MULTIGENT CREATININE (ENZYMATIC) ASSAY

K073634 · SENTINEL CH. SpA · JFY · Jun 19, 2008 · Clinical Chemistry

Device Facts

• Record ID: K073634
• Device Name: MULTIGENT CREATININE (ENZYMATIC) ASSAY
• Applicant: SENTINEL CH. SpA
• Product Code: JFY · Clinical Chemistry
• Decision Date: Jun 19, 2008
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1225
• Device Class: Class 2

Indications for Use

The MULTIGENT Creatinine (Enzymatic) assay is a device intended to measure creatinine levels in human serum, plasma, and urine using the ARCHITECT c8000 System and the AEROSET System. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a component of various calculations for determination or estimation of creatinine clearance, glomerular filtration rate (GFR) or estimated GFR (eGFR).

Device Story

The MULTIGENT Creatinine (Enzymatic) Assay is a dual-reagent, liquid, ready-to-use kit for use on Abbott ARCHITECT c8000 and AEROSET systems. The assay utilizes enzymatic colorimetry to measure creatinine levels in human serum, plasma, and urine. Reagent 1 contains creatinase, sarcosine oxidase, ascorbate oxidase, and catalase; Reagent 2 contains creatininase and peroxidase. The reaction produces a quinoneimine dye, with absorbance measured at 548 nm. The change in absorbance is proportional to creatinine concentration. The device is intended for clinical laboratory use by trained personnel. Results assist clinicians in diagnosing renal disease, monitoring dialysis, and calculating GFR or creatinine clearance. The assay is traceable to IDMS values via SRM967.

Clinical Evidence

Bench testing only. Performance evaluated per CLSI guidelines (EP5-A, EP6-A, EP17-A, EP9-A2). Precision studies showed total CVs < 2% for serum and < 1.5% for urine. Linearity confirmed for serum (0.1-40 mg/dL) and urine (2.5-400 mg/dL). Method comparison against predicate yielded correlation coefficients of 0.999-1.000. Interference testing identified alpha-methyldopa as an interferent in serum; EDTA is not recommended as an anticoagulant due to -9.1% bias.

Technological Characteristics

Enzymatic colorimetric assay. Reagents: creatininase, creatinase, sarcosine oxidase, peroxidase, 4-aminoantipyrine, ESPMT. Sensing: spectrophotometric absorbance at 548 nm. Platform: AEROSET and ARCHITECT c8000 automated clinical chemistry analyzers. Calibration: traceable to IDMS.

Indications for Use

Indicated for the quantitative measurement of creatinine in human serum, plasma, and urine to aid in the diagnosis and treatment of renal diseases and monitoring of renal dialysis in adult populations.

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.

Predicate Devices

• Roche Creatinine assay (K003261)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
k073634

B. Purpose for Submission:
New Device

C. Measurand:
Creatinine

D. Type of Test:
Enzymatic, quantitative

E. Applicant:
Sentinel CH. SpA

F. Proprietary and Established Names:
MULTIGENT Creatinine (Enzymatic) Assay

G. Regulatory Information:

| Product Code | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| JFY | Class II | 21 CFR§ 862.1225
Creatinine test system | 75 - Clinical Chemistry |

H. Intended Use:

1. Intended use(s):
See indications for use below.

2. Indication(s) for use:
The MULTIGENT Creatinine (Enzymatic) assay is a device intended to measure

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creatinine levels in human serum, plasma, and urine using the ARCHITECT c8000 System and the AEROSET System. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a component of various calculations for determination or estimation of creatinine clearance, glomerular filtration rate (GFR) or estimated GFR (eGFR).

3. Special conditions for use statement(s):

For prescription use only

4. Special instrument requirements:

Abbot ARCHITECT c8000 and AEROSET systems

I. Device Description:

The MULTIGENT Creatinine (Enzymatic) Assay is a dual reagent kit. Reagent one contains Good's buffer, creatinase, sarcosine oxidase, ascorbate oxidase, catalase and ESPMT (N-ethyl-N-sulfopropyl-M-toluidine). Reagent 2 contains Good's buffer, creatininase, peroxidase and 4-Aminoantipyrine.

