The ADVIA® Chemistry Cystatin C 2 (CYSC 2) assay is for the in vitro diagnostic use in the quantitative determination of cystatin C in human serum and plasma (lithium heparin, potassium EDTA) on ADVIA Chemistry systems. Measurement of cystatin C aids in the diagnosis and treatment of renal disease.

Device Description

The ADVIA Cystatin C_2 assay (CYSC_2) is an in vitro diagnostics kit containing reagents for the quantitative determination of cystatin C in human serum and plasma by means of particle-enhanced turbidimetry using the ADVIA Chemistry Systems. Used in conjunction with other clinical and laboratory findings, ADVIA Chemistry Cystatin C 2 measurements are used as an aid in the diagnosis and treatment of renal diseases.

The ADVIA Chemistry Cystatin C 2 latex reagent is a suspension of uniform latex particles coated with anti-cystatin-C antibody. When serum or plasma containing cystatin C is mixed with the latex reagent, agglutination takes place resulting in an increase in turbidity. This turbidity is measured at 571 and 805 nm. The cystatin C concentration in serum or plasma is determined from a calibration curve that is generated with the calibrators.

AI/ML Overview

The provided text describes the 510(k) premarket notification for the ADVIA Chemistry Cystatin C 2 Assay (CYSC 2). This is an in vitro diagnostic (IVD) device, not an AI/ML software device. Therefore, many of the requested criteria related to AI/ML device performance (e.g., human-in-the-loop, training set, ground truth experts) are not applicable.

However, I can extract and present the relevant acceptance criteria and study information for this IVD device based on the provided text.

Here's the breakdown of the acceptance criteria and the study proving the device meets them, focusing on the appropriate metrics for an IVD assay:

Acceptance Criteria and Device Performance for ADVIA Chemistry Cystatin C 2 Assay (CYSC 2)

Note: This device is an In Vitro Diagnostic (IVD) assay designed to quantitatively measure Cystatin C in human serum and plasma. Its performance is evaluated through analytical studies, not typically through human-in-the-loop or AI-related metrics. Thus, many of the requested fields (e.g., number of experts, adjudication, MRMC study, standalone AI performance, training set details) are not applicable to this type of device.

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria (Implicit from Study Design/Results)	Reported Device Performance (ADVIA CYSC_2)
Method Comparison (vs. Predicate)	High correlation (r ≥ 0.99 for good agreement), slope close to 1, intercept close to 0.	Passing-Bablok Regression: Slope: 1.008 (95% CI: 0.998 to 1.022) Intercept: 0.101 mg/L (95% CI: 0.086 to 0.113) r-Value: 1.000Weighted Least Square Linear Regression: Slope: 1.021 (95% CI: 1.006 to 1.037) Intercept: 0.079 mg/L (95% CI: 0.063 to 0.96) r-Value: 1.000
Repeatability (Intra-assay precision)	Low Coefficient of Variation (%CV) and Standard Deviation (SD) for various concentration levels.	Repeatability (SD / %CV): 0.52 mg/L: 0.01 / 2.0 0.85 mg/L: 0.01 / 1.1 3.91 mg/L: 0.04 / 1.1 1.09 mg/L: 0.01 / 0.9 8.92 mg/L: 0.12 / 1.4
Within-Lab Precision (Inter-assay precision)	Low Coefficient of Variation (%CV) and Standard Deviation (SD) for various concentration levels.	Within-Lab Precision (SD / %CV): 0.52 mg/L: 0.02 / 3.7 0.85 mg/L: 0.01 / 1.5 3.91 mg/L: 0.07 / 1.9 1.09 mg/L: 0.01 / 1.2 8.92 mg/L: 0.21 / 2.4
Linearity	Deviation from linearity < 10% for values > 2.50 mg/L and ≤ 0.25 mg/L for values ≤ 2.50 mg/L.	Samples above 2.5 mg/L deviated no more than 10%. Samples below or equal to 2.5 mg/L demonstrated a bias no greater than 0.03. (Linear fit deviation for entire range: <10% or <0.25 mg/L)
Limit of Blank (LoB)	Acceptably low value to avoid false positives.	0.10 mg/L (Calculated non-parametrically with <5% false positives)
Limit of Detection (LoD)	Acceptably low value to detect low concentrations.	0.25 mg/L (Calculated non-parametrically with <5% false negatives)
Limit of Quantitation (LoQ)	Low concentration with a %CV < 10%.	0.25 mg/L (Lowest amount quantifiable at <10% CV)
Interference (from common substances)	No significant interference (NSI), defined as a percentage effect > 10%.	NSI observed for all tested interferents at specified levels and Cystatin C concentrations: Bilirubin (conjugated/unconjugated) at 60 mg/dL Lipemia (triglycerides) at 1000 mg/dL Hemolysis (hemoglobin) at 1000 mg/dL Rheumatoid Factor at 1200 IU/mL
Expected Values (Reference Interval)	Well-defined reference interval for healthy individuals.	0.64 - 1.23 mg/L (2.5th to 97.5th percentile for healthy individuals)
Calibrator Traceability	Traceable to an international reference material.	Traceable to IFCC European Reference Material ERM-DA471/IFCC.

