The ADVIA Chemistry® Creatine Kinase (CK_L) assay is for in vitro diagnostic use in the quantitative determination of creatine kinase activity in human plasma (lithium heparin) or serum on ADVIA Chemistry systems. The assay can be used to aid in the diagnosis and treatment of myocardial infarction and muscle diseases, such as Duchenne progressive muscular dystrophy.

ADVIA Chemistry® Enzyme 3 Calibrator:

ADVIA Chemistry® Enzyme 3 Calibrator is intended for in vitro diagnostic use in the calibration of the ADVIA Chemistry Creatine Kinase (CK L) assay on the ADVIA Chemistry systems.

Device Description

ADVIA Chemistry Creatine Kinase (CK L) assay is a ready-to-use liquid reagent packaged for use on the automated ADVIA Chemistry systems. Creatine Kinase reacts with creatine phosphate and ADP to form adenosine triphosphate (ATP), which is coupled to the hexokinase-G6PD reaction, generating NADPH. The concentration of NADPH is measured by the increase in absorbance at 340/596 nm.

ADVIA Chemistry ENZ 3 CAL:

ENZ 3 CAL is a liquid frozen human serum albumin based product containing creatine kinase MM from human heart. Enzyme 3 Calibrator kit consists of six vials of the same calibrator which is ready for use (no preparation is required).

AI/ML Overview

The provided document is a 510(k) Premarket Notification for an in vitro diagnostic device, the ADVIA Chemistry® Creatine Kinase (CK L) Assay and ADVIA Chemistry® Enzyme 3 Calibrator. It describes the device's technical specifications, intended use, and performance characteristics to demonstrate substantial equivalence to a legally marketed predicate device.

However, the request asks for information relevant to the development and validation of an AI/ML-driven medical device, which typically involves acceptance criteria for model performance (e.g., accuracy, sensitivity, specificity), study design for clinical validation (e.g., test set sample size, ground truth establishment by experts, MRMC studies), and training set details.

The provided document describes the analytical validation of a chemical assay, which measures the concentration of a substance (Creatine Kinase) in human samples. Its performance is evaluated through parameters like method comparison, precision, linearity, detection capability, and interference testing. These are fundamentally different from the performance metrics and study designs used for AI/ML devices, which often involve image analysis, pattern recognition, and diagnostic classification.

Therefore, the provided text does not contain the information requested regarding acceptance criteria related to AI/ML device performance, expert adjudication, MRMC studies, or training set details typical of AI/ML model development.

I cannot create the table or answer the specific questions about an AI/ML device's acceptance criteria and study data based on the provided document. The document describes a traditional in-vitro diagnostic assay rather than an AI/ML-driven device.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

SIEMENS HEALTHCARE DIAGNOSTICS, INC. KATHLEEN DRAY-LYONS REGULATORY AND CLINICAL AFFAIRS SPECIALIST 500 GBC DRIVE NEWARK DE 19714

September 7, 2016

Re: K160724

Trade/Device Name: ADVIA Chemistry® Creatine Kinase (CK L) Assay. ADVIA Chemistry® Enzyme 3 Calibrator Regulation Number: 21 CFR 862.1215 Regulation Name: Creatine phosphokinase/creatine kinase or isoenzymes test system Regulatory Class: II Product Code: CGS, JIT Dated: August 2, 2016 Received: August 3, 2016

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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Katherine Serrano -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) K160724

Device Name ADVIA Chemistry® Creatine Kinase (CK L) Assay ADVIA Chemistry® Enzyme 3 Calibrator

Indications for Use (Describe)

ADVIA Chemistry® Creatine Kinase (CK L) Assay:

ADVIA Chemistry® Enzyme 3 Calibrator:

ADVIA Chemistry® Enzyme 3 Calibrator is intended for in vitro diagnostic use in the calibration of the ADVIA Chemistry Creatine Kinase (CK L) assay on the ADVIA Chemistry systems.

