The ADVIA CHEMISTRY C-Reactive Protein_2 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) on the ADVIA Chemistry systems. Such measurements are used in the evaluation of infection, tissue injury, inflammatory disorders, and associated diseases. Increases in CRP values are non-specific for many disease processes and should not be interpreted without a complete clinical evaluation.

The ADVIA Chemistry C-Reactive Protein_2 Calibrators are for in vitro diagnostic use in the calibration of ADVIA Chemistry systems for the C-Reactive Protein 2 (CRP 2) method.

Device Description

The ADVIA Chemistry C-Reactive Protein_2 (CRP_2) assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein in human serum and plasma on the ADVIA® Chemistry systems. The ADVIA Chemistry C-Reactive Protein_2 Calibrators are used to calibrate this method. The proposed labeling indicates the ADVIA Chemistry CRP_2 reagents and Calibrators are for use on the family of ADVIA Chemistry Systems (1200 / 1650 / 1800 / 2400).

The CRP_2 latex reagent is a suspension of uniform polystyrene latex particles coated with rabbit anti-CRP antibody. When serum or plasma containing CRP is mixed with the latex reagent, agglutination takes place resulting in an increase in the 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 C-Reactive Protein_2 Calibrators consist of six (6) levels of protein stabilized matrices containing varying concentrations of recombinant human CRP. The Calibrators have targeted expected values (lot specific) of 0, 5, 20, 40, 160, and 320 mg/L.

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

AI/ML Overview

Here's an analysis of the acceptance criteria and study detailed in the provided 510(k) summary:

This document describes an in vitro diagnostic (IVD) device, specifically an assay and calibrators for measuring C-Reactive Protein (CRP). The acceptance criteria are primarily focused on demonstrating substantial equivalence to existing predicate devices through performance studies.

Acceptance Criteria and Reported Device Performance

The acceptance criteria for this IVD device are implicitly defined by demonstrating performance that is comparable to or better than the predicate device across various analytical characteristics.

Table of Acceptance Criteria and Reported Device Performance:

Performance Characteristic	Acceptance Criteria (Implicit for Substantial Equivalence)	Reported Device Performance (ADVIA Chemistry C-Reactive Protein_2)
Imprecision (Total CV)	Comparable to or better than predicate device	ADVIA 1650:
		- CRP level 31 mg/L: 1.3%
		- CRP level 56 mg/L: 1.1%
		- CRP level 83 mg/L: 1.5%
		- CRP level 221 mg/L: 1.5%
Correlation ($r$)	Strong correlation (e.g., $r \ge 0.975$) with predicate	0.990 (Serum, ADVIA 1650 vs. ADVIA 1650 CRP)
& Linear Regression	Slope near 1.0, intercept near 0.0	$Y = 0.99x - 2.8$
Analytical Range	Meet specified clinical range and compare to predicate	4 to Calibrator 6 (304-336) mg/L on ADVIA 1650
Interfering Substances	Minimal clinically significant interference	Hemoglobin (1000 mg/dL): 0.7% change
	(e.g., % change < 10% or within set limits)	Lipids (Intralipid 1000 mg/dL): -0.7% change
		Lipids (Triglycerides 1000 mg/dL): 0.5% change
		Bilirubin, free (60 mg/dL): 1.8% change
		Bilirubin, conjugated (60 mg/dL): 2.0% change
		Rheumatoid Factor (200 IU/mL): 8.4% change
Serum/Plasma Equivalency	To demonstrate comparability of results between sample types	Not explicitly detailed but mentioned as a performed study. Implies acceptable equivalency.
Calibrator Stability (Open Vial)	To ensure acceptable performance for indicated duration	60 days stored @2-8°C (predicate: 28 days)

Study Details Proving Acceptance Criteria

The studies conducted are primarily analytical performance studies comparing the new device to its predicate.