2. Sample Size and Data Provenance for Test Set

Sample Size for Method Comparison: 158 frozen human serum samples.
Data Provenance: Not explicitly stated regarding country of origin or whether samples were prospective/retrospective. The samples were "frozen human serum samples." The predicate device (N Latex Cystatin C) is from Siemens as well, suggesting internal or collaboration data. The healthy samples for expected values were from a "normal range study, performed by Siemens."

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

Not Applicable.
For an IVD assay measuring a quantitative analyte like Cystatin C, the "ground truth" is established by direct measurement using a reference method or by comparing analytical performance to a legally marketed predicate device. This does not involve human expert interpretation of images or other subjective data.

4. Adjudication Method for the Test Set

Not Applicable.
As stated above, this is an IVD assay for quantitative measurement, not an AI/ML device relying on human interpretation and adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

Not Applicable.
This is an IVD assay, not an AI/ML diagnostic aid for human readers. Its performance is evaluated through analytical studies, not comparative effectiveness of human readers.

6. Standalone (i.e. algorithm only without human-in-the-loop performance) Performance

The listed performance characteristics are the standalone performance of the assay. The device itself (reagents, calibrators, and system) performs the measurement. There is no "human-in-the-loop" once the sample is loaded and the assay run on the instrument, other than for initial setup, quality control, and result interpretation by a clinician.

7. Type of Ground Truth Used

For the method comparison study, the "ground truth" or reference was the N Latex Cystatin C assay (K171072), the predicate device.
For other analytical performance characteristics (precision, linearity, detection capability, interference), the "ground truth" is inherent to the statistical and analytical methods used (e.g., gravimetric dilutions for linearity, certified reference materials for traceability, statistical analysis of replicates for precision/detection limits).
For expected values, the "ground truth" was established by measuring 208 apparently healthy samples (i.e., a healthy population study).

8. Sample Size for the Training Set

Not Applicable.
This is a laboratory diagnostic assay, not a machine learning algorithm that requires a "training set" in the computational sense. The "training" of the assay refers to its development and optimization through extensive laboratory testing and validation, not a data-driven training process.

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

Not Applicable.
There is no "training set" ground truth in the context of an IVD assay as understood for AI/ML devices. The "ground truth" for developing and validating the assay is primarily defined by established metrological principles, analytical chemistry standards, and comparison to recognized reference methods or predicate devices.

Summary

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May 25, 2018

Siemens Healthcare Diagnostics, Inc. Kathleen Dray-Lyons Regulatory and Clinical Affairs Specialist 500 GBC Drive Newark, NJ 19714

Re: K181082

Trade/Device Name: ADVIA Chemistry Cystatin C 2 Assay (CYSC 2) Regulation Number: 21 CFR 862.1225 Regulation Name: Creatinine test system Regulatory Class: Class II Product Code: NDY Dated: April 23, 2018 Received: April 24, 2018

Dear Kathleen Dray-Lyons:

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. 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 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); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR

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Part 820); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

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/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Kellie B. Kelm -S

for Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known)

K181082

Device Name ADVIA® Chemistry Cystatin C 2 (CYSC 2) assay

Indications for Use (Describe)

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 submitted in accordance with the requirements of SMDA 1990 and 21 CFR §807.92.

The assigned 510(k) number is:

1. Submitter

Company	Siemens Healthcare Diagnostics Inc.
Address	500 GBC DriveNewark, DE 19702
Contact	Kathleen Dray-Lyons
Telephone	617-688-6117
Date of Preparation	May 24, 2018

2. Trade Name:

ADVIA® Chemistry Cystatin C_2 Assay (CYSC_2)

Common Name:

Test, Cystatin C

Classification:

21 CFR § 862.1225; Class II

Product Code:

NDY

Panel:

Clinical Chemistry

3. Identification of the Predicate Devices:

N Latex Cystatin C (K171072)

The ADVIA Cystatin C_2 (CYSC_2) assay is substantially equivalent to the N Latex Cystatin C assay cleared under K171072.

