat. A total of 110 samples were tested in singleton using one reagent lot and one VITROS 5600 Integrated System.

Accuracy was evaluated consistent with CLSI document EP09c. The plot and table show the results of a method comparison study using patient (serum) samples analyzed on the VITROS CEA assay QuidelOrtho

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compared with those analyzed on the VITROS CEA assay (K041322) on the VITROS 5600 Integrated System. The relationship between the 2 methods was determined by a Passing and Bablok regression as shown in the Figure below.

Image /page/13/Figure/2 description: The image is a regression plot for CEA (GEM.1110A) Lot 9993 versus a comparative method. The x-axis represents the comparative method VITROS CEA (GEM.1110) in ng/mL, while the y-axis represents 5600 PM 118 Lot 9993 in ng/mL. The plot includes a Passing-Bablok fit line represented by the equation y = 0.1059 + 1.006x, and dashed lines indicating the allowable difference of ±10%.

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System	n	Slope(95% CI)	CorrelationCoefficient	Conventional Units (U/mL)
				Range ofSamples	Intercept (95%CI)
5600 vs. ComparativeMethod	110	1.01(0.9972 to1.012)	0.999	0.56-396	0.106(-0.01602 to -0.3729)

Conclusion

The conclusions drawn from the nonclinical tests (discussed above) demonstrate the updated VITROS Immunodiagnostic Products CEA Reagent pack 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.