(157 days)
The CRE2 method is an in vitro diagnostic test for the quantitative measurement of creatinine in human serum, plasma, and urine on the Dimension® clinical chemistry system. Creatinine measurements are used in the diagnosis and treatment of certain renal disease, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.
The CRE2 method uses a modified kinetic Jaffe technique. In the presence of a strong base such as sodium hydroxide, picrate reacts with creatinine to form a red chromophore. The rate of increasing absorbance at 510 nm due to the formation of this chromophore is directly proportional to the creatinine concentration in the sample and is measured using a bichromatic (510, 600nm) rate technique. Bilirubin is oxidized by potassium ferricyanide to prevent interference.
The provided text describes a 510(k) premarket notification for a new in vitro diagnostic device, the Dimension® Creatinine (CRE2) Flex® reagent cartridge. This document is a summary of the safety and effectiveness information, comparing the new device to a predicate device already on the market.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. A table of acceptance criteria and the reported device performance
The document does not explicitly present a table of acceptance criteria for performance parameters in a pass/fail format. Instead, it provides the results of various performance studies and implies that these results demonstrate substantial equivalence to the predicate device and/or meet established industry guidelines (CLSI). The acceptance criteria are implicitly defined by what is considered "substantially equivalent" or within acceptable limits as per CLSI guidelines.
Below is a table summarizing the reported device performance, categorized by the studies conducted. It's important to note that specific numerical acceptance criteria (e.g., "slope must be between 0.98 and 1.02") are not explicitly stated, but the reported values passed the FDA's substantial equivalence review.
| Performance Characteristic | Reported Device Performance (CRE2 Flex®) | Implied Acceptance Criteria / Context |
|---|---|---|
| Method Comparison (vs. Predicate CREA Assay) | Agreement with predicate device (CREA). | |
| Serum Sample (n=191) | Range: 0.4 - 19.8 mg/dL | Good agreement. |
| Slope: 1.00 | Ideal slope is 1.0. | |
| Intercept: -0.08 mg/dL | Ideal intercept is 0. | |
| Correlation Coefficient (r): 0.999 | Close to 1.0 indicates strong correlation. | |
| Urine Sample (n=113) | Range: 13.5 - 372.7 mg/dL | Good agreement. |
| Slope: 1.04 | Close to 1.0. | |
| Intercept: -3.58 mg/dL | Close to 0. | |
| Correlation Coefficient (r): 0.996 | Close to 1.0 indicates strong correlation. | |
| Method Comparison (vs. IDMS Reference Method) | Agreement with a recognized gold standard. | |
| Serum Sample (n=48) | Range: 0.18 - 6.32 mg/dL | Good agreement. |
| Slope: 1.04 | Close to 1.0. | |
| Intercept: 0.02 mg/dL | Close to 0. | |
| Correlation Coefficient (r): 0.997 | Close to 1.0 indicates strong correlation. | |
| Serum Plasma Equivalency | Agreement between serum and plasma samples. | |
| Lithium Heparin Plasma (n=56) | Range: 0.50 - 17.35 | - |
| Slope: 1.05 | Close to 1.0. | |
| Intercept: -0.02 | Close to 0. | |
| Correlation Coefficient (r): 0.998 | Close to 1.0 indicates strong correlation. | |
| Precision (Repeatability & Within-Lab CV) | Within acceptable limits for clinical chemistry assays. | |
| Serum Pool 1 (Mean 1.32 mg/dL) | Repeatability SD: 0.04, %CV: 3.0 | Low %CV indicates high precision. |
| Within-Lab SD: 0.04, %CV: 3.2 | Low %CV indicates high precision. | |
| Serum Pool 2 (Mean 15.79 mg/dL) | Repeatability SD: 0.19, %CV: 1.2 | Low %CV. |
| Within-Lab SD: 0.19, %CV: 1.2 | Low %CV. | |
| BioRad Multiqual Level 1 (Mean 0.71 mg/dL) | Repeatability SD: 0.03, %CV: 4.7 | Low %CV. |
| Within-Lab SD: 0.04, %CV: 5.1 | Low %CV. | |
| ... (other samples shown in table, similar low CVs) | ||
| Limit of Blank (LoB) | Meet or exceed claimed LoB. | |
| Serum LoB | 0.05 mg/dL (consistent with claim) | Claimed LoB: 0.05 mg/dL |
| Urine LoB | 0.87 mg/dL (consistent with claim) | Claimed LoB: 1.0 mg/dL |
| Limit of Detection (LoD) | Meet or exceed claimed LoD. | |
| Serum LoD | 0.08 mg/dL (consistent with claim) | Claimed LoD: 0.1 mg/dL |
| Urine LoD | 1.51 mg/dL (consistent with claim) | Claimed LoD: 2.0 mg/dL |
| Limit of Quantitation (LoQ) | Defined by allowable total error. | |
| Serum LoQ | 0.15 mg/dL (based on 0.15 mg/dL allowable total error) | - |
| Urine LoQ | 5.00 mg/dL (based on 3.00 mg/dL allowable total error) | - |
| Linearity (Measurement Range) | Demonstrate linearity across the claimed measuring range. | |
| Serum (0.15* - 22.00 mg/dL) | Slope: 1.01 | Close to 1.0. |
| Intercept: -0.01 | Close to 0. | |
| Correlation Coefficient (r): 1.0 | Indicates perfect linearity. | |
| Urine (3.00* - 425.34 mg/dL) | Slope: 0.998 | Close to 1.0. |
| Intercept: -0.41 | Close to 0. | |
| Correlation Coefficient (r): 1.0 | Indicates perfect linearity. | |
| Analytical Specificity (Interference) | Interference less than 10% bias, or disclosed. | |