J. Substantial Equivalence Information:

1. Predicate device name(s):

Roche Creatinine Plus Assay

2. Predicate K number(s):

k003261

3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Form | Liquid, ready to use | Same |
| Test Method | Enzymatic colorimetry | Same |
| Sample | Serum, plasma, urine | Same |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Measuring Range | Serum: 0.10-40 mg/dl | Serum:0.03-30 mg/dl |
| | Plasma: 0.10-40 mg/dl | Plasma: 0.03-30 mg/dl |
| | Urine: 2.5-400 mg/dl | Urine: 0.3-400 mg/dl |
| Instruments | Abbott Aeroset and Architect systems | Roche Hitachi 911 system |

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K. Standard/Guidance Document Referenced (if applicable):

CLSI EP5-A, CLSI EP-6A, CLSI EP17A, and CLSI EP9-A2

L. Test Principle:

Creatininase (in reagent 1) hydrolyzes creatinine in a sample to creatine. Creatine is hydrolyzed by creatinase to sarcosine and urea. Sarcosine from this reaction is oxidized by sarcosine oxidase to glycine and formaldehyde and hydrogen peroxide. The hydrogen peroxide reacts with 4-aminoantipyrine and ESPMT in the presence of peroxidase to yield a quinoneimine dye. The resulting change in absorbance at 548 nm is proportional to the creatinine concentration in the sample.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

i.) Precision studies for serum samples were evaluated using CLSI EP5-A as a guideline. For within-run (intra-assay) and total precision studies, testing was performed on both Architect c8000 and Aeroset systems. For within-run precision, 3 serum controls were run in singlet for one day. For total precision, 3 serum controls were tested twice daily, in duplicate, for over 20 days. Results of the precision studies were shown below:

| MULTIGENT Creatinine (Enzymatic)
ARCHITECT Serum Precision | | | | |
| --- | --- | --- | --- | --- |
| Intra-Assay Precision | | | | |
| Control | | Level 1 | Level 2 | Level 3 |
| N | | 20 | 20 | 20 |
| Mean (mg/dL) | | 0.623 | 0.958 | 3.752 |
| Intra-assay | SD | 0.0055 | 0.0052 | 0.0089 |
| | %CV | 0.88 | 0.55 | 0.24 |

Total Precision

| N | | 80 | 80 | 80 |
| --- | --- | --- | --- | --- |
| Mean (mg/dL) | | 0.654 | 1.827 | 6.604 |
| Within Run | SD | 0.0042 | 0.0061 | 0.0199 |
| | %CV | 0.64 | 0.33 | 0.30 |
| Between Day | SD | 0.0173 | 0.0265 | 0.0300 |
| | %CV | 2.65 | 1.45 | 0.45 |
| Between Run | SD | 0.0100 | 0.0173 | 0.0520 |

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| MULTIGENT Creatinine (Enzymatic)
AEROSET Serum Precision | | | | |
| --- | --- | --- | --- | --- |
| Intra-Assay Precision | | | | |
| Control | | Level 1 | Level 2 | Level 3 |
| N | | 20 | 20 | 20 |
| Mean (mg/dL) | | 0.624 | 0.973 | 3.746 |
| Intra-assay | SD | 0.0059 | 0.0080 | 0.0190 |
| | %CV | 0.94 | 0.82 | 0.51 |

Total Precision

| N | | 80 | 80 | 80 |
| --- | --- | --- | --- | --- |
| Mean (mg/dL) | | 0.647 | 1.826 | 6.606 |
| Within Run | SD | 0.0077 | 0.0077 | 0.0165 |
| | %CV | 1.19 | 0.42 | 0.25 |
| Between Day | SD | 0.0100 | 0.0224 | 0.0374 |
| | %CV | 1.55 | 1.23 | 0.57 |
| Between Run | SD | 0.0000 | 0.0000 | 0.0245 |
| | %CV | 0.00 | 0.00 | 0.37 |
| Total | SD | 0.0126 | 0.0237 | 0.0475 |
| | %CV | 1.95 | 1.30 | 0.72 |

ii.) Precision studies for urine samples were evaluated according to the CLSI EP5-A guideline. For total precision studies, two urine controls were tested twice daily, in duplicate, for over 20 days and were assayed on both the Architect c8000 and the Aeroset system. Urine controls were diluted x 10 with 0.9% saline before testing. Results of the total precision studies were shown below:

| MULTIGENT Creatinine (Enzymatic)
ARCHITECT Urine Precision
Total precision Data Summary | | |
| --- | --- | --- |
| Control | Level 1 | Level 2 |
| N | 80 | 80 |
| Mean (mg/dL) | 69.940 | 124.724 |

