ADVIA Chemistry Cystatin C_2 Assay (CYSC_2)

K181082 · Siemens Healthcare Diagnostics, Inc. · NDY · May 25, 2018 · Clinical Chemistry

Device Facts

• Record ID: K181082
• Device Name: ADVIA Chemistry Cystatin C_2 Assay (CYSC_2)
• Applicant: Siemens Healthcare Diagnostics, Inc.
• Product Code: NDY · Clinical Chemistry
• Decision Date: May 25, 2018
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1225
• Device Class: Class 2

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.

Device Story

The ADVIA Chemistry Cystatin C 2 (CYSC 2) assay is an in vitro diagnostic kit for quantitative cystatin C measurement in human serum and plasma. The device uses particle-enhanced turbidimetry; latex particles coated with anti-cystatin-C antibodies agglutinate in the presence of cystatin C, increasing sample turbidity. Turbidity is measured at 571 and 805 nm on ADVIA Chemistry systems. Concentration is determined via a 5-level calibration curve. Used in clinical laboratories by technicians to assist physicians in diagnosing and treating renal disease; results are interpreted alongside other clinical and laboratory findings.

Clinical Evidence

Bench testing only. Method comparison study (n=158) against the predicate showed high correlation (r=1.000) with Passing-Bablok slope 1.008 and intercept 0.101 mg/L. Precision testing (n=80 replicates) demonstrated repeatability CVs of 0.9-2.0% and within-lab CVs of 1.2-3.7%. Linearity confirmed across 0.25-8.93 mg/L range. LoB/LoD/LoQ established at 0.10 mg/L, 0.25 mg/L, and 0.25 mg/L respectively. Interference testing showed no significant interference from bilirubin, lipemia, hemolysis, or rheumatoid factor.

Technological Characteristics

Particle-enhanced turbidimetry assay. Reagents consist of latex particles coated with rabbit anti-cystatin-C antibodies. Measures turbidity at 571 and 805 nm. Calibrators are traceable to IFCC ERM-DA471/IFCC. Compatible with ADVIA Chemistry systems. Measuring range 0.25-8.93 mg/L (up to 26.79 mg/L with dilution).

Indications for Use

Indicated for the quantitative determination of cystatin C in human serum and plasma (lithium heparin, potassium EDTA) to aid in the diagnosis and treatment of renal disease.

Regulatory Classification

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.

Submission Summary (Full Text)

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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 ([e-mail]) or phone [phone] 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)

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.

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 Drive<br>Newark, 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:

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

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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.

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.

#### 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 | Proposed<br>ADVIA Cystatin C_2 Assay | Predicate<br>N Latex Cystatin C<br>(K171072) |
|--------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | The ADVIA® Chemistry Cystatin<br>C_2 (CYSC_2) assay is for the <i>in vitro</i> diagnostic use in the<br>quantitative determination of<br>cystatin C in human serum and<br>plasma (lithium heparin,<br>potassium EDTA) on ADVIA<br>Chemistry systems.<br>Measurement of cystatin C aids<br>in the diagnosis and treatment of<br>renal disease. | N Latex Cystatin C is an <i>in vitro</i><br>diagnostics kit containing<br>reagents for the quantitative<br>determination of cystatin C in<br>human serum and lithium-<br>heparinized plasma by means of<br>particle enhanced<br>immunonephelometry using the<br>BN Systems. Cystatin C<br>measurements are used in the<br>diagnosis and treatment of renal<br>diseases. |
| Assay format | Turbidimetry | Immunonephelometry |
| Antibody | Rabbit | Same |
| Traceability | The assay calibrator is traceable<br>to the IFCC European Reference<br>Material ERM-DA471/IFCC | Same |

## ADVIA Cystatin C 2 Assay versus N Latex Cystatin C

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| | certified for cystatin C<br>measurements | |
|--------------------|--------------------------------------------------------|---------------------------------------|
| Analyzers | ADVIA Chemistry Systems | BN Systems |
| Sample type | Serum and Plasma (lithium<br>heparin, potassium EDTA) | Serum and Plasma (lithium<br>heparin) |
| Units | mg/L | Same |
| Measuring<br>Range | 0.25 to 8.93 mg/L<br>0.25 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 Latex<br>Sample<br>Range<br>Analyzed<br>(mg/L) | Slope<br>(95% CI) | Intercept<br>mg/L<br>(95% CI) | r-<br>Value* |
|-------------------------------------------------|-----|--------------------------------------------------|------------------------------|-------------------------------|--------------|
| ADVIA CYCS_2<br>versus<br>N Latex<br>Cystatin C | 158 | 0.44 to 8.07 | 1.008<br>(0.998 to<br>1.022) | 0.101<br>(0.086 to<br>0.113) | 1.000 |

## Weighted Least Square Linear regression yielded the following:

| Methods | n | N Latex<br>Sample<br>Range<br>Analyzed<br>(mg/L) | Slope<br>(95% CI) | Intercept<br>mg/L<br>(95% CI) | r-<br>Value* |
|------------------|---|--------------------------------------------------|-------------------|-------------------------------|--------------|
| ADVIA CYCS_2 158 | | | 1.021 | 0.079 | 1.000 |

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| versus<br>N Latex<br>Cystatin C | 0.44 to 8.07 | (1.006 to<br>1.037) | (0.063 to<br>0.96) |
|---------------------------------|--------------|---------------------|--------------------|
|---------------------------------|--------------|---------------------|--------------------|

* 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-Lab<br>Precision | |
|---------------------|----|------|---------------|-----|-------------------------|-----|
| | | 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.

| ADVIA<br>System | Linear Regression | | | Percent<br>Deviation | Absolute<br>Deviation | n | Sample<br>Range<br>mg/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<br>(conjugated) | 60 mg/dL | 0.69 mg/L | NSIa |
| | 60 mg/dL | 2.51 mg/L | NSI |
| Bilirubin<br>(unconjugated) | 60 mg/dL | 0.78 mg/L | NSI |
| | 60 mg/dL | 2.74 mg/L | NSI |
| Lipemia<br>(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.