| Non-interfering Substances (e.g., Acetaminophen, Caffeine, Glucose, etc.) | % Diff typically between -2% to 6% | Bias < 10% (threshold for non-interference). Some exceptions like Total Protein (6% at low pool, -1% at high pool) are also acceptable. |
| Interfering Substances (e.g., Acetone, Bilirubin (unconjugated), Cefoxitin, Glucose, Intralipid 20%, Pyruvate, Triglycerides, Ascorbic Acid) | % Diff > 10% (e.g., Acetone up to 11% bias) | Identified as interfering; implications for use would be in labeling (not detailed in this section for the new device, but assumed to be consistent with predicate/known interferences). |
| HIL Interference (Hemolysis, Icterus, Lipemia) | Some substances show >10% bias (e.g., Hemoglobin at 1000 mg/dL, Bilirubin (conj) at 40 mg/dL, Bilirubin (unconj) at 20 mg/dL, Intralipid 20% at 1500 mg/dL) | Identified as interfering; implications for use would be in labeling. The predicate's stated interferences (e.g., Hemoglobin at 1000 mg/dL, Bilirubin (unconjugated) at 5 mg/dL, Lipemia (Intralipid) at 200 mg/dL) are less tolerant than the new device in some cases for Bilirubin and Lipemia. |
2. Sample sizes used for the test set and the data provenance
- Method Comparison (vs. Predicate CREA Assay):
- Serum: 191 remnant de-identified patient samples.
- Urine: 113 patient samples.
- Provenance: Remnant de-identified samples. "No patient history information was obtained on these samples." The studies were conducted internally by Siemens Healthcare Diagnostic Inc. R&D organization personnel, implying a US-based setting. The data is retrospective as it used "remnant de-identified serum/urine samples."
- Method Comparison (vs. IDMS Reference Method):
- Serum: 48 remnant de-identified patient samples.
- Provenance: Remnant de-identified samples. "No patient history information was obtained on these samples." Conducted internally by Siemens Healthcare Diagnostic Inc. R&D. Retrospective.
- Serum Plasma Equivalency:
- Samples: 56 matched serum and lithium heparin plasma samples.
- Provenance: "All samples in the study were fresh and never frozen." The eight spiked sample sets were prepared. Conducted internally by Siemens Healthcare Diagnostic Inc. R&D. Retrospective, likely sourced from a local population.
- Precision:
- Samples: Two serum pools, three levels of BioRad Multiqual material, two levels of BioRad Liquicheck material, and two urine pools. Testing involved 20 days with 2 separate runs and 2 test samples for each material. The specific number of individual patient samples is not given, as this study uses control materials and pools.
- Provenance: Not specified, but likely prepared internally or from commercial sources.
- Limit of Blank/Detection (LoB/LoD):
- Samples: 4 samples with no analyte (for LoB), 4 low patient serum/urine samples (for LoD). Each tested for 3 days, one run per day, across 2 reagent lots.
- Provenance: Not specified, but generally prepared internally with blank/low-level samples.
- Linearity (Measurement Range):
- Samples: 12 equally spaced serum samples and 12 urine samples.
- Provenance: Prepared by mixing high and low creatinine concentration samples.
- Analytical Specificity (Interference):
- Samples: Not specified in terms of number of patient samples, but involved "fresh sample pools containing either low or high levels of creatinine analyte in both serum pools and urine pools." These pools were spiked with various interfering substances.
- Provenance: Likely developed from internal pools and commercially available substances.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
This section is not applicable to this type of device (in vitro diagnostic for quantitative measurement of creatinine). The "ground truth" for clinical chemistry assays like creatinine is established by:
- Reference methods (e.g., IDMS, considered the "gold standard" for creatinine measurement in some contexts).
- Predicate devices (already cleared and established to perform reliably).
- Known concentrations in control materials or spiked samples.
There are no human "experts" (like radiologists interpreting images) involved in establishing ground truth for the test set in this context. The "personnel carrying out the study were laboratory technicians with training similar to personnel who would conduct the tests in a hospital laboratory setting."
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
This concept of "adjudication" is typical for studies involving human interpretation (e.g., medical imaging, pathology slides) where there might be disagreement among readers. For an automated in vitro diagnostic device, the measurement is quantitative and typically objective. Therefore, an adjudication method for the test set is not applicable. The "ground truth" is determined by instrumental readings and reference methods.
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
An MRMC study is not applicable here. This device is a fully automated in vitro diagnostic assay, not an AI-assisted diagnostic tool for human readers. Its performance is evaluated against chemical reference methods and a predicate device, not in terms of how it assists human interpretation.