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| MULTIGENT Creatinine (Enzymatic) AEROSET Urine Precision Total precision Data Summary | | | |
| --- | --- | --- | --- |
| Control | | Level 1 | Level 2 |
| N | | 80 | 80 |
| Mean (mg/dL) | | 68.769 | 121.937 |
| Within Run | SD | 0.8699 | 1.4059 |
| | %CV | 1.26 | 1.15 |
| Between Day | SD | 0.3317 | 0.2387 |
| | %CV | 0.48 | 0.20 |
| Between Run | SD | 0.4136 | 0.5834 |
| | %CV | 0.60 | 0.48 |
| Total | SD | 0.9023 | 1.5033 |
| | %CV | 1.31 | 1.23 |

# b. Linearity/assay reportable range:

Linearity study was assessed according to CLSI EP-6A.

i.) Serum samples: Serum linearity was assessed on three different ranges of human sera: whole analytical measuring range (2.3 to $53\mathrm{mg / dL}$ ), pathologic analytical measuring range (pre dialysis range of 0.39 to $9.7\mathrm{mg / dL}$ ) and low analytical measuring range (0.04 to $2.2\mathrm{mg / dL}$ ). The spiked pools were serially diluted to obtain a set of at least 10 samples with proportionally decreased concentrations of creatinine. Serum sample pools were assayed in triplicates. The sponsor's acceptance criterion was a bias of $5\%$ between the expected values and the observed values. The study supported the sponsor's linearity claim range of 0.1 to $40.0\mathrm{mg / dL}$ .

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ii.) Urine samples: Urine linearity was assessed on a pool of human urine that was spiked with a concentrated solution to obtain a final analyte concentration exceeding the targeted high linearity and was serially diluted to obtain a set of at least 12 samples with proportionally decreased concentrations of creatinine. The study covered the entire analytical measuring range (22.9 to 476.6 mg/dL) and the low analytical measuring range (2.39 to 52.45 mg/dL). Urine sample pools were run in triplicates and the sponsor's acceptance criterion was a bias of 5% between the expected values and the observed values. The study supported the sponsor's linearity claim range of 2.5 to 400 mg/dL.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

The assay is traceable to IDMS values through SRM967.

This device does not include the calibrator materials. The sponsor's labeling recommends using the MULTIGENT Clin Chem Calibrators (cleared in k070971). The sponsor states that the recommended calibrators are stable for 60 days when stored on-board and is required for each new lot of reagent.

The sponsor conducted open on-board, closed stability (reagent) and calibration stability of reagents 1 and 2 on both the ARCHITECT c8000 and AEROSET systems. On-board stability of the assay reagents was conducted with new calibrators, two control materials and a prepared human serum sample and calibrator were analyzed over 98 days- every 3 to 4 days. Shelf-life stability was determined using an accelerated stability study. The sponsor's on-board/open stability for the MULTIGENT Creatinine (Enzymatic) Assay reagents is stable up to 60 days at 2-10° C and has a shelf life stability of 120 days when stored at 2-8° C.

d. Detection limit:

i.) A detection limits study was performed according to the CLSI EP17A guideline for the serum samples. The serum LOB was determined by assaying saline and human control serum in replicates of 20 for 3 different runs on the Aeroset and Architect instruments. The serum LOD was determined by assaying a human control serum mixed with a pool of human sera (for a concentration 4 to 6 times higher than the found LOB) assayed in 20 replicates for 3 different runs on the Aeroset and Architect instruments. The serum LOQ was determined with a pool of human sera with concentrations around the clinical decision level (1.00 mg/dL). The sera pool was serially diluted with a commercially available analyte free human serum material. Each sample was tested on the Aeroset and the Architect in replicates of 10. The sponsor's acceptance criterion was a total error no greater than 15% (defined by the sponsor as %bias + 2X %CV). The detection limits study supported the sponsor's measuring range claims of 0.1-40.0

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mg/dL for serum samples.

Serum results:

| Analytical Item | Instrument | Sample | N | mg/dL |
| --- | --- | --- | --- | --- |
| LoB | Aeroset | Saline | 60 | 0.0097 |
| LoB | Aeroset | Negative serum | 60 | 0.0154 |
| LOD | Aeroset | Low Serum | 60 | 0.0589 |
| LOQ | Aeroset | Serum | 10 | 0.092 |
| | | | | |
| LoB | C8000 | Saline | 60 | 0.0076 |
| LoB | C8000 | Negative serum | 60 | 0.0086 |
| LOD | C8000 | Low serum | 60 | 0.0523 |
| LOQ | C8000 | Serum | 10 | 0.092 |

