The ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma (lithium heparin or potassium EDTA) on the ADVIA Chemistry systems. In acute phase response, increased levels of a number of plasma proteins, including CRP, are observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders, and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurement of hsCRP, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndromes.

The ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein Calibrators are for in vitro diagnostic use in the calibration of ADVIA Chemistry systems for the CardioPhase High Sensitivity C-Reactive Protein method.

Device Description

The ADVIA Chemistry CardioPhase™ High Sensitivity C-Reactive Protein assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma on the ADVIA Chemistry systems. The CardioPhaseTM hsCRP latex reagent is a suspension of uniform polystyrene latex particles coated with anti-CRP antibody. When serum or plasma containing CRP is mixed with the latex reagent, agglutination takes place resulting in an increase in turbidity. This turbidity is measured at 571 nm. The CRP concentration in serum or plasma is determined from a calibration curve that is generated with the calibrators.

The ADVIA® Chemistry CardioPhase™ High Sensitivity C-Reactive Protein Calibrators consist of six (6) levels of protein stabilized matrices containing varying concentrations of recombinant human CRP. The Calibrators have targeted values (lot specific) of 0, 0.53, 1.05, 1.58, 5.25, and 10.50 mg/L.

The calibrators (1 mL/vial) are liquid and ready to use. Storage is at 2 - 8℃.

AI/ML Overview

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Important Note: The provided document is a 510(k) summary for an in vitro diagnostic (IVD) device, specifically a C-Reactive Protein (CRP) assay. For IVDs, the "device performance" and "acceptance criteria" are typically related to analytical performance (e.g., precision, accuracy, linearity, interference) rather than diagnostic accuracy (e.g., sensitivity, specificity, AUC) in the way a medical imaging AI would be evaluated. The "ground truth" and "experts" mentioned in your request are more relevant to AI/imaging diagnostics. Therefore, I will adapt the answers to fit the context of this IVD device.

Acceptance Criteria and Device Performance for ADVIA® Chemistry CardioPhase High Sensitivity C-Reactive Protein (hsCRP) Assay (K081294)

1. Table of Acceptance Criteria and Reported Device Performance

Since this is an IVD device, acceptance criteria are generally established against pre-defined analytical performance targets or by demonstrating substantial equivalence to a predicate device. The document explicitly states that "All of the evaluation studies gave acceptable results compared to the predicate device." While specific numerical acceptance limits aren't always explicitly listed in the summary, the reported performance metrics are presented in comparison to the predicate or against generally accepted analytical standards for such assays.

Performance Characteristic	Acceptance Criteria (Implied/Compared to Predicate)	Reported Device Performance (ADVIA Chemistry CardioPhase hsCRP)
Imprecision (Within Run CV%)	Comparable to predicate device; generally low CV% for IVD assays.	Levels (mg/L):- 0.21: 3.2%- 1.04: 1.1%- 3.12: 0.8%- 10.27: 1.4%
Imprecision (Total CV%)	Comparable to predicate device; generally low CV% for IVD assays.	Levels (mg/L):- 0.21: 4.2%- 1.04: 1.2%- 3.12: 1.3%- 10.27: 1.6%
Method Comparison (Correlation with Predicate)	Strong linear correlation (e.g., slope near 1, intercept near 0, high `r` value) with predicate.	Regression Equation (Passing Bablok): Y = 1.00x + 0.01Regression Equation (Least Squares): Y = 1.01x - 0.01Correlation Coefficient (r): 0.998
Interfering Substances (Effect % Change)	Minimal interference (e.g., within +/- 10% or pre-defined clinical significance).	Effect (Max % Change from listed substances):- Hemoglobin: -9%- Lipids: -7%- Bilirubin, free: 4%- Bilirubin, conjugated: 0%- Rheumatoid Factor: 8%
Analytical Range	Appropriately wide and clinically relevant range.	0.16 to 10 mg/L

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

Sample Size for Method Comparison (Test Set): 167 (for serum samples comparing the new device to the predicate).
Data Provenance: The document does not specify the country of origin or whether the data was retrospective or prospective. Given the nature of laboratory method comparison studies, these are typically prospective evaluations using clinical samples collected for testing.

