K Number
K070727
Date Cleared
2007-08-03

(141 days)

Product Code
Regulation Number
862.1225
Reference & Predicate Devices
Predicate For
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

For in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma, and urine on the ADVIA Chemistry Systems. Such measurements are used in the diagnosis and treatment of renal diseases, and in monitoring renal dialysis.

Device Description

The ADVIA Chemistry Enzymatic Creatinine_2 is used for the in vitro quantitative determination of creatinine in human serum, plasma and urine on the ADVIA® Chemistry Systems. The proposed labeling indicates the ADVIA Chemistry Enzymatic Creatinine 2 reagents can be used on the ADVIA Chemistry 1200 / 1650 / 1800 / 2400 Systems.

The principle of the method is based on the enzymatic method employing creatininase, creatinase, sarcosine oxidase, horseradish peroxidase and N-(3-sulfopropy))-3methoxy-5-methylaniline (HMMPS) as the color agent. When a sample is mixed with Reagent 1 and Reagent 2, creatinine in the sample is converted to creatine by the action of creatininase. The creatine formed is hydrolyzed by creatinase to produce sarcosine and urea. The sarcosine is then decomposed by sarcosine oxidase to form glycine, formaldehyde and hydrogen peroxide. In the presence of peroxidase (POD), the hydrogen peroxide formed yields a blue pigment by quantitative oxidative condensation with N-(3-sulfopropy)-3-methoxy-5-methylaniline (HMMPS) and 4aminoantipyrine. The creatinine concentration is obtained by measuring the absorbance of blue color. The increase in optical absorbance is determined as an endpoint assay, which is proportional to the concentration of creatinine in the sample.

AI/ML Overview

Here's a summary of the acceptance criteria and study findings for the ADVIA® Chemistry Enzymatic Creatinine_2 (ECRE_2) device, based on the provided 510(k) submission:

1. Table of Acceptance Criteria and Reported Device Performance

The submission demonstrates substantial equivalence by testing various performance characteristics and comparing them to predicate devices. The "acceptance criteria" are implied by showing the new device's performance to be comparable to, and within an acceptable range of, the predicate devices.

Performance CharacteristicAcceptance Criteria (Implied by Predicate Device Performance and Comparability)Reported Device Performance (ADVIA Chemistry Enzymatic Creatinine_2)
Imprecision (Serum)Comparable total CV (%) to predicate devices (ADVIA Chemistry Creatinine_2 and Enzymatic Creatinine)ADVIA 1650: 0.6% - 1.1% (across creatinine levels 1.29-8.80 mg/dL)ADVIA 2400: 0.8% - 1.4% (across creatinine levels 1.28-8.81 mg/dL)ADVIA 1200: 0.9% - 1.1% (across creatinine levels 1.29-8.79 mg/dL)
Imprecision (Urine)Comparable total CV (%) to predicate devices (ADVIA Chemistry Creatinine_2)ADVIA 1650: 0.9% - 1.3% (across creatinine levels 41.56-130.59 mg/dL)ADVIA 2400: 0.9% - 1.0% (across creatinine levels 41.13-131.33 mg/dL)ADVIA 1200: 1.0% - 1.1% (across creatinine levels 42.34-133.09 mg/dL)
Method Comparison (Correlation)Linear regression results (slope, intercept, correlation coefficient 'r') and Sy.x values demonstrating strong correlation and similar performance to predicate devices.Serum (vs. predicate Creatinine_2): Slopes 1.017-1.026; Intercepts -0.04 to 0.03; Sy.x 0.07-0.13; r 1.000Serum (vs. predicate Enzymatic Creatinine): Slopes 0.933-0.957; Intercepts 0.01 to 0.11; Sy.x 0.07-0.14; r 1.000Urine (vs. predicate Creatinine_2): Slopes 1.019-1.042; Intercepts -0.99 to 2.47; Sy.x 1.80-2.99; r 0.999-1.000
Interfering Substances (Hemoglobin, Lipids, Bilirubin)Minimal percentage change in creatinine concentration due to interferent, comparable to acceptable clinical limits.Hemoglobin (500-1000 mg/dL): -3.8% to 7.5% changeLipids (Intralipid, 1000 mg/dL): -5.7% to 6.6% changeBilirubin, free (22.5-30.0 mg/dL): -6.6% to -9.8% changeBilirubin, conjugated (30.0 mg/dL): -2.7% to -6.0% change
Analytical Range (Serum/Plasma)Defined operational range covering clinically relevant concentrations.0.1 - 30.0 mg/dL
Analytical Range (Urine)Defined operational range covering clinically relevant concentrations.1.0 - 245 mg/dL