ii.) A detection limit study was performed according to the CLSI EP17A guideline for the urine samples. The urine LOB was determined by assaying saline in replicates of 20 for 3 different runs on the Aeroset and Architect instruments. The urine LOD was determined by assaying human urine that was diluted with saline (for a creatine concentration around 5 to 6 times higher than the found LOB) and run in 20 replicates in 3 different runs on the Aeroset and Architect instruments. The urine LOQ was determined with two human urine samples with a concentration about 40 mg/dL. The samples were serially diluted with saline to obtain two set of samples with decreased concentrations of creatinine and run in replicated of 10 on the Aeroset and Architect instruments. The detection limits study supported the sponsor's measuring range claims of 2.5-400.0 mg/dL for the urine samples.

Urine results:

| Analytical Item | Instrument | Sample | N | mg/dL |
| --- | --- | --- | --- | --- |
| LoB | Aeroset | Saline | 60 | 0.097 |
| LOD | Aeroset | Diluted urine | 60 | 0.676 |
| LOQ | Aeroset | Urine | 10 | 2.02 |
| | | | | |
| LoB | C8000 | Saline | 60 | 0.061 |
| LOD | C8000 | Diluted urine | 60 | 0.671 |
| LOQ | C8000 | Urine | 10 | 1.74 |

e. Analytical specificity:

The MULTIGENT Creatinine (Enzymatic) Assay was evaluated for

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interferences caused by bilirubin (conjugated and unconjugated), hemoglobin, triglyceride (intralipid), creatine, ascorbic acid, and glucose in serum samples. The MULTIGENT Creatinine (Enzymatic) Assay was also evaluated for interferences caused by ascorbic acid, glucose, hemoglobin, conjugated bilirubin, protein (albumin) and pH in urine samples. The following substances demonstrated no significant bias as defined by the sponsor as $+/-$ $8\%$ difference between the interferent result and the unspiked result.

MULTIGENT Creatinine (Enzymatic)
Serum - Endogenous Interferent Summary

| Interfering Substance | Interfering Substance Concentration | Target (mg/dL) | Observed (mg/dL) | % Recovery | % Interference at 1 mg/dL |
| --- | --- | --- | --- | --- | --- |
| Bilirubin (conjugated) | 39.6 mg/dL | 1.09 | 1.01 | 92.6% | -8.0% |
| Bilirubin (unconjugated) | 46.2 mg/dL | 0.99 | 0.94 | 94.9% | -5.0% |
| Hemoglobin | 1000 mg/dL | 1.044 | 0.97 | 92.9% | -7.4% |
| Triglyceride* | 2,000 mg/dL | 0.981 | 0.94 | 95.8% | -4.1% |
| Creatine | 100 mg/dL | 1.16 | 1.21 | 104.3% | +5.0% |
| Ascorbic Acid | 120 mg/dL | 1.16 | 1.09 | 94.0% | -7.0% |
| Glucose | 6,000 mg/dL | 1.15 | 1.10 | 95.7% | -5.0% |

MULTIGENT Creatinine (Enzymatic)
Urine - Endogenous Interferent Summary

| Interfering Substance | Maximum Interfering Substance Concentration | Target (mg/dL) | Observed (mg/dL) | % Recovery |
| --- | --- | --- | --- | --- |
| Ascorbic Acid | 250 mg/dL | 78.86 | 79.29 | 100.5% |
| Glucose | 3,000 mg/dL | 81.71 | 78.98 | 96.7% |
| Hemoglobin | 1,000 mg/dL | 80.90 | 83.85 | 103.6% |
| Conjugated Bilirubin | 400 mg/dL | 81.42 | 76.00 | 93.4% |
| Proteins (albumin) | 300 mg/dL | 78.41 | 80.93 | 103.1% |

The sponsor conducted a urine preservative study to determine compatibility of different preservatives that may be used for urine sample collection with the device. The sponsor determined that the following seven preservatives at the stated concentrations caused no interferences.

- Boric acid to $1000\mathrm{mg / dL}$
Hydrochloric acid (6N) to $5\mathrm{mL} / \mathrm{dL}$

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- Acetic acid (8.5N) to 10 mL/dL
- Nitric acid (6N) to 6 mL/dL
- Sodium Carbonate to 1.5 g/dL
- Sodium Oxalate to 70 mg/dL
- Sodium Fluoride to 500 mg/dL

The sponsor conducted a drug interferent study with the MULTIGENT Creatinine (Enzymatic) Assay. The following drugs, when spiked into serum or urine samples were tested at a low and high level and the only one that interfered was alpha-methyldopa in serum. This is noted in the package insert.