6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done
Yes, this entire submission and its performance data represent a standalone (algorithm only) performance evaluation. The device is an automated clinical chemistry system that measures creatinine levels directly from biological samples (serum, plasma, urine) without human intervention in the interpretation of the core measurement. The reported results (slope, intercept, correlation, precision, LoB/LoD, linearity, interference) directly reflect the device's inherent analytical performance.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth used for evaluating the Dimension® Creatinine (CRE2) Flex® reagent cartridge includes:
- Reference Method: The IDMS (Isotope Dilution Mass Spectrometry) method for creatinine measurement. This is considered a highly accurate and precise reference method.
- Predicate Device: The Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA, K925668). The predicate device's cleared performance serves as a benchmark for demonstrating substantial equivalence.
- Known Concentrations: For studies like precision, LoB/LoD, linearity, and interference, known concentrations of analytes in control materials, spiked samples, or blank samples serve as the ground truth.
8. The sample size for the training set
This document describes a 510(k) submission for an in vitro diagnostic reagent cartridge that uses a modified kinetic Jaffe technique (a traditional chemical assay), not a machine learning or AI-based device. Therefore, the concept of a "training set" for an algorithm is not applicable. The "training" for such a device would refer to its development and optimization based on chemical principles, rather than data-driven machine learning.
9. How the ground truth for the training set was established
As answered in point 8, the device does not employ a training set in the context of an AI/ML algorithm. Its "ground truth" for development and calibration would be rooted in established chemical and analytical principles, reference measurement procedures (like IDMS), and potentially existing characterized samples. The manufacturing process of reagents, calibrators, and the instrument's detection capabilities are based on fundamental scientific understanding rather than a data training process as understood in AI/ML.
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5. 510(k) Summary
5.1 Description
Dimension® Creatinine (CRE2) Flex® reagent cartridge
This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of SMDA 1990 and 21 CFR §807.92.
5.2. Assigned 510(k) number
The assigned 510(k) number is: K132638
5.3 Applicant and Date
Laura J. Duggan Applicant: Siemens Healthcare Diagnostics Inc. P.O. Box 6101 Newark, DE 19714-6101
Auqust 22, 2013 Date:
5.4 Proprietary and Established Names
Dimension® Creatinine (CRE2) Flex® reagent cartridge
Common Name
Creatinine
5.5 Regulatory Information
Dimension® Creatinine (CRE2) Flex® reagent cartridge
The CRE2 method is an in vitro diagnostic test for the quantitative measurement of creatinine in human serum, plasma, and urine on the Dimension® clinical chemistry system. Creatinine measurements are used in the diagnosis and treatment of certain renal disease, in monitoring renal dialysis, and as a calculation basis for measuring other urine analvtes.
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Classification Name: Requlation Section: Classification: Product Code: Panel:
Creatinine test system 21CFR862.1225 - Creatinine test system Class II CGX Clinical Chemistry
5.6 Predicate Device
The predicate device used to demonstrate substantial equivalence to the Dimension® Creatinine (CRE2) Flex® reagent cartridge is the Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA) previously cleared under K925668.
5.7 Device Description / Test Principle
The CRE2 method uses a modified kinetic Jaffe technique. In the presence of a strong base such as sodium hydroxide, picrate reacts with creatinine to form a red chromophore. The rate of increasing absorbance at 510 nm due to the formation of this chromophore is directly proportional to the creatinine concentration in the sample and is measured using a bichromatic (510, 600nm) rate technique. Bilirubin is oxidized by potassium ferricyanide to prevent interference.
5.8 Intended Use
The CRE2 method is an in vitro diagnostic test for the quantitative measurement of creatinine in human serum, plasma, and urine on the Dimension® clinical chemistry system. Creatinine measurements are used in the diagnosis and treatment of certain renal disease. in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.
5.9 Indication(s) for Use
The CRE2 method is an in vitro diaqnostic test for the quantitative measurement of creatinine in human serum, plasma, and urine on the Dimension® clinical chemistry system. Creatinine measurements are used in the diagnosis and treatment of certain renal disease, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.