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

  • Imprecision Study (Serum): Levels tested were 1.29 mg/dL through 8.80 mg/dL. The number of samples for each level or total sample size is not explicitly stated but implied to be sufficient for precision calculations (CV%).
  • Imprecision Study (Urine): Levels tested were 41.56 mg/dL through 130.59 mg/dL. The number of samples for each level or total sample size is not explicitly stated.
  • Method Comparison (Correlation):
    • Serum: 60 samples (for comparison against Creatinine_2 predicate), 28 or 42 samples (for comparison against Enzymatic Creatinine predicate), depending on the system (ADVIA 1200, 1650, 2400).
    • Urine: 44 to 49 samples (for comparison against Creatinine_2 predicate), depending on the system.
  • Interfering Substances: Specific sample sizes are not explicitly stated for each interferent test but are implied to be sufficient to determine the effect at specific analyte and interferent concentrations.
  • Data Provenance: The document does not specify the country of origin of the data or explicitly state whether the studies were retrospective or prospective. Given the nature of an in vitro diagnostic device validation, these are typically prospective studies using well-characterized samples or spiked samples.

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

This type of information (number and qualifications of experts) is generally not applicable or provided for in vitro diagnostic (IVD) device submissions like this one, especially for quantitative assays. The "ground truth" for creatinine measurements in this context is established by the direct measurement by the predicate devices or by well-established reference methods (e.g., ID-MS, HPLC candidate reference method as mentioned for standardization), not by human expert consensus or clinical interpretation of images.

4. Adjudication Method for the Test Set

Not applicable. As noted above, the "ground truth" for an IVD quantitative assay like creatinine is based on instrument measurements and reference methods, not subjective human assessment requiring adjudication.

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. This device is an in vitro diagnostic assay (a laboratory test) that directly measures creatinine levels, not an imaging device or an AI-assisted diagnostic tool that would involve human "readers" or clinical interpretations.

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

Yes, this entire submission represents the "standalone" performance of the assay itself. The ADVIA Chemistry Enzymatic Creatinine_2 assay is an automated in vitro diagnostic test system. All the performance data (imprecision, method comparison, interference, analytical range) reflect the performance of the algorithm/reagent system as a standalone measurement tool. There is no human interpretation or "in-the-loop" component in the direct measurement of creatinine by the device itself.

7. The Type of Ground Truth Used

The ground truth for the comparison studies was established by:

  • Predicate Devices: The measurements obtained from the legally marketed predicate devices: ADVIA Chemistry Creatinine_2 (Jaffe method) and ADVIA Chemistry Enzymatic Creatinine (Enzymatic Deiminase/GLDH method). The new device's performance was evaluated against these established methods.
  • Standardization: The new device (ECRE_2) uses ID-MS (SRM 967) for standardization. The predicate devices used an HPLC candidate reference method. These reference methods serve as the ultimate "ground truth" for standardization and traceability of the creatinine measurements.

8. The Sample Size for the Training Set

The document does not explicitly delineate a "training set" in the context of deep learning or AI model development, as this is a chemical assay, not an AI algorithm in that sense. The "training" in this context would refer to the optimization and verification during the assay's development. The data presented here are validation data for the established final product.

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

As explained above, there isn't a traditional "training set" in the AI sense for this chemical assay. The development of the assay (analogous to "training") would involve establishing the chemical reactions, optimizing reagent concentrations, and calibrating the system. The "ground truth" for this development/optimization would be based on:

  • Known concentrations of creatinine standards.
  • Traceability to recognized reference methods (like ID-MS and HPLC).
  • Performance established by predicate devices.

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K070727

510(k) Summary

AUG - 3 2007

Submitter information
Contact person:Philip Liu
Manager, Regulatory Affairs & Compliance
Address:Siemens Medical Solutions Diagnostics
511 Benedict Avenue
Tarrytown, NY 10591
Phone:914-524-2443
914-524-2500 (fax)
Date summary prepared:July 27, 2007
Device Trade or Proprietary Name:ADVIA® Chemistry Enzymatic Creatinine_2 (ECRE_2)
Device Common/Usual Name or Classification Name:Enzymatic Method, Creatinine Test System
Classification Number/Class:JFY / 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:

Predicate Devices:

Predicate Device #1Predicate Device #2
Device NameADVIA® Chemistry SystemsCreatinine_2ADVIA® Chemistry SystemsEnzymatic Creatinine
Common nameCreatinine Test SystemCreatinine Test System
510(k) NumberK973993K991576
ManufacturerSiemens Medical SolutionsDiagnostics (formerly BayerHealthCare LLC)Siemens Medical SolutionsDiagnostics (formerly BayerHealthCare LLC)

Device Description:

The ADVIA Chemistry Enzymatic Creatinine_2 is used for the in vitro quantitative determination of creatinine in human serum, plasma and urine on the ADVIA®

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Chemistry Systems. The proposed labeling indicates the ADVIA Chemistry Enzymatic Creatinine 2 reagents can be used on the ADVIA Chemistry 1200 / 1650 / 1800 / 2400 Systems.