Summary of Drug Interference Results – Serum

| Drug Name | Drug Units | Low Drug Conc. | Maximum %Bias | Pass Fail | High Drug Conc. | Maximum% Bias | Pass Fail |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Acetaminophen | μmol/L | 132.4 | -1.2% | Pass | See Note 1 below. | | |
| Acetazolamide | μmol/L | 270 | 0.6% | Pass | 400 | 0.6% | Pass |
| Acetylsalicylic acid | mmol/L | 3.62 | -1.7% | Pass | 5 | -0.8% | Pass |
| Ascorbic acid | μmol/L | 342 | 0.8% | Pass | 500 | 0.8% | Pass |
| Cefazolin | μmol/L | 2643 | -0.8% | Pass | 4000 | -2.5% | Pass |
| Chlorothiazide | μmol/L | 67.6 | 2.5% | Pass | 100 | 2.5% | Pass |
| Cimetidine | μmol/L | 252 | 1.7% | Pass | 500 | 0.0% | Pass |
| Digoxin | nmol/L | 7.8 | -0.8% | Pass | 10 | -0.8% | Pass |
| Furosemide | μmol/L | 181 | -0.8% | Pass | 250 | -0.8% | Pass |
| Gliclazide | μmol/L | 100 | 2.5% | Pass | 200 | 1.6% | Pass |
| Ibuprofen | μmol/L | 2425 | -1.7% | Pass | 5000 | -1.7% | Pass |
| Phenidione | μmol/L | 75 | 2.5% | Pass | 150 | 1.6% | Pass |
| Ranitidine | μmol/L | 19.1 | 0.8% | Pass | 30 | -0.8% | Pass |
| Spironolactone | μmol/L | 1.44 | -0.8% | Pass | 3 | -0.8% | Pass |
| Triamterene | μmol/L | 35 | -0.8% | Pass | 50 | -0.8% | Pass |
| Alpha-methyldopa | μmol/L | 71 | -20.8% | Fail | 100 | -25.8% | Fail |
| Dexamethasone | μmol/L | 1.53 | -1.7% | Pass | 3 | -0.8% | Pass |
| Nitrofurantoin | μmol/L | 16.8 | -0.8% | Pass | 30 | -0.8% | Pass |

Note 1: Due to the low solubility of acetaminophen in water, only one concentration was tested.

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Summary of Drug Interference Results - Urine

| Drug Name | Drug Units | Drug Conc. | Maximum %Bias | Pass/Fail | Drug Conc. | Maximum %Bias | Pass/Fail |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Acetaminophen | μmol/L | 132.4 | -3.2% | Pass | See Note 1 below. | | |
| Acetazolamide | μmol/L | 270 | -2.2% | Pass | 400 | -2.1% | Pass |
| Acetylsalicylic acid | mmol/L | 3.62 | 1.2% | Pass | 5 | 0.5% | Pass |
| Ascorbic acid | μmol/L | 342 | 2.5% | Pass | 500 | 2.9% | Pass |
| Cefazolin | μmol/L | 2643 | 3.9% | Pass | 4000 | 1.0% | Pass |
| Chlorothiazide | μmol/L | 67.6 | 2.2% | Pass | 100 | 2.7% | Pass |
| Cimetidine | μmol/L | 252 | 1.7% | Pass | 500 | 1.7% | Pass |
| Digoxin | nmol/L | 7.8 | 2.0% | Pass | 10 | 1.7% | Pass |
| Furosemide | μmol/L | 181 | -0.9% | Pass | 250 | 1.2% | Pass |
| Gliclazide | μmol/L | 100 | -3.2% | Pass | 200 | 0.9% | Pass |
| Ibuprofen | μmol/L | 2425 | 1.5% | Pass | 5000 | 2.9% | Pass |
| Phenidione | μmol/L | 75 | -3.2% | Pass | 150 | -3.0% | Pass |
| Ranitidine | μmol/L | 19.1 | 1.3% | Pass | 30 | 1.2% | Pass |
| Spironolactone | μmol/L | 1.44 | -0.5% | Pass | 3 | -1.5% | Pass |
| Triamterene | μmol/L | 35 | -3.1% | Pass | 50 | 0.9% | Pass |
| Alpha-methyldopa | μmol/L | 71 | 1.0% | Pass | 100 | 1.2% | Pass |
| Dexamethasone | μmol/L | 1.53 | 0.3% | Pass | 3 | 0.9% | Pass |
| Nitrofurantoin | μmol/L | 16.8 | 1.6% | Pass | 30 | -1.8% | Pass |

Note 1: Due to the low solubility of acetaminophen in water, only one concentration was tested.

f. Assay cut-off:

Not applicable.