5.10 Substantial Equivalence Information
Both the Dimension® Creatinine (CRE2) Flex® reagent cartridge and the predicate Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA) employ prepackaged reagents for use on automated clinical chemistry test systems. A comparison of the similarities and differences between the devices is provided in the following tables:
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| New Device | Predicate Device | |||
|---|---|---|---|---|
| Feature | Dimension® Creatinine (CRE2)Flex® reagent cartridge (K132638) | Creatinine Method for Use on theDimension® Clinical ChemistrySystem (CREA) (K925668) | ||
| Intended Use | The CRE2 method is an in vitrodiagnostic test for the quantitativemeasurement of creatinine inhuman serum, plasma, and urineon the Dimension® clinicalchemistry system. Creatininemeasurements are used in thediagnosis and treatment of certainrenal disease, in monitoring renaldialysis, and as a calculation basisfor measuring other urineanalytes. | The CREA method used on theDimension® clinical chemistrysystem is an in vitro diagnostic testintended for the quantitativedetermination of creatinine inhuman serum, plasma and urine. | ||
| DeviceTechnology(detection) | Modified Jaffe Methodology(creatinine alkaline picrate) withphotometric detection | Same | ||
| DetectionConditions | Wavelength = 510 and 600 nmType of Measurement =Bichromatic rate | Same | ||
| Sample Volume | 20 pl | Same | ||
| Reagents | Reagent 1 = Lithium Picrate (125mM)Reagent 2 = Sodium Hydroxide(2000 mM) with potassiumferricyanide (2.7 mM) | Same | ||
| Reagent Volumes | Volume of Reagent 1 used = 74 µLVolume of Reagent 2 used = 18 µLVolume of Diluent used = 258 µL | Same | ||
| CalibrationInterval | 90 days - same reagent lot | Same |
Similarities for the Dimension® Creatinine (CRE2) Flex® reagent cartridge:
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| Limit ofBlank/AnalyticalSensitivity | Limit of Blank: 0.05 mg/dL | Analytical Sensitivity : 0.05 mg/dL |
|---|---|---|
| Calibration | Chem 1 Calibrator (K860021)3 levels (n=3) | Same (K860021) |
Differences for the Dimension® Creatinine CRE2 Flex® reagent cartridge:
| Feature | New DeviceDimension® Creatinine (CRE2)Flex® reagent cartridge (K132638) | Predicate DeviceCreatinine Method for Use on theDimension® Clinical ChemistrySystem (CREA) (K925668) |
|---|---|---|
| Measuring Range(serum) | 0.15 - 20.00 mg/dL | 0 - 20.0 mg/dL |
| Measuring Range(urine) | 5.00 - 400.00 mg/dL | 0 - 200.0 mg/dL |
| Expected Values | Serum and PlasmaMales: 0.70 -- 1.30 mg/dLFemales: 0.55 - 1.02 mg/dLUrineMales: 0.95 - 2.49 g/24 hrFemales: 0.60 - 1.80 g/24 hr | SerumMales: 0.8 – 1.3 mg/dLFemales: 0.6 - 1.0 mg/UrineMales: 0.6 – 2.5 g/24 hrFemales: 0.6 – 1.5 g/24 hr |
| Interferences | No significant interference at aCreatinine concentration of 1.5mg/dL from:Hemoglobin at 500 mg/dLBilirubin (conjugated) at 20 mg/dL,Bilirubin (unconjugated) at 10mg/dLLipemia (Intralipid) at 1000 mg/dL. | No significant interference at aCreatinine concentration of 1.7mg/dL from:Hemoglobin at 1000 mg/dL,Bilirubin (unconjugated) at 5 mg/dLLipemia (Intralipid) at 200 mg/dL |
.
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5.11 Standard/Guidance Document Reference
- Stability Testing of In Vitro Diagnostic Reagents (CEN 13640) .
- CLSI EP07-A2; Interference Testing in Clinical Chemistry; Approved Guideline· .
- CLSI EP09-A2-IR; Method Comparison and Bias Estimation Using Patient Samples; . Approved Guideline
- CLSI EP05-A2; Evaluation of Precision Performance of Quantitative Measurement . Methods: Approved Guideline
- CLSI EP06-A; Evaluation of the Linearity of Quantitative Measurement .
- CLSI EP17-A2: Protocols for Determination of Limits of Detection and Limits of . Quantitation
- CLSI C28-A3c; Defining, Establishing, and Verifying Reference Intervals in the . Clinical Laboratory: Approved Guideline - Third Edition
- In Vitro Diagnostic Creatinine Test System Guidance for Industry July 2, 1998 .
- In Vitro Diagnostic Devices: Guidance for the Preparation of 510(k) Submissions . Jan. 1997
- . Format for Traditional and Abbreviated 510(k)'s - Guidance for Industry and Staff -Nov. 17, 2005
- Guidance for Industry and FDA Staff: Administrative Procedures for CLIA . Categorization - May 7, 2008
- eCopy Program for Medical Device Submissions Guidance for Industry and Food . and Drug Administration Staff - December 31, 2012,
- Refuse to Accept Policy for 510(k)s Guidance for Industry and Food and Drug o Administration Staff - December 31, 2012
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5.12 Performance Characteristics
The following data represent typical method performance. These data were collected on the Dimension EXL 200 integrated chemistry system.
5.12.1 Method Comparison
The predicate device selected for the method comparison was the Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA) cleared under K925668. Remnant de-identified serum samples were tested. No patient history information was obtained on these samples. Inclusion/exclusion data criteria are not applicable. All of the samples were native.
These studies were conducted internally by Siemens Healthcare Diagnostic Inc. R&D orqanization personnel. The personnel conducting the study were laboratory technicians with training similar to personnel who would conduct the tests in a hospital laboratory setting. They were trained on the operation of both the device and the predicate device. A split sample method comparison, following EP09-A2, demonstrated good agreement between the Dimension® Creatinine (CRE2) Flex® reagent cartridge and the predicate Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA) with serum patient samples.
One hundred ninety one serum patient samples across the assay range were tested on the Dimension® Creatinine (CRE2) Flex® reagent cartridge and the Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA). In a second study, 113 urine samples were tested on the Dimension® Creatinine (CRE2) Flex® reagent cartridge and the Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA). The results across the full assay range were analyzed by linear regression. Although the samples were tested in duplicate, only the first result was used for the analvsis.
| ComparativeMethod | Range(mg/dL) | Slope | Intercept(mg/dL) | CorrelationCoefficient | n | Sampletype |
|---|---|---|---|---|---|---|
| DimensionCREA Assay | 0.4 - 19.8 | 1.00 | -0.08 | 0.999 | 191 | serum |
| DimensionCREA Assay | 13.5 - 372.7 | 1.04 | -3.58 | 0.996 | 113 | urine |
The model equation for the regression statistics is: [results for Dimension® CRE2 Flex® reagent cartridge] = slope x [comparative method results] + intercept.