Sample Size Used for the Test Set and Data Provenance:
- Imprecision: Not explicitly stated for the test set, but typical precision studies involve running samples multiple times across several days. The reported values are "Level (mg/L)" and "Total CV (%)", suggesting multiple measurements per sample.
- Correlation/Method Comparison: N=47 samples were used for the method comparison study (Serum, ADVIA 1650 vs. ADVIA 1650 CRP).
- Interfering Substances: For each interfering substance, performance was assessed at a CRP concentration of 5 mg/L (for Hemoglobin, Lipids, Bilirubin) or 4 mg/L (for Rheumatoid Factor). The number of replicates or distinct samples tested with interferent is not specified, but typically involves spiked samples.
- Data Provenance: Not specified, but generally for IVD devices, samples are sourced from clinical laboratories or biobanks, representing a relevant patient population. These are typically retrospective samples or spiked samples for analytical studies.
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts:
- For IVD assays measuring biomarkers like CRP, the "ground truth" is typically established by measurement against a reference method or a validated, widely accepted existing method (the predicate device in this case), rather than expert consensus on diagnostic images or clinical cases. Therefore, experts are not used in the traditional sense to establish individual sample ground truth. The "expertise" lies in the validation of the chosen reference method and the analytical methodologies themselves, overseen by scientific and clinical personnel.
Adjudication Method for the Test Set:
- None in the context of expert adjudication for clinical cases. As mentioned above, for biomarker assays, the "truth" for a sample's concentration is determined by the reference method.
If a Multi-Reader, Multi-Case (MRMC) Comparative Effectiveness Study was done:
- No. MRMC studies are relevant for devices where human interpretation is involved (e.g., radiology AI). This is an in vitro diagnostic assay where a machine quantitatively measures a biological marker. There is no human interpretative component in the performance evaluation described.
If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, this entire submission effectively describes a standalone performance evaluation. The device (ADVIA Chemistry C-Reactive Protein_2 assay) is an automated system that measures CRP concentration. Its performance characteristics (imprecision, correlation, interference, analytical range) are evaluated directly, without human intervention in the measurement process (other than sample preparation and loading). The comparison is between two automated systems (new device vs. predicate device).
The Type of Ground Truth Used:
- The ground truth for the analytical studies is based on:
  - Measurements from the legally marketed predicate device (ADVIA Chemistry C-Reactive Protein assay, K992662) for method comparison studies.
  - Known concentrations for spiked samples in imprecision and interference studies.
  - Standardization against CRM-470 (a certified reference material), indicating traceability to a recognized international standard for CRP. This reference material effectively establishes the "true" concentration values for calibration and control materials.
The Sample Size for the Training Set:
- The document does not detail a "training set" in the context of machine learning model development. For IVD assays, "training" typically refers to the process of calibration to establish the relationship between instrument signal and analyte concentration. Calibration is performed using the ADVIA Chemistry C-Reactive Protein_2 Calibrators. These calibrators consist of six levels (0, 5, 20, 40, 160, and 320 mg/L) of recombinant human CRP. The specific number of times or ways these calibrators were run for the development of the assay is not specified in this summary, but the six levels constitute the basis for the calibration curve.
How the Ground Truth for the Training Set was Established:
- The ground truth for the calibrators (which serve as the "training set" for the instrument's measurement) is established by:
  - Using recombinant human CRP at specific, manufactured concentrations.
  - Standardization to CRM-470, meaning the lot-specific expected values of the calibrators are traceable to this international reference material for CRP. This ensures the accuracy and consistency of the assigned values across different lots and manufacturers.

Summary

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510(k) Summary

APR - 1 2008

Submitter InformationContact person:	Philip LiuManager, Regulatory Affairs & Compliance
Address:	Siemens Healthcare Diagnostics511 Benedict AvenueTarrytown, NY 10591
Phone:	914-524-2443914-524-2500 (fax)
Date summary prepared:	February 18, 2008
Device Trade or Proprietary Names:	ADVIA® Chemistry C-Reactive Protein_2(CRP_2) AssayADVIA® Chemistry C-Reactive Protein_2Calibrators
Device Common/Usual Name orClassification Name:	C-Reactive Protein immunological test systemCalibrators
Classification Number/Class:	DCN / Class IIJIX / Class II