The principle of the method is based on the enzymatic method employing creatininase, creatinase, sarcosine oxidase, horseradish peroxidase and N-(3-sulfopropy))-3methoxy-5-methylaniline (HMMPS) as the color agent. When a sample is mixed with Reagent 1 and Reagent 2, creatinine in the sample is converted to creatine by the action of creatininase. The creatine formed is hydrolyzed by creatinase to produce sarcosine and urea. The sarcosine is then decomposed by sarcosine oxidase to form glycine, formaldehyde and hydrogen peroxide. In the presence of peroxidase (POD), the hydrogen peroxide formed yields a blue pigment by quantitative oxidative condensation with N-(3-sulfopropy)-3-methoxy-5-methylaniline (HMMPS) and 4aminoantipyrine. The creatinine concentration is obtained by measuring the absorbance of blue color. The increase in optical absorbance is determined as an endpoint assay, which is proportional to the concentration of creatinine in the sample.

Statement of Intended Use:

The ADVIA Chemistry Enzymatic Creatinine 2 assay is for in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma or urine on the ADVIA® Chemistry Systems. Such measurements are used in the diagnosis and treatment of renal disease, and in monitoring renal dialysis.

Comparison to the Predicate Device:

Similarities

ADVIA ChemistryEnzymatic Creatinine_2(ECRE_2)( new device )ADVIA Chemistry Creatinine_2(CREA_2)( predicate device )ADVIA Chemistry EnzymaticCreatinine(CREA_E)( predicate device )
Intended UseQuantitative determination ofcreatinineQuantitative determination ofcreatinineQuantitative determination ofcreatinine
Specimen TypeHuman serum or plasma(lithium heparin / K₂EDTA) orurineHuman serum or plasma(lithium heparin) or urineHuman serum or plasma(lithium heparin)
CalibrationSingle pointSingle pointSingle point
Expected ValuesSerum/plasma*Males: 0.6 - 1.1 mg/dL*Females: 0.5 - 0.8 mg/dLMales: 0.7 - 1.3 mg/dLFemales: 0.5 - 1.1 mg/dL**Males: 0.9 - 1.3 mg/dL**Females: 0.6 - 1.1 mg/dL
Expected ValuesUrine*Males: 800 - 2000 mg/day*Females: 600 - 1800 mg/day*Males: 800 – 2000 mg/day*Females: 600 - 1800 mg/dayNot Applicable

*Tietz NW. Clinical Guide to Laboratory Tests, 400 Edition

** Tietz NW. Clinical Guide to Laboratory Tests, 3d Edition

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Differences

ADVIA Chemistry EnzymaticCreatinine_2 (ECRE_2)( new device )ADVIA ChemistryCreatinine_2(CREA_2)( predicate device )ADVIA Chemistry EnzymaticCreatinine(CREA_E)( predicate device )
PrincipleEnzymatic (Creatininase)Jaffe, alkaline picrate, kineticwith blank rate correctionEnzymatic (CreatinineDeiminase / GLDH)
Reaction TypeColorimetric EndpointColorimetric RateColorimetric Rate
ReagentsTwo liquid reagents, ready touseTwo liquid reagents, ready touseTwo lyophilized reagents,requiring reconstitution
StandardizationID-MS (SRM 967)HPLC candidate referencemethodHPLC candidate referencemethod

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 Enzymatic Creatinine_2 assay is substantially equivalent to the ADVIA Chemistry Creatinine_2 assay and the ADVIA Chemistry Enzymatic Creatinine assay that are currently marketed.

Imprecision (Serum)

ADVIA Chemistry Enzymatic Creatinine_2ADVIA Chemistry Creatinine_2ADVIA Chemistry Enzymatic Creatinine
ADVIA 1650ADVIA 2400ADVIA 1200ADVIA 1650ADVIA 1650
Level (mg/dL)Total CV (%)Level (mg/dL)Total CV (%)Level (mg/dL)Total CV (%)Level (mg/dL)Total CV (%)Level (mg/dL)Total CV (%)
1.291.11.281.291.1--------
1.760.91.750.81.731.11.55.70.96.4
3.071.13.060.93.040.9----6.12.3
8.800.68.811.48.790.98.43.49.52.0

Imprecision (Urine)