An additional study was completed comparing the Dimension® Creatinine (CRE2) Flex® reagent cartridge for the IDMS reference method. Remnant de-identified serum samples were tested. No patient history information was obtained on these samples. Inclusion/exclusion data criteria are not applicable. All of the samples were native.
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Forty eight patient samples were tested on the Dimension® Creatinine (CRE2) Flex® reagent cartridge and the IDMS reference method. The results were analyzed by linear regression. Although the samples were tested in duplicate, only the first result was used for the analysis.
| ComparativeMethod | Range(mg/dL) | Slope | Intercept(mg/dL) | CorrelationCoefficient | n | Sampletype |
|---|---|---|---|---|---|---|
| IDMSReferenceMethod | 0.18-6.32 | 1.04 | 0.02 | 0.997 | 48 | serum |
The model equation for the reqression statistics is: [results for Dimension® Creatinine (CRE2) Flex® reagent cartridge] = slope x [comparative method results] + intercept.
5.12.2 Serum Plasma Equivalency
Serum and lithium heparin plasma equivalency was demonstrated for the Dimension® Creatinine (CRE2) Flex® reagent cartridge. Fifty six matched serum and lithium heparin plasma samples were tested using the Dimension® Creatinine (CRE2) Flex® reagent cartridge. The table below summarizes the linear regression statistics.
| Serum vs. | Slope | Intercept | CorrelationCoefficient (r) | Range | n |
|---|---|---|---|---|---|
| Lithium HeparinPlasma | 1.05 | -0.02 | 0.998 | 0.50 - 17.35 | 56 |
One replicate of each sample was processed. All samples in the study were fresh and never frozen. The eight spiked sample sets were prepared by spiking equal amounts of purified creatinine into the matched serum and lithium heparin plasma samples.
5.12.3 Precision
Precision testing was performed in accordance with CLSI EP05-A2 Evaluation of Precision Performance of Quantitative Measurement Methods: Approved Guideline ~ Second Edition. Samples consisted of two (2) serum pools, three (3) levels of BioRad Multiqual material, two (levels) of BioRad Liguicheck material and two (2) urine pools. Testing was performed over twenty (20) days, two (2) separate runs with two test samples for each test material. Analysis of variance (ANOVA) was used to evaluate the data consistent with the recommendations of EP05-A2. The data are summarized in the following table:
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| Repeatability | Within-Lab | |||||
|---|---|---|---|---|---|---|
| Sample | Mean(mg/dL) | SD | %CV | SD | %CV | |
| Serum | Serum Pool 1 | 1.32 | 0.04 | 3.0 | 0.04 | 3.2 |
| Serum Pool 2 | 15.79 | 0.19 | 1.2 | 0.19 | 1.2 | |
| BioRad Multiqual Level 1 | 0.71 | 0.03 | 4.7 | 0.04 | 5.1 | |
| BioRad Multiqual Level 2 | 1.79 | 0.04 | 2.1 | 0.05 | 2.8 | |
| BioRad Multiqual Level 3 | 7.04 | 0.07 | 1.0 | 0.09 | 1.3 | |
| Urine | Urine Pool 1 | 39.31 | 1.52 | 3.9 | 1.53 | 3.9 |
| Urine Pool 2 | 339.56 | 4.28 | 1.3 | 4.59 | 1.4 | |
| BioRad Liquicheck Level 1 | 62.28 | 0.61 | 1.0 | 1.41 | 2.3 | |
| BioRad Liquicheck Level 2 | 142.80 | 1.56 | 1.1 | 3.39 | 2.4 |
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BioRad® is a registered trademark of Bio-Rad Laboratories, Irvine, CA 92618, USA. Multiqual® is a registered trademark of Bio-Rad Laboratories, Irvine, CA 92618, USA. Liquichek™ is a trademark of Bio-Rad Laboratories, Irvine, CA 92618, USA.
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5.12.4 Limit of Blank and Limit of Detection
The Limit of Blank (LoB) and Limit of Detection (LoD) were evaluated in accordance with CLSI EP17-A2 Protocols for Determination of Limits of Detection and Limits of Quantitation: Approved Guideline.
| Dimension® Creatinine (CRE2) Flex® reagent cartridgeLimit of Detection Results with Serum | ||||||
|---|---|---|---|---|---|---|
| Limit | Protocol | Value | ||||
| LoB | 4 samples with no analytewere tested (N=5) for 3 days,one run per day, 2 reagentlots, | 0.05 mg/dL | ||||
| LoD | 4 low patient serum sampleswere tested (N=5) for 3 days,one run per day, 2 reagentlots | 0.1 mg/dL. |
| Limit | Protocol | Value |
|---|---|---|
| LoB | 4 samples with no analytewere tested (N=5) for 3 days,one run per day, 2 reagentlots, | 1.0 mg/dL |
| LoD | 4 low patient urine sampleswere tested (N=5) for 3 days,one run per day, 2 reagentlots | 2.0 mg/dL |
The nonparametric approach described in EP-17A2 was followed to determine the Limit of Detection.
LoB = Mean of Blank Measurement + 1.645 x Standard Deviation of Blank Measurements LoD = Limit of Blank + CpSDs
• Co is a correction factor for the 95% CI normal variate to account for bias in · the SDs estimate.