4. Device Description:

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conjunction with other clinical and laboratory findings, ADVIA Chemistry Cystatin C 2 measurements are used as an aid in the diagnosis and treatment of renal diseases.

5. Device Intended Use:

The ADVIA Chemistry Cystatin C 2 (CYSC 2) assay is for the in vitro diagnostic use in the quantitative determination of cystatin C in human serum and plasma (lithium heparin, potassium EDTA) on ADVIA Chemistry systems. Measurement of cystatin C aids in the diagnosis and treatment of renal disease.

6. Technical Characteristics:

Similarities and Differences to the predicate:

A comparison of the similarities and differences between the proposed ADVIA Chemistry Cystatin C 2 assay versus the N Latex Cystatin C assay (predicate) is provided in the table below.

Attributes	ProposedADVIA Cystatin C_2 Assay	PredicateN Latex Cystatin C(K171072)
Intended Use	The ADVIA® Chemistry CystatinC_2 (CYSC_2) assay is for the in vitro diagnostic use in thequantitative determination ofcystatin C in human serum andplasma (lithium heparin,potassium EDTA) on ADVIAChemistry systems.Measurement of cystatin C aidsin the diagnosis and treatment ofrenal disease.	N Latex Cystatin C is an in vitrodiagnostics kit containingreagents for the quantitativedetermination of cystatin C inhuman serum and lithium-heparinized plasma by means ofparticle enhancedimmunonephelometry using theBN Systems. Cystatin Cmeasurements are used in thediagnosis and treatment of renaldiseases.
Assay format	Turbidimetry	Immunonephelometry
Antibody	Rabbit	Same
Traceability	The assay calibrator is traceableto the IFCC European ReferenceMaterial ERM-DA471/IFCC	Same

ADVIA Cystatin C 2 Assay versus N Latex Cystatin C

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	certified for cystatin Cmeasurements
Analyzers	ADVIA Chemistry Systems	BN Systems
Sample type	Serum and Plasma (lithiumheparin, potassium EDTA)	Serum and Plasma (lithiumheparin)
Units	mg/L	Same
MeasuringRange	0.25 to 8.93 mg/L0.25 to 26.79 mg/L (1:3 dilution)	0.27 – 9.4 mg/L
Calibrators	5 levels	One level

7. Non-Clinical Performance Evaluation:

Method Comparison versus the Predicate:

The ADVIA Chemistry Cystatin C_2 assay on the ADVIA 1800 system was compared to the predicate N Latex Cystatin C assay (K171072) on the BN ProSpec system in accordance with CLSI EP09-A3: Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline Third Edition. One hundred and fifty-eight (158) frozen human serum samples were assayed in singlicate across the assay range of 0.25 - 8.93 mg/L. Analysis of the results using weighted linear regression, standard Passing-Bablok regression and Least Squares was calculated. The correlation coefficient (r) was obtained by linear regression.

Passing-Bablok regression analysis vielded the following:

Methods	n	N LatexSampleRangeAnalyzed(mg/L)	Slope(95% CI)	Interceptmg/L(95% CI)	r-Value*
ADVIA CYCS_2versusN LatexCystatin C	158	0.44 to 8.07	1.008(0.998 to1.022)	0.101(0.086 to0.113)	1.000

Weighted Least Square Linear regression yielded the following:

Methods	n	N LatexSampleRangeAnalyzed(mg/L)	Slope(95% CI)	Interceptmg/L(95% CI)	r-Value*
ADVIA CYCS_2 158			1.021	0.079	1.000

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versusN LatexCystatin C	0.44 to 8.07	(1.006 to1.037)	(0.063 to0.96)
---------------------------------	--------------	---------------------	--------------------

Correlation coefficient (r) was obtained from ordinary least squares regression.

Repeatability and Within Lab Precision:

Testing was performed over twenty (20) days, two (2) runs per day, two (2) times per run for a total 80 replicates/sample. Analysis of variance (ANOVA) was used to calculate the Repeatability and Within-Lab imprecision. Typical precision observed on the ADVIA Cystatin C 2 assay is summarized below.