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

This is not applicable in the typical sense for this IVD assay. For an IVD, the "ground truth" for method comparison is essentially the result obtained from the established, legally marketed predicate device. The analytical validity is determined by how closely the new device's results correlate with the predicate, rather than by expert interpretation of individual cases.

4. Adjudication Method for the Test Set

Not applicable. There is no adjudication process involving human experts interpreting results to establish a ground truth for a quantitative immunoassay like this. The comparison is purely numerical between two analytical instruments/methods.

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. MRMC studies are relevant for medical imaging diagnostics where human readers (e.g., radiologists) interpret images, and AI might assist in that interpretation. This document describes an automated laboratory assay for measuring a biomarker (CRP), not an imaging AI.

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

Yes, in the context of an IVD, the performance outlined is the "standalone" performance of the assay system itself. The reported imprecision, method correlation, and interference studies describe how the ADVIA Chemistry CardioPhase hsCRP assay performs autonomously on the ADVIA 1650 system. The human involvement is in operating the instrument and interpreting the quantitative results, not in a diagnostic interpretation loop that the device enhances or replaces.

7. The Type of Ground Truth Used

For the analytical performance studies:

Method Comparison: The "ground truth" was established by the results from the predicate device (Siemens Healthcare CardioPhase™ High Sensitivity CRP on the BNII Systems). The objective was to show that the new device's measurements align with those of an already accepted method.
Imprecision, Interfering Substances, Analytical Range: These studies used known concentrations of analytes (e.g., controls, spiked samples) as their internal reference ("ground truth") to measure the device's consistency, susceptibility to interference, and operational range.

8. The Sample Size for the Training Set

Not applicable in the context of this traditional IVD assay. "Training set" refers to data used to train machine learning algorithms. This device is a biochemical assay, not an AI/ML product, and therefore does not have a "training set" in that sense. Its development involved chemical and engineering optimization, and its performance is demonstrated through analytical studies.

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

Not applicable, as there is no training set for this type of device.

Summary

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510(k) Summary

Submitter informationContact person:	Philip LiuManager, Regulatory Affairs & Compliance
Address:	Siemens Healthcare Diagnostics Inc.511 Benedict AvenueTarrytown, NY 10591
Phone:	914-524-2443914-524-2500 (fax)
Date summary prepared:	May 1, 2008
Device Trade or Proprietary Names:	ADVIA® Chemistry CardioPhase High SensitivityC-Reactive Protein (hsCRP) AssayADVIA® Chemistry CardioPhase High SensitivityC-Reactive Protein (hsCRP) Calibrators
Device Common/Usual Name orClassification Name:	Cardiac C-Reactive Protein, Antigen, Antiserum,and ControlCalibrators
Classification Number/Class:	NQD / Class IIJIX / Class II

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

The assigned 510(k) number is:	K081294
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Assay Predicate Devices:

	Predicate Device
Device Name	CardioPhase™ High Sensitivity C-Reactive Protein(hsCRP) on the BNII Systems
Common name	High Sensitivity C-Reactive Protein (hsCRP)
510(k) Number	K033908
Manufacturer	Siemens Healthcare Diagnostics(formerly Dade Behring, Inc.)

Siemens Healthcare Diagnostics

ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein Premarket Notification 510(k) ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein Calibrators Premarket Notification 510(k) 510(k) Summary

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Calibrator Predicate Device:

	Predicate Device
Device Name	ADVIA Chemistry wrCRP
Common name	C-Reactive Protein Calibrators
510(k) Number	K022682 (Randox Labs, Ltd)
Manufacturer	Siemens Healthcare Diagnostics(formerly Siemens Medical Solutions Diagnostics)

Device Description:

The ADVIA Chemistry CardioPhase™ High Sensitivity C-Reactive Protein assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma on the ADVIA Chemistry systems. The CardioPhaseTM hsCRP latex reagent is a suspension of uniform polystyrene latex particles coated with anti-CRP antibody. When serum or plasma containing CRP is mixed with the latex reagent, agglutination takes place resulting in an increase in turbidity. This turbidity is measured at 571 nm. The CRP concentration in serum or plasma is determined from a calibration curve that is generated with the calibrators.

The calibrators (1 mL/vial) are liquid and ready to use. Storage is at 2 - 8℃.