ADVIA Chemistry Enzymatic Creatinine_2ADVIA Chemistry Creatinine_2
ADVIA 1650ADVIA 2400ADVIA 1200ADVIA 1650ADVIA 1200ADVIA 2400
Level(mg/dL)Total CV(%)Level(mg/dL)Total CV(%)Level(mg/dL)Total CV(%)Level(mg/dL)Total CV(%)Level(mg/dL)Total CV(%)Level(mg/dL)Total CV(%)
41.561.341.131.042.341.0------------
77.271.077.540.979.781.181.54.379.72.180.72.1
130.590.9131.330.9133.091.0202.71.8182.51.9199.71.4

Siemens Medical Solutions Diagnostics ADVIA Chemistry Enzymatic Creatinine 2 Premarket Notification 510(k) Section 5 - 510(k) Summary

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Specimen type,System (y)Comparison System (x)NRegressionEquationSy.x(mg/dL)rSampleRange(mg/dL)
Serum, ADVIA1200ADVIA 1200Creatinine 260$Y = 1.017x + 0.03$0.071.0000.3 – 12.3
Serum, ADVIA1200ADVIA 1200Enzymatic Creatinine28$Y = 0.933x + 0.11$0.141.0000.5 - 25.6
Serum, ADVIA1650ADVIA 1650Creatinine 260$Y = 1.018x - 0.04$0.131.0000.3 - 11.9
Serum, ADVIA1650ADVIA 1650Enzymatic Creatinine42$Y = 0.957x + 0.04$0.121.0000.6 - 25.7
Serum, ADVIA2400ADVIA 2400Creatinine 260$Y = 1.026x - 0.03$0.131.0000.3 - 12.1
Serum, ADVIA2400ADVIA 2400Enzymatic Creatinine42$Y = 0.954x + 0.01$0.071.0000.6 - 25.4
Urine, ADVIA1200ADVIA 1200Creatinine 246$Y = 1.042x + 0.41$1.801.00020.0 - 238.1
Urine, ADVIA1650ADVIA 1650Creatinine 249$Y = 1.019x - 0.99$1.881.00017.8 - 239.4
Urine, ADVIA2400ADVIA 2400Creatinine 244$Y = 1.025x + 2.47$2.990.99918.9 - 218.1

Correlation (y = ADVIA Chemistry Enzymatic Creatinine_2, x = comparison system)

Interfering Substances (Enzymatic Creatinine 2)

InterferingSubstanceConc.(mg/dL)Creatinine conc. (mg/dL)Effect(% change)
(mg/dL)ADVIA1200ADVIA1650ADVIA2400ADVIA1200ADVIA1650ADVIA2400
Hemoglobin5000.940.920.917.56.66.6
10003.083.063.00-2.8-3.8-2.2
Lipids (Intralipid)10000.910.880.876.6-5.7-1.2
10003.093.032.97-2.4-5.3-4.2
Bilirubin, free30.00.961.010.94-8.9-7.4-9.6
22.53.053.053.22-6.6-6.1-9.8
Bilirubin, conjugated30.00.920.900.91-2.7-5.6-5.5
30.02.962.972.94-4.6-5.4-6.0

Analytical Range – Serum/Plasma

PlatformADVIA Chemistry EnzymaticCreatinine 2
ADVIA 16500.1 - 30.0 mg/dL
ADVIA 24000.1 - 30.0 mg/dL
ADVIA 12000.1 - 30.0 mg/dL

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Analytical Range - Urine

PlatformADVIA Chemistry EnzymaticCreatinine 2
ADVIA 16501.0 - 245 mg/dL
ADVIA 24001.0 - 245 mg/dL
ADVIA 12001.0 - 245 mg/dL

Conclusions:

The ADVIA Chemistry Enzymatic Creatinine 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 Diagnostics (formerly Bayer HealthCare LLC) ADVIA Chemistry Creatinine_2 (K973993) and Enzymatic Creatinine methods (K991576).

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Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a stylized caduceus symbol, which features three figures in profile facing to the right. The figures are arranged in a way that they appear to be interconnected. Encircling the caduceus is the text "DEPARTMENT OF HUMAN SERVICES - USA" in a circular arrangement.

Public Health Service

Food and Druq Administration 2098 Gaither Road Rockville MD 20850

AUG - 3 2007

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

Re: K070727 Trade Name: Advia Chemistry Enzymatic Creatinine-2 Regulation Number: 21 CFR 862.1225 Regulation Name: Creatinine test system Regulatory Class: Class II Product Code: JFY Dated: July 20, 2007 Received: July 23, 2007

Dear Mr. 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 requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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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 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) 276-0490. Also, please note 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-free number (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): KD10727

Device Name: ADVIA CHEMISTRY ENZYMATIC CREATININE_2

Indications For Use:

For in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma, and urine on the ADVIA Chemistry Systems. Such measurements are used in the diagnosis and treatment of renal diseases, and in monitoring renal dialysis.

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)

Carol C. Benson

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

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070727

§ 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.