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

The assigned 510(k) number is: K160724

1. Manufacturer's Name, Address, Telephone, and Contact Person, Date of Preparation

Applicant:
------------	--

Contact Information:

Siemens Healthcare Diagnostics Inc. 500 GBC Drive Newark, DE 19714

Siemens Healthcare Diagnostics Inc. P.O. Box 6101 Newark, DE 19714 Attn: Kathleen Dray-Lyons Tel: 781-826-4551 Email: kathleen.a.dray-lyons@siemens.com

Date of Preparation:

September 6, 2016

2. Device Names:

ADVIA Chemistry® Creatine Kinase (CK_L) Assay
ADVIA Chemistry® Enzyme 3 Calibrator

Classification:

21 CFR §862.1215; Creatine phosphokinase/creatine kinase or O isoenzymes test system, Class II
21 CFR §862.1150; Calibrator Secondary, Class II O

Product Code:

o CGS
o JIT

Panel:

o Clinical Chemistry
Clinical Chemistry o

3. Identification of the Predicate Devices:

ADVIA Chemistry Creatine Kinase (CKNAC) Assay - K991576 Dimension Vista ENZ 6 CAL - K083579

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4. Device Description:

ADVIA Chemistry Creatine Kinase Assay:

ADVIA Chemistry ENZ 3 CAL:

5. Device Intended Use:

ADVIA Chemistry Creatine® Kinase (CK_L) Assay:

The ADVIA Chemistry® Creatine Kinase (CK L) assay is for in vitro diagnostic use in the quantitative determination of creatine kinase activity in human plasma (lithium heparin) or serum on ADVIA Chemistry systems. The assay can be used to aid in the diagnosis and treatment of myocardial infarction and muscle diseases, such as Duchenne progressive muscular dystrophy.

ADVIA Chemistry ENZ 3 CAL:

ADVIA Chemistry® Enzyme 3 Calibrator is intended for in vitro diagnostic use in the calibration of the ADVIA Chemistry Creatine Kinase (CK L) assay on the ADVIA Chemistry systems.

6. Medical device to which equivalence is claimed:

ADVIA Chemistry Creatine® Kinase (CK L) Assay:

The modified ADVIA Chemistry CK L assay is substantially equivalent in intended use and technology to the predicate ADVIA Chemistry Creatine Kinase (CKNAC) assay cleared under K991576. Both assays utilize creatine kinase, which reacts with creatine phosphate and ADP to form ATP that is coupled to the hexokinase-G6PD reaction, generating NADPH. The concentration of NADPH is measured by the increase in absorbance. A comparison of the similarities and differences between the currently marketed ADVIA Chemistry CKNAC (predicate) versus the proposed modified ADVIA Chemistry CK L assay is provided in the table below.

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Similarities and Differences ADVIA Chemistry CK Assay (K991576) versus Modified ADVIA Chemistry CK_L Assay

Feature	PredicateADVIA Chemistry CKNACK991576	ProposedADVIA Chemistry CK_LModified Device
Intended UseStatement	For in vitro diagnostic use in thequantitative determination ofcreatine kinase activity in humanserum and plasma on the ADVIAChemistry systems. Suchmeasurements are used mainlyin the diagnosis and treatment ofmyocardial infarction and musclediseases such as Duchenneprogressive muscular dystrophy.	The ADVIA Chemistry® CreatineKinase (CK_L) assay is for invitro diagnostic use in thequantitative determination ofcreatine kinase activity in humanplasma (lithium heparin) orserum on ADVIA Chemistrysystems. The assay can beused to aid in the diagnosis andtreatment of myocardialinfarction and muscle diseases,such as Duchenne progressivemuscular dystrophy.
Principle	Creatine Kinase reacts withcreatine phosphate and ADP toform ATP which is coupled to thehexokinase-G6PD reaction,generating NADPH. Theconcentration of NADPH ismeasured by the increase inabsorbance at 340/410 nm.	Creatine Kinase reacts withcreatine phosphate and ADP toform ATP which is coupled to thehexokinase-G6PD reaction,generating NADPH. Theconcentration of NADPH ismeasured by the increase inabsorbance at 340/596 nm.
Kit Components	Reagent 1 - lyophilizedReagent 1 mix - lyophilized	Reagent 1 - liquidReagent 2 - liquid
Calibrator	None - fixed calibrator value	ADVIA Enzyme 3 Calibrator
Sample Type	Serum and lithium heparinplasma	Same
Analytical Range	0 to 1300 U/L	15 to 1300 U/L
Extended Range	1300 to 7800 U/L	Same
Analyzers	ADVIA Chemistry 1650, 1200,1800, 2400 and XPT Systems	ADVIA Chemistry 1800 System

ADVIA Chemistry ENZ 3 CAL:

The ENZ 3 CAL is substantially equivalent in intended use to the predicate Dimension Vista ENZ 6 CAL (K083579). A comparison of the similarities and differences between the currently Dimension Vista ENZ 6 CAL versus the proposed ADVIA Chemistry ENZ 3 CAL is provided in the table below.