Statement of Intended Use:

The ADVIA Chemistry CardioPhase™ High Sensitivity C-Reactive Protein assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma (lithium heparin and potassium EDTA) on the ADVIA Chemistry systems. In acute phase response, increased levels of a number of plasma proteins, including CRP, are observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injurv, inflammatory disorders, and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurement of hsCRP, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndromes.

The ADVIA Chemistry CardioPhase™ High Sensitivity C-Reactive Protein Calibrators are for in vitro diagnostic use in the calibration of ADVIA Chemistry systems for the CardioPhase High Sensitivity C-Reactive Protein method.

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Comparisons to the Predicate Device:

Assay Similarities

	ADVIA Chemistry CardioPhase™High Sensitivity C-Reactive Protein(hsCRP)( new device )	Siemens Healthcare CardioPhase™High Sensitivity CRP on the BNIISystems(formerly Dade Behring)( predicate device )
Intended Use	For in vitro diagnostic use in thequantitative determination of C-Reactive Protein	For in vitro diagnostic use in thequantitative determination of C-Reactive Protein
Specimen Type	Human serum or plasma (lithiumheparin, potassium EDTA)	Human serum or plasma (lithiumheparin, potassium EDTA)
Calibration	Multi-point (6)	Reference curves generated by multi-point calibration
Standardization	IRMM Reference Material CRM 470	IRMM Reference Material CRM 470
Expected Values	Healthy individuals ≤ 3 mg/L	Healthy individuals ≤ 3 mg/L
	Risk for cardiovascular diseaseprediction*:Low < 1 mg/LAverage 1-3 mg/LHigh > 3 mg/L	Relative risk/average hsCRP:Low <1 mg/LAverage 1.0-3.0 mg/LHigh >3.0 mg/L

*AHA/CDC Scientific Statement

Assay Differences

	ADVIA Chemistry CardioPhase™High Sensitivity C-Reactive Protein(hsCRP)( new device )	Siemens Healthcare CardioPhase™High Sensitivity CRP on the BNIISystems(formerly Dade Behring)( predicate device )
Assay Principle	Latex-enhanced immuno-turbidimetricassay	Particle enhanced immuno-nephelometry on the BN system
Calibrator	ADVIA Chemistry CardioPhase™High Sensitivity C-Reactive ProteinCalibrators	N Rheumatology Standard SLN Diluent
Reagents	Two liquid reagents, ready to use	Ready to use reagent
Analytical Range(mg/L)	0.16 – 10.0 mg/L	0.10 – 20 mg/L

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Calibrator Similarities

	ADVIA ChemistryCardioPhase High SensitivityC-Reactive Protein Calibrators( new device )	ADVIA ChemistryWide Range C-Reactive ProteinCalibrators( predicate device )
Intended Use	For in vitro diagnostic use in thecalibration of ADVIA Chemistrysystems for the Cardiophase hsCRPmethod	For in vitro diagnostic use in thecalibration of ADVIA Chemistrysystems for the wrCRP method
Matrix	Liquid, ready to use	Liquid, ready to use
Calibrator Levels	6	6
CalibratorIngredients	Recombinant human CRP in astabilized protein matrix; containssodium azide	Recombinant human CRP in astabilized protein matrix; containssodium azide
Shelf Life	18 months	18 months
Standardization	CRM-470	CRM-470

Calibrator Differences

	ADVIA ChemistryCardioPhase High SensitivityC-Reactive Protein Calibrators(new device)	ADVIA ChemistryWide Range C-Reactive ProteinCalibrators(predicate device)
Expected Values	Lot specific:0, 0.53, 1.05, 1.58, 5.25, and 10.50mg/L	Lot specific:0, 2.5, 10, 20, 80, and 160 mg/L
Open Vial(capped) Stability	60 days stored @2-8°C	28 days stored @2-8°C

Performance:

Substantial equivalence was demonstrated by testing several performance characteristics including imprecision, method comparison, interfering substances, serum/plasma equivalency, and analytical range. The following tables summarize the precision (within run), interfering substances, analytical range, and method comparison results.

All of the evaluation studies gave acceptable results compared to the predicate device (this predicate device was used in clinical studies supporting an indication for cardiovascular use). These studies support that the ADVIA Chemistry CardioPhase™ High Sensitivity C-Reactive Protein assay is substantially equivalent to the Siemens Healthcare CardioPhase™ High Sensitivity CRP on the BNII Systems that is currently marketed.