· SDs is an estimate of method imprecision pooled from replicates of the low analyte samples
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The LoB was determined to be 0.05 mg/dL with serum samples and is consistent with the claim of 0.05 mq/dL. With urine samples, the LoB was determined to be 0.87 mg/dL and is consistent with the claim of 1.0 mg/dL.
The LoD was determined to be 0.08 mg/dL with serum samples and is consistent with the claim of 0.1 mg/dL. With urine samples, the LoD was determined to be 1.51 mg/dL. and is ' consistent with the claim of 2.0 mg/dL.
5.12.5 Limit of Quantitation
The Limit of Quantitation (LoQ) for the Dimension® Creatinine (CRE2) Flex® reagent cartridge for serum and plasma is 0.15 mg/dL and based on allowable total error of 0.15 mg/dL, determined consistent with CLSI Guideline EP17-A2.
The Limit of Quantitation (LoQ) for the Dimension® Creatinine (CRE2) Flex® reagent cartridge for urine is 5.00 mg/dL and based on allowable total error of 3.00 mg/dL, determined consistent with CLSI Guideline EP17-A2.
5.12.6 Linearity (Measurement Range)
Linearity was evaluated for serum and urine samples by using 12 equally spaced samples which spanned the assay range. Each was prepared by mixing high and low creatinine concentration samples across the measurement range as described in CLSI Evaluation of the Linearity of Quantitative Measurement Procedure (EP06-A).
Regression Statistics
| Range of samples | Slope | Intercept | CorrelationCoefficient | N |
|---|---|---|---|---|
| serum0.15* - 22.00 mg/dL | 1.01 | -0.01 | 1.0 | 12 |
| urine3.00* - 425.34 mg/dL | 0.998 | -0.41 | 1.0 | 12 |
*represents the LoQ
5.13 Analytical Specificity
5.13.1 Non-interfering Substances
CLSI EP7A2 was followed for the interference testing. The interference study was conducted using a "paired difference worst case scenario" approach where these compounds were spiked into fresh sample pools containing either low or high levels of creatinine analyte in both serum pools and urine pools.
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| LOW pool (~ 1.5mg/dL) | HIGH pool (~ 5.0 mg/dL) | ||||||
|---|---|---|---|---|---|---|---|
| Substance | Concentration ofSubstance(mg/dL) | Mean | Control | % Diff | mean | control | % Diff |
| Acetaminophen | 20 | 1.35 | 1.37 | -2% | 4.90 | 4.75 | 3% |
| Acetoacetate | 20 | 1.43 | 1.43 | 0% | 4.83 | 4.81 | 0% |
| Amikacin | 8 | 1.39 | 1.37 | 1% | 4.76 | 4.75 | 0% |
| Ampicillin | 5.3 | 1.39 | 1.37 | 1% | 4.72 | 4.75 | -1% |
| Ascorbic Acid | 6 | 1.41 | 1.39 | 2% | 4.90 | 4.74 | 3% |
| Caffeine | 6 | 1.38 | 1.37 | 1% | 4.76 | 4.75 | 0% |
| Carbamazepine | 3 | 1.39 | 1.39 | 0% | 4.77 | 4.84 | -1% |
| Cephalexin | 25 | 1.46 | 1.43 | 2% | 4.88 | 4.81 | 1% |
| Cephapirin | 25 | 1.46 | 1.43 | 2% | 4.86 | 4.87 | 0% |
| Cephradine | 25 | 1.43 | 1.43 | 0% | 4.88 | 4.87 | 0% |
| Chloramphenicol | 5 | 1.41 | 1.36 | 3% | 4.76 | 4.79 | -1% |
| Chlordiazepoxide | 1 | 1.37 | 1.38 | -1% | 4.79 | 4.72 | 1% |
| Chlorpromazine | 0.2 | 1.36 | 1.37 | -1% | 4.77 | 4.70 | 1% |
| Cholesterol Supertrate | 503 | 1.31 | 1.31 | 0% | 4.42 | 4.35 | 2% |
| Cimetidine | 2 | 1.37 | 1.37 | 0% | 4.74 | 4.75 | 0% |
| Dextran 40 | 6000 | 1.55 | 1.49 | 4% | 4.98 | 5.04 | -1% |
| Diazepam | 0.51 | 1.39 | 1.38 | 1% | 4.76 | 4.72 | 1% |