Material	N	Mean	Repeatability		Within-LabPrecision
		mg/L	SD	%CV	SD	%CV
Multiqual 1 Control	80	0.52	0.01	2.0	0.02	3.7
Randox 2 Control	80	0.85	0.01	1.1	0.01	1.5
Randox 3 Control	80	3.91	0.04	1.1	0.07	1.9
Serum Pool 1	80	1.09	0.01	0.9	0.01	1.2
Serum Pool 2	80	8.92	0.12	1.4	0.21	2.4

Repeatability and Within-Lab Results

Linearity

Linearity across the assay range (0.25 to 8.93 mg/L) was confirmed in accordance with CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach, by testing a high concentration of cystatin C on the ADVIA Chemistry 1800 system using one lot of reagent and calibrators. This high concentration sample was serially diluted with a low concentration sample (serum) with equally spaced dilution levels ranging from 0.19 to 9.06 mg/L. Linearity was demonstrated by linear fit deviation of <10% for samples > 2.50 mg/L and linear fit deviation of ≤ 0.25 mg/L for samples ≤ 2.50 mg/L. Samples above 2.5 mg/L were found to deviate no more than 10%, while samples below or equal to 2.5 mg/L did not demonstrate a bias greater than 0.03.

ADVIASystem	Linear Regression			PercentDeviation	AbsoluteDeviation	n	SampleRangemg/L
1800	1.087	-0.014	0.999	10%	0.25 mg/L	11	0.19 - 9.06

ADVIA Cystatin C_2 Assay

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Detection Capability

LoB: Four (4) blank samples were prepared at a concentration of 0 mg/L. All four samples were tested in replicates of twenty (20) on the ADVIA 1800 system over three (3) days using two (2) reagent lots for a total of N=480 replicates. The LoB for the ADVIA Chemistry CYSC 2 assay is 0.10 mg/L.

LoD: Four (4) samples were prepared at a concentration of approximately 0.1 mg/L. All four samples were tested in replicates of twenty (20) on the ADVIA 1800 system over three (3) days using two (2) reagent lots for a total of N=480 replicates. The LoD for the ADVIA Chemistry CYSC_2 assay is 0.25 mg/L.

LoQ: Four (4) serum samples were prepared at a concentration of approximately 0.1 mg/L. All four samples were tested in replicates of twenty (20) on the ADVIA 1800 system over three (3) days using two (2) reagent lots. The LoQ for the ADVIA Chemistry CYSC_2 assay is 0.25 mg/L.

LoB and LoD values were calculated non-parametrically with proportions of false positives (α) less than 5% and false negatives (β) less than 5%, based on 480. LoQ is the lowest amount of cystatin C that can be determined quantitatively at < 10% CV.

Interference Testing

Interference testing was performed according to CLSI EP07-A2: Approved Guideline Interference Testing in Clinical Chemistry to determine the effect of various endogenous and exogenous substances on the ADVIA Cystatin C 2 assay. For all interferents the percent recovery was determined by testing a control sample without the interferent and comparing it to the value obtained from a test sample to which the potential interferent had been added. Interferents were tested at two levels of cystatin c concentrations: 0.4 to 1.2 mg/L and 2.5 to 3.5 mg/L.

Interferent	Interferent Level	Cystatin C Sample Concentration	Interference
Bilirubin(conjugated)	60 mg/dL	0.69 mg/L	NSIa
	60 mg/dL	2.51 mg/L	NSI
Bilirubin(unconjugated)	60 mg/dL	0.78 mg/L	NSI
	60 mg/dL	2.74 mg/L	NSI
Lipemia(triglycerides from Intralipid)	1000 mg/dL	0.79 mg/L	NSI
	1000 mg/dL	2.75 mg/L	NSI
Hemolysis (hemoglobin)	1000 mg/dL	1.13 mg/L	NSI
	1000 mg/dL	2.64 mg/L	NSI
Rheumatoid Factor	1200 IU/mL	0.89 mg/L	NSI
	1200 IU/mL	3.14 mg/L	NSI

ADVIA Chemistry 1800 system

a NSI = No significant interference. A percentage effect > 10% is considered a significant interference.

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Expected Values:

The expected values for healthy individuals are from 0.64-1.23 mg/L. These are the 2.5 and the 97.5 percentile values from the results of a normal range study, following CLSI Procedure EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory with 208 apparently healthy samples, performed by Siemens.

ADVIA Cystatin C_2
Median
2.5 Percentile	0.64 mg/L
97.5 Percentile	1.23 mg/L

Calibrator Traceability:

The assay is standardized using calibrators, which are traceable to the IFCC European Reference Material ERM-DA471/IFCC, certified for Cystatin C measurements.

8. Conclusion:

The ADVIA Chemistry Cystatin C_2 assay is substantially equivalent to the predicate devices based on intended use, principle and the performance characteristics above.

Regulation Number and Section

§ 862.1225 Creatinine test system.

(a)
Identification. A creatinine test system is a device intended to measure creatinine levels in plasma and urine. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.(b)
Classification. Class II.