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Imprecision

ADVIA ChemistryCardioPhase hsCRP			Siemens Healthcare(former Dade Behring)CardioPhase hsCRP
ADVIA 1650			BNII
Level (mg/L)	Within runCV (%)	TotalCV (%)	Level (mg/L)	Within runCV (%)
0.21	3.2%	4.2%	0.5	2.5%
1.04	1.1%	1.2%	1.3	3.8%
3.12	0.8%	1.3%	2.1	2.1%
10.27	1.4%	1.6%	14	2.6%
			24	3.9%

Correlation

(y = ADVIA Chemistry CardioPhase hsCRP, x = comparison method/system)

Specimen type,System (y)	Comparison System (x)	N	RegressionEquation	Sy.x(mg/L)	r	SampleRange(mg/L)
Serum,ADVIA 1650	former Dade BehringCardioPhase hsCRP onBNII	167	Passing Bablok:$Y = 1.00x + 0.01$	N/A	N/A	0.17 - 9.05
Serum,ADVIA 1650	former Dade BehringCardioPhase hsCRP onBNII	167	Least Squares:$Y = 1.01x - 0.01$	0.13	0.998	0.17 - 9.05

Interfering Substances

(ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein on ADVIA 1650)

Interfering Substance	InterferentConc. (mg/dL)	CRP conc.(mg/L)	Effect(% change)
Hemoglobin	500 mg/dL	0.43	- 9%
Lipids (Intralipid)	1000 mg/dL	0.52	- 7%
Bilirubin, free	30 mg/dL	0.53	4%
Bilirubin, conjugated	30 mg/dL	0.51	0
Rheumatoid Factor	1040 IU/mL	3.15	8%

Analytical Range (Serum/Plasma)

Platform	ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein
ADVIA 1650	0.16 to 10 mg/L

Siemens Healthcare Diagnostics ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein Premarket Notification 510(k) ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein Calibrators Premarket Notification 510(k) 510(k) Summary

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Conclusions:

The ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein assay is substantially equivalent to other products in commercial distribution intended for similar Most notably, it is substantially equivalent to the currently marketed Siemens use. Healthcare Diagnostics (formerly Dade Behring) CardioPhase High Sensitivity CRP on the BNII Systems (this predicate device was used in clinical studies supporting an indication for cardiovascular use).

The ADVIA® Chemistry CardioPhase High Sensitivity C-Reactive Protein Calibrators are substantially equivalent to other products in commercial distribution intended for similar use. Most notably, it is substantially equivalent to the currently marketed ADVIA Chemistry Wide Range C-Reactive Protein Calibrators (K022682).

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Image /page/6/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo features a stylized eagle with three lines representing its wings and body. The eagle is facing right. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

JUL 2 9 2008

Siemens Healthcare Diagnostics Inc. c/o Philip Liu Manager, Regulatory Affairs & Compliance 511 Benedict Avenue Tarrytown, NY 10591

Re: K081294

Trade/Device Name: ADVIA® Chemistry CardioPhase High Sensitivity C-Reactive Protein (hsCRP) Assay, ADVIA Chemistry CardioPhase High Sensitivity C-Reactive Protein Calibrators Regulation Number: 21CFR Sec .- 866.5270 Regulation Name: C-Reactive Protein Immunological Test System. Regulatory Class: Class II Product Code: NQD, JIX Dated: May 5, 2008 Received: May 7, 2008

Dear Dr. Liu:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA), You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice

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Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a logally marketed predicate device results in a classification for your device of July , permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. Also, please othe the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll the (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Jean M. Cooper, M.S., D.V.M.

Jean M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known):

Device Name(s):

ADVIA CHEMISTRY CardioPhase™ High Sensitivity C-Reactive Protein Assay ADVIA CHEMISTRY CardioPhase™ High Sensitivity C-Reactive Protein Calibrators

Indications For Use:

Prescription Use (Part 21 CFR 801 Subpart D) AND/OR

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

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

Concurrence of CDRH, Office of In Vitro Djagnostic Devices (OIVD) and

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Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

K081294

Regulation Number and Section

§ 866.5270 C-reactive protein immunological test system.

(a)
Identification. A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.(b)
Classification. Class II (performance standards).