| Digoxin | 6.1ng/mL | 1.42 | 1.41 | 0% | 4.72 | 4.71 | 0% |
| EDTA | 200 | 1.37 | 1.36 | 0% | 4.86 | 4.80 | 1% |
| Erythromycin | 6 | 1.38 | 1.36 | 1% | 4.72 | 4.79 | -1% |
| Ethanol | 400 | 1.39 | 1.39 | 0% | 4.77 | 4.74 | 0% |
| Ethosuximide | 25 | 1.39 | 1.37 | 1% | 4.74 | 4.75 | 0% |
| Furosemide | 6 | 1.40 | 1.36 | 2% | 4.77 | 4.79 | 0% |
| Gentamicin | 1 | 1.38 | 1.39 | 0% | 4.72 | 4.74 | -1% |
| Heparin (196 Units/mg) | 3 U/mL | 1.38 | 1.37 | 1% | 4.74 | 4.74 | 0% |
| Ibuprofen | 50 | 1.41 | 1.39 | 2% | 4.80 | 4.84 | -1% |
| Immunoglobulin G (IgG) | 5000 | 1.56 | 1.49 | 5% | 5.07 | 5.04 | 1% |
| Isopropanol | 1.0 g/dL | 1.38 | 1.36 | 1% | 4.81 | 4.80 | 0% |
| Lidocaine | 1.2 | 1.39 | 1.36 | 2% | 4.79 | 4.79 | 0% |
| Lithium | 2.2 | 1.37 | 1.37 | 0% | 4.73 | 4.70 | 0% |
| Nicotine | 0.1 | 1.40 | 1.39 | 0% | 4.82 | 4.84 | 0% |
| Nortriptyline | 1000 ng/mL | 1.40 | 1.36 | 2% | 4.85 | 4.80 | 1% |
| Penicillin G (1654 Units/mg) | 25 U/mL | 1.37 | 1.37 | 0% | 4.71 | 4.70 | 0% |
| Pentobarbital | 8 | 1.41 | 1.37 | 3% | 4.74 | 4.79 | -1% |
| Phenobarbital | 10 | 1.39 | 1.37 | 1% | 4.79 | 4.79 | 0% |
| Phenytoin | 5 | 1.38 | 1.38 | 0% | 4.81 | 4.72 | 2% |
| Potassium oxalate | 500 mg/dL | 1.46 | 1.43 | 2% | 4.90 | 4.81 | 2% |
| Primidone | 4 | 1.40 | 1.39 | 1% | 4.75 | 4.84 | -2% |
| DM CRE2 | Serum/Plasma Substances | ||||||
| LOW pool (~1.5mg/dL) | HIGH pool (~ 5.0 mg/dL) | ||||||
| Substance | Concentration ofSubstance(mg/dL) | Mean | Control | % Diff | mean | control | % Diff |
| Protein, Albumin | 6000 | 1.49 | 1.49 | 0% | 4.73 | 5.20 | -9% |
| Protein, Total | 12g/dL | 1.57 | 1.49 | 6% | 4.95 | 4.98 | -1% |
| Salicylic acid | 60 | 1.41 | 1.36 | 4% | 4.79 | 4.79 | 0% |
| Sodium fluoride | 400 | 1.35 | 1.34 | 1% | 4.59 | 4.59 | 0% |
| Theophylline | 4 | 1.39 | 1.37 | 1% | 4.83 | 4.75 | 2% |
| Urea | 500 | 1.42 | 1.37 | 3% | 4.80 | 4.70 | 2% |
| Uric acid | 20 | 1.40 | 1.39 | 0% | 4.98 | 4.77 | 4% |
| Valproic acid | 50 | 1.38 | 1.37 | 1% | 4.76 | 4.75 | 0% |
| Vancomycin | 10 | 1.42 | 1.39 | 2% | 4.81 | 4.74 | 1% |
| DM CRE2 | Urine Substances | ||||||
| Substance | Concentration ofSubstance(mg/dL) | LOW pool (~40 mg/dL) | HIGH pool (~175 mg/dL) | ||||
| Mean | Control | % Diff | mean | control | % Diff | ||
| 50% Acetic Acid | 25mL/24 hr collection | 41.23 | 40.82 | 1% | 180.56 | 178.44 | 1% |
| 6N Hydrochloric Acid | 0.6% | 41.76 | 41.41 | 1% | 180.84 | 181.20 | 0% |
| 6N Nitric Acid | 0.6% | 41.95 | 41.41 | 1% | 181.85 | 181.20 | 0% |
| Acetone | 100 mg/dL | 41.53 | 42.10 | -1% | 181.95 | 183.29 | -1% |
| Bilirubin (conjugated) | 2 mg/dL | 41.39 | 41.05 | 1% | 179.95 | 180.73 | 0% |
| Boric Acid | 1% w/v | 40.46 | 41.91 | -3% | 183.69 | 183.76 | 0% |
| Ethanol | 1 g/dL | 41.44 | 42.20 | -2% | 180.88 | 184.21 | -2% |
| Gamma Globulin | 0.5 g/dL | 41.24 | 41.69 | -1% | 182.54 | 180.88 | 1% |
| Glucose | 2 g/dL | 41.06 | 41.69 | -2% | 178.55 | 180.88 | -1% |
| Hemoglobin | 115 mg/dL | 42.09 | 41.93 | 0% | 183.40 | 179.88 | 2% |
| Human Serum Albumin | 0.5 g/dL | 40.55 | 41.49 | -2% | 180.8 | 179.8 | 1% |
| Oxalic Acid | 0.1 g/dL | 39.94 | 39.50 | 1% | 173.04 | 172.25 | 0% |
| Sodium Carbonate | 5g/24 hr collection | 41.26 | 40.74 | 1% | 179.24 | 180.10 | 0% |
| Sodium Fluoride | 1% w/v | 41.65 | 41.91 | -1% | 184.79 | 183.76 | 1% |
.