This 510(k) summary of safety and effectiveness is being submitted in accordance with

This 510(k) summary of satety and effect ctiveness is being subm

The assigned 510(k) number is: _______________________________________________________________________________________________________________________________________________

Assay Predicate Device:

	Predicate Device
Device Name	ADVIA® Chemistry Systems C-Reactive Protein
Common name	C-Reactive Protein Immunological Test System
510(k) Number	K992662
Manufacturer	Siemens Healthcare Diagnostics(formerly Siemens Medical Solutions Diagnostics /Bayer HealthCare LLC)

Siemens Healthcare Diagnostics (formerly Siemens Medical Solutions Diagnostics) ADVIA Chemistry C-Reactive Protein_2 Premarket Notification 510(K)
ADVIA Chemistry C-Reactive Protein_2 Calibrator Premarket Notification 510(K) Attachment 1-510(k) Summary Revised

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Calibrator Predicate Device:

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

Device Description:

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

Statement of Intended Use:

The ADVIA Chemistry C-Reactive Protein_2 assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein in human serum and plasma (lithium heparin) on the ADVIA® Chemistry systems. Such measurements are used in the evaluation of infection, tissue injury, inflammatory disorders, and associated diseases. Increases in CRP values are non-specific for many disease processes and should not be interpreted without a complete clinical evaluation.

The ADVIA Chemistry C-Reactive Protein_2 Calibrators are for in vitro diagnostic use in the calibration of ADVIA Chemistry Systems for the ADVIA Chemistry C-Reactive Protein_2 (CRP_2) method.

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Comparisons to the Predicate Devices:

Assay Similarities

	ADVIA ChemistryC-Reactive Protein_2 (CRP_2)( new device )	ADVIA ChemistryC-Reactive Protein (CRP)( predicate device )
Intended Use	Quantitative determination of C-Reactive Protein	Quantitative determination of C-Reactive Protein
Specimen Type	Human serum or plasma (lithiumheparin)	Human serum
Calibration	Multi-point (6)	Multi-point (6)
Reaction Type	Turbidimetric Endpoint	Turbidimetric Endpoint
Reagents	Two liquid reagents, ready to use	Two liquid reagents, ready to use
Standardization	CRM-470	CRM-470

Assay Differences

	ADVIA ChemistryC-Reactive Protein_2 (CRP_2)( new device )	ADVIA ChemistryC-Reactive Protein (CRP)( predicate device )
Assay Principle	Latex turbidimetric immunoassay	Polyethylene glycol assistedturbidimetric immunoassay
ReadWavelength	571 nm	340/ 694 nm
Calibrators	ADVIA Chemistry CRP_2Calibrators	ADVIA Chemistry CRP Calibrators
Analytical Range(mg/L)*	4 to Calibrator 6(Cal 6 target 304– 336)	5 to Calibrator 6(Cal 6 target 195 – 205)
Expected Values	<10 mg/L**	<10 mg/L**

** Tletz NW. Clinical Guide to Laboratory Tests, 4th Edition

Callbrator Simllarities

	ADVIA ChemistryC-Reactive Protein_2 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 CRP_2 method	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

Slemens Healthcare Diagnostics (formerly Slemens Medical Solutions Diagnostics)
ADVIA Chemistry C-Reactive Protein_2 Premarket Notification 510(k)
ADVIA Chemistry C-Fleactive Attachment 1- 510(k) Summary Revised

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Calibrator Differences

	ADVIA ChemistryC-Reactive Protein_2 Calibrators(new device)	ADVIA ChemistryWide Range C-Reactive ProteinCalibrators(predicate device)
Expected Values	Lot specific:0, 5, 20, 40, 160, and 320 mg/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 (total), interfering substances, analytical range, and method comparison results.

All of the evaluation studies gave acceptable results compared to the predicate devices. These studies support that the ADVIA Chemistry C-Reactive Protein_2 assay is substantially equivalent to the ADVIA Chemistry C-Reactive Protein assay that is currently marketed.