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Similarities and Differences Dimension Vista ENZ 6 CAL (K083579) versus ADVIA Chemistry ENZ 3 CAL

Feature	PredicateDimension Vista® ENZ 6 CAL	ProposedADVIA Chemistry® ENZ 3 CAL
Intended Use	The ENZ 6 CAL is an in vitrodiagnostic product for the calibrationof Creatine Kinase (CKI) andCreatine Kinase MB (MBI) methodson the Dimension Vista® System	ADVIA Chemistry® Enzyme 3Calibrator is intended for in vitrodiagnostic use in the calibration ofADVIA Chemistry Creatine Kinase(CK_L) assay on the ADVIAChemistry® systems.
Traceable to:	IFCC Reference Method	Same
Composition	ENZ 6 CAL is a liquid frozen humanserum albumin based productcontaining creatinine kinase BB fromporcine brain and creatine kinaseMM from human heart.	ADVIA Chemistry ENZ 3 CAL is aliquid frozen human serum albumin(5%) and preservatives with lot-specific concentrations of creatinekinase MM from human heart.
Packaging Content	3 vials: Calibrator A, 2mL per vial	6 vials of calibrator, 2mL per vial
Storage	-20 °C or below	-25 to -15°C

7. Performance Characteristics

Method Comparison:

A split sample method comparison between the ADVIA Chemistry CK_L assay versus the predicate ADVIA Chemistry CKNAC (K991576) assay was performed with 116 native de-identified human serum samples across the assay range (15 to 1300 U/L) on the ADVIA Chemistry 1800 system. Analysis of the results using Deming (Orthogonal) regression yielded the following:

Method	n	PredicateMethodSampleRangeU/L	ProposedMethodSampleRangeU/L	Slope(95% CI)	InterceptU/L(95% CI)	CorrelationCoefficient(R)
ADVIA CKNACversus ADVIA CK_L	116	23 to 1253	22 to 1280	1.01(1.00 to1.02)	-1.8(-3.3 to -0.3)	1.00

Precision:

Testing was performed over twenty (20) days, two (2) runs per day, a single test from two (2) independent cups were analyzed for each test material using the ADVIA

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Chemistry CK L assay on the ADVIA Chemistry 1800 System. Analysis of variance (ANOVA) was used to evaluate the data consistent with the recommendations of CLSI EP05-A2. Typical precision is summarized below.

		Repeatability		Within-Lab
Product	Mean U/L	SD	%CV	SD	%CV
BIORAD QC 1	75	1.3	1.7	1.9	2.6
BIORAD QC 2	232	1.5	0.6	3.1	1.4
BIORAD QC 3	639	2.6	0.4	8.1	1.3
PLASMA POOL 1	1202	4.7	0.4	6.3	0.5
SERUM POOL 1	85	1.7	2.0	2.9	3.4
SERUM POOL 2	194	3.0	1.5	3.2	1.7
SERUM POOL 3	938	5.2	0.6	5.6	0.6

Repeatability and Within-Lab Results ADVIA CK_L on the ADVIA 1800

Linearity

Linearity across the assay range was confirmed according to CLSI EP06-A, Evaluation of the Linearity of Quantitative Measurement, by testing a sample with a high concentration of creatine kinase on the ADVIA Chemistry CK_L assay and diluting it with low serum sample. Data were analyzed using weighted linear regression analysis [x-axis: theoretical concentration versus y-axis: measured concentration]. A 200 - and 36 -order polynomial regressions of the mean observed analyte values vs. expected concentrations were generated. These data support the measuring range of 15 to 1300 U/L. A summary of the linearity data is presented below.