and the comments of the comments of
:
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5.13.2 Interfering Substances
The CRE2 method was evaluated for interference according to CLSI EP7-A2. Bias is the difference in the results between the control sample (without the interferent) and the test sample (contains the interferent) expressed in percent. Bias exceeding 10% is considered interference. Dilution studies were conducted to determine the level at which the spiked substance no longer displayed significant interference. These studies were conducted at
{12}------------------------------------------------
two Creatinine analyte concentrations, if both sample pools show significant interference. This study was conducted as needed for both serum pools and urine pools.
| Substance | Concentrationof Substance | Mean Test CRE2Result (mg/dL) | Mean ControlCRE2 Result(mg/dL) | %Diff |
|---|---|---|---|---|
| Serum/Plasma Sample Type | ||||
| Acetone | 18.75 mg/dL | 1.56 | 1.41 | 11% |
| Acetone | 75 mg/dL | 5.37 | 4.84 | 11% |
| Bilirubin (unconj) | 20 mg/dL | 1.20 | 1.50 | -20.2% |
| Cefoxitin | 5 mg/dL | 1.62 | 1.43 | 13% |
| Cephalothin | 12.5 mg/dL | 1.57 | 1.41 | 12% |
| Glucose | 500 mg/dL | 1.60 | 1.43 | 12% |
| Intralipid 20% | 1500 mg/dL | 1.50 | 1.35 | 11.3% |
| Pyruvate | 10.5 mg/dL | 5.71 | 4.81 | 19% |
| Triglycerides | 3000 mg/dL | 1.42 | 1.22 | 16% |
| Urine Sample Type | ||||
| Ascorbic Acid | 0.15 g/dL | 44.29 | 39.97 | 11% |
| Ascorbic Acid | 0.3 g/dL | 199.52 | 178.25 | 12% |
5.13.3 Hemolysis, Icterus, Lipemia (HIL) Interference
The CRE2 method was evaluated for interference according to CLSI EP7-A2. Bias is the difference in the results between the control sample (without the interferent) and the test sample (contains the interferent) expressed in percent. Bias exceeding 10% is considered interference.
| DM CRE2 | HIL Interference | |||
|---|---|---|---|---|
| Substance | Concentration ofSubstance (mg/dL) | Mean Test CRE2Result (mg/dL) | Mean Control CRE2Result (mg/dL) | % Difference |
| Hemoglobin | 1000 | 4.54 | 4.69 | -3.2% |
| Hemoglobin | 1000 | 1.24 | 1.4 | -11.1% |
| Hemoglobin | 500 | 1.37 | 1.44 | -4.9% |
| Bilirubin (conj) | 40 | 4.79 | 4.86 | -1.3% |
| Bilirubin (conj) | 40 | 1.16 | 1.40 | -17.2% |
| Bilirubin (conj) | 20 | 1.38 | 1.46 | -5.5% |
| Bilirubin (unconj) | 40 | 4.79 | 4.89 | -2.0% |
| Bilirubin (unconj) | 20 | 1.20 | 1.50 | -20.2% |
| Bilirubin (unconj) | 10 | 1.32 | 1.46 | -9.6% |
| Intralipid 20% | 2000 | 4.66 | 4.56 | 2.2% |
| Intralipid 20% | 1500 | 1.50 | 1.35 | 11.3% |
| Intralipid 20% | 1000 | 1.49 | 1.39 | 7.2% |
{13}------------------------------------------------
5.14 Conclusion
The Dimension® Creatinine (CRE2) Flex® reagent cartridge (DF33B) is substantially equivalent in principle and performance to the Creatinine Method for Use on the Dimension® Clinical Chemistry System (CREA) cleared under K925668. Comparative testing described in the submission demonstrates substantially equivalent performance.
{14}------------------------------------------------
DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/14/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an abstract symbol resembling an eagle or bird in flight, composed of three curved lines.
Public Health Service
Food and Orug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
January 27, 2014
SIEMENS HEALTHCARE DIAGNOSTICS INC. LAURA DUGGAN, PH.D. REGULATORY TECHNICAL SPECIALIST P.O. BOX 6101 NEWARK DE 19714
Re: K132638
Trade/Device Name: Dimension® Creatinine (CRE2) Flex® reagent cartridge Regulation Number: 21 CFR 862.1225 Regulation Name: Creatinine test system Regulatory Class: II Product Code: CGX Dated: November 13, 2013 Received: November 14, 2013
Dear Dr. Duggan:
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 (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
{15}------------------------------------------------
Page 2-Dr. Duggan
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance 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" (21CFR 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/Safetw/ReportalProblem/default.htm for the CDRH's Office of Surveillance and Biometries/Division of Postmarket Surveillance.
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 (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/Resourcesfor.You/Industry/default.htm.
Sincerely vours.
CourtneyH.Lias-S
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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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known) K132638
Device Name
Dimension® Creatinine (CRE2) Flex® reagent cartridge
Indications for Use (Describe)
The CRE2 method is an in vitro diagnostic test for the quantitative measurement of creatinine in human serum, plasma, and urine on the Dimension® clinical chemistry system. Creatinine measurements are treatment of certain rend disease. in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.
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)
PLEASE DO NOT WRITE BELOW THIS LINE – CONTINUE ON A SEPARATE PAGE IF NEEDED.
FOR FDA USE ONLY
Concurrence of Center for Devices and Radiological Health (CDRH) (Signalure)
uth A. Chesler
FORM FDA 3881 (1/14)
PSC Pobliching Services (101) 413-4740 EF
Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement on last page.
§ 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.