	ADVIA ChemistryC-Reactive Protein_2	ADVIA ChemistryC-Reactive Protein
	ADVIA 1650	ADVIA 1650
Level (mg/L)	Total CV (%)	Level (mg/L)	Total CV (%)
31	1.3	5	13.6
56	1.1	42	4.6
83	1.5
221	1.5

Imprecision

Correlation

(y = ADVIA Chemistry C-Reactive Protein_2, x = comparison method/system)

Specimen type,System (y)	Comparison System (x)	N	RegressionEquation	Sy.x(mg/L)	r	SampleRange(mg/L)
Serum, ADVIA1650	ADVIA 1650 CRP	47	$Y = 0.99x - 2.8$	9.8	0.990	5 - 199

Siemens Healthcare Diagnostics (formerly Siemens Medical Solutions Diagnostics) Clemono Frountibure Protein_2 Premarket Notification 510(K) ADVIA ChemIstry C-Reactive Protein_2 Calibrator Premarket Notification 510(k) Attachment 1- 510(k) Summary Revised

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Interfering Substance	InterferentConc. (mg/dL)	CRP conc.(mg/L)	Effect(% change)
Hemoglobin	1000 mg/dL	5	0.7
Lipids (Intralipid)	1000 mg/dL	5	- 0.7
Lipids (Triglycerides)	1000 mg/dL	5	0.5
Bilirubin, free	60 mg/dL	5	1.8
Bilirubin, conjugated	60 mg/dL	5	2.0
Rheumatoid Factor	200 IU/mL	4	8.4

Interfering Substances (ADVIA Chemistry C-Reactive Protein_2 on ADVIA 1650)

Analytical Range - Serum/Plasma

Platform	ADVIA Chemistry C-Reactive Protein_2
ADVIA 1650	4 to Calibrator 6 (304-336) mg/L

Conclusions:

The ADVIA Chemistry C-Reactive Protein_2 assay is substantially equivalent to other products in commercial distribution intended for similar use. Most notably, it is substantially equivalent to the currently marketed Siemens Healthcare Diagnostics (formerly Bayer HealthCare LLC) ADVIA Chemistry C-Reactive Protein (K992662) assay.

The ADVIA® Chemistry C-Reactive Protein _2 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/5/Picture/0 description: The image shows the logo for the Department of Health & Human Services. The logo consists of a stylized caduceus symbol, which is a staff with two snakes coiled around it, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" arranged in a circular pattern around the symbol. The text is in all caps and is relatively small compared to the caduceus symbol.

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Siemens Medical Solutions Diagnostics c/o Philip Liu, Ph.D. Manager, Regulatory Affairs and Compliance 511 Benedict Avenue Tarrytown, NY 10591

Re: K072658

Trade/Device Name: ADVIA® Chemistry C-Reactive Protein_2 (CRP_2) Assay ADVIA® Chemistry C-Reactive Protein_2 Calibrators Regulation Number: 21 CFR 866.5270 Regulation Name: C-reactive protein immunological test system Regulatory Class: Class II Product Code: DCN, JIX Dated: February 19, 2008 Received: February 21, 2008

APR - 1 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 the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The

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Page 2 -

FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific 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) 276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at 240-276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at 240-276-3464. 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-free number (800) 638-2041 or (240) 276-3150 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Clara Beckerf

Robert L. Becker, Jr., M.D., Ph.D. Director Division of Immunology and Hematology Devices 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): K072658

Device Name: ADVIA CHEMISTRY C-Reactive Protein 2 Assay ADVIA CHEMISTRY C-Reactive Protein 2 Calibrators

Indications For Use:

The ADVIA Chemistry C-Reactive Protein_2 Calibrators are for in vitro diagnostic use in the calibration of ADVIA Chemistry systems for the C-Reactive Protein 2 (CRP 2) method.

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 Diagnostic Devices (OIVD)

Mana M. Chen
Division Sign Off

Division Stan-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

Page 1 of 1

510(k) K072657

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).