Range ofSamples		LinearRegressionEquation	RegressionConstant	R	P-Value
Low	High				Quadratic X2	Cubic X2	Cubic X3
1	1372	Y=1.00X+0.5	0.5	1.00	0.2346	0.1962	0.2610

	Expected	Observed Results (U/L)						Linear	% Bias from thePredicted
SampleNumber	Results(U/L)	Result 1	Result 2	Result 3	MeanValues	SD	CV	Predicted(U/L)	% Bias	Bias(U/L)
1	1	0	1	1	1	0.6	86.6	1	N/A	0
2	172	177	175	180	177	2.5	1.4	172	3	6
3	344	346	347	343	345	2.1	0.6	343	1	2
4	516	513	516	518	516	2.5	0.5	514	0	1
5	687	686	689	682	686	3.5	0.5	685	0	1
6	859	861	865	867	864	3.1	0.4	856	1	8
7	1031	1025	1023	1014	1021	5.9	0.6	1027	-1	-6

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SampleNumber	ExpectedResults(U/L)	Observed Results (U/L)			MeanValues	SD	CV	LinearPredicted(U/L)	% Bias from thePredicted
		Result 1	Result 2	Result 3					% Bias	Bias(U/L)
8	1202	1195	1196	1197	1196	1.0	0.1	1197	0	-1
9	1374	1371	1370	1375	1372	2.6	0.2	1369	0	3

Detection Capability

The LoB and LoD values are determined with proportions of false positives (α) less than 5% and false negatives (β) less than 5%, based on 450 determinations with 225 blank and 225 low-level sample replicates.

The LoB is the highest measurement result that is likely to be observed on a blank sample. The LoB for the ADVIA Chemistry CK_L assay is 3 U/L.

The LoD is the smallest amount that this assay can reliably detect to determine presence or absence of an analyte. The LoD for the ADVIA Chemistry CK L assay is 6 U/L.

The LoQ is the lowest amount of creatine kinase that can be determined quantitatively within a defined total error. The LoQ for the ADVIA Chemistry CK_L assay is 15 U/L.

Interference Testing

Interference testing was performed according to CLSI/NCCLS EP07-A2: Approved Guideline Interference Testing in Clinical Chemistry to determine the effect of various endogenous and exogenous substances on the ADVIA Chemistry CK_L assay. For all interferents, the percent bias 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 creatine kinase, 95 ± 14 U/L and 265 ± 40 U/L. For each spiked sample, the % recovery was determined. A summary of the non-interfering substance data is presented below.

Interferent	Interferent TestConcentration	CK Test Level(U/L)	% Difference
Hemolysate	125 (mg/dL)	100	7%
	125 (mg/dL)	284	1%
BilirubinConjugated	60 (mg/dL)	93	1%
	60 (mg/dL)	256	2%
BilirubinUnconjugated	60 (mg/dL)	94	2%
	60 (mg/dL)	264	2%
Lipemia(Intralipid)	1000 (mg/dL)	94	5%
	1000 (mg/dL)	276	0%
Ascorbid Acid	6 (mg/dL)	91	4%

Interference Testing CK L on the ADVIA 1800

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Interferent	Interferent TestConcentration	CK Test Level(U/L)	% Difference
	6 (mg/dL)	271	1%
Sulfasalazine	300 (mg/L)	94	0%
	300 (mg/L)	264	2%
Sulfapyridine	300 (mg/L)	93	1%
	300 (mg/L)	263	2%

Method Comparison versus IFCC Reference Method

A split sample method comparison between the ADVIA Chemistry CK_L assay on the ADVIA Chemistry 1800 system versus the IFCC certified reference method on the Konelab 30i analyzer (Thermo Fisher Scientific) was performed with 100 native de-identified human serum samples across the assay range (15 to 1300 U/L). Analysis of the results yielded the following:

Method	n	PredicateMethodSampleRangeU/L	ProposedMethodSampleRangeU/L	Slope(95% CI)	InterceptU/L(95% CI)	CorrelationCoefficient(R)
ADVIA CK_L versusIFCC Reference Method	100	21 to 1178	16 to 1245	1.05(1.03 to1.07)	-6.9(-8.8 to -4.9)	1.00

Matrix Comparison

To confirm the equivalency of sample types, the performance of the ADVIA Chemistry CK L assay was compared for serum and lithium heparin plasma samples. Testing was performed using one lot of reagents and a single replicate from a matched set of serum and plasma samples in accordance with CLSI EP09-A3.

SpecimenType	n	SerumSampleRangeU/L	Plasma(Lithiumheparin)SampleRangeU/L	Slope	InterceptU/L	CorrelationCoefficient(R)
Serum versusPlasma	55	37–1282	39 to 1284	1.01	-0.6	1.00

8. Conclusion:

The proposed modified ADVIA Chemistry CK_L assay is substantially equivalent to the current legally marketed device based on intended use, principle and the performance characteristics above.

Regulation Number and Section

§ 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system.

(a)
Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.(b)
Classification. Class II.