2. Comparison studies:

a. Method comparison with predicate device:

A comparison study was performed using CLSI EP9-A2 as a guideline and available enzymatic method as a reference on both instruments for serum and urine. The chart below lists the linear equations, ranges, matrix and instruments.

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i.) The serum method comparison contained eighty native samples ranging from 0.320 to $19.700\mathrm{mg / dL}$ and fourteen spiked samples that ranged from 20.91 to $39.15\mathrm{mg / dL}$ . Results of the method comparison study were shown below:

MULTIGENT Creatinine (Enzymatic) - Serum

Method Comparison

| Regression Parameter | AEROSET vs. Hitachi | ARCHITECT vs. Hitachi | ARCHITECT vs. AEROSET |
| --- | --- | --- | --- |
| Slope | 1.00 (0.992 to 1.007) | 1.011 (1.003 to 1.019) | 1.028 (1.003 to 1.018) |
| Y - Intercept | -0.025 (-0.222 to 0.082) | -0.100 (-0.205 to 0.005) | -0.079 (-0.182 to 0.023) |
| Correlation Coefficient | .999 | 0.999 | .999 |
| Range of all samples tested (mg/dL) | 0.32 to 38.58 | 0.32 to 38.58 | 0.31 to 39.24 |
| Std. Error of estimate (Sy/X) | 0.349 | 0.381 | 0.371 |
| Average Bias (mg/dL) | -0.019 (-0.090 to 0.053) | -0.006 (-0.86 to 0.075) | 0.013 (-0.066 to 0.091) |
| N | 94 | 94 | 94 |

ii.) The urine method comparison study contains 60 native samples ranging from 5.98 to $398.26\mathrm{mg / dL}$ collected from volunteers. Samples over $20\mathrm{mg / dL}$ are automatically diluted x10 by the ARCHITECT and AEROSET analyzers.

MULTIGENT Creatinine (Enzymatic) - Urine

Method Comparison

| Regression Parameter | AEROSET vs. Hitachi | ARCHITECT vs. Hitachi | ARCHITECT vs. AEROSET |
| --- | --- | --- | --- |
| Slope | 0.964 (0.955 to 0.973) | 0.986 (0.980 to 0.992) | 1.022 (1.015 to 1.028) |

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| Y - Intercept | 1.027 (-0.205 to 2.258) | 0.488 (-0.302 to 1.278) | -0.487 (-1.371 to 0.397) |
| --- | --- | --- | --- |
| Correlation Coefficient | 0.999 | 1.000 | 1.000 |
| Range of samples tested (mg/dL) | 5.98 to 398.26 | 5.98 to 398.26 | 6.06 to 378.02 |
| Std. Error of estimate (Sy/X) | 2.867 | 1.839 | 2.046 |
| Average Bias (mg/dL) | -2.924 (-3.991 to -1.856) | 1.079 (-1.641 to -0.517) | 1.845 (1.152 to 2.538) |
| N | 60 | 60 | 60 |

# b. Matrix comparison:

A matrix comparison study was conducted to assess the acceptability of 5 different blood collection tube types. Li-heparin plasma (without gel), Li-heparin plasma (with gel barrier), Na-heparin plasma, Serum (with gel barrier), and EDTA plasma were tested against a serum tube (without gel). The creatinine samples (22 native and 49 spiked) ranged from 0.49 to 36.23 mg/dl from 71 subjects were used for the study. The sponsors acceptance criterion is a slope between 0.95 to 1.05 and a correlation coefficient greater than 0.970. The following table supports the usage of lithium heparin (with or without gel barrier), sodium heparin and SST for sample collection for the Multigent Creatinine (enzymatic) assay. However, EDTA returned a bias of - $9.1\%$ and is not a recommended anticoagulant. This is noted in the package insert.

| Y | Li-heparin | Li-heparin (Gel barrier) | Na-heparin | Serum (Gel barrier) |
| --- | --- | --- | --- | --- |
| Slope | 1.002 (0.984 to 1.020) | 0.993 (0.979 to 1.006) | 0.978 (0.964 to 0.992) | 1.000 (0.991 to 1.009) |
| Y-intercept | 0.019 (-0.273 to 0.311) | -0.009 (-0.223 to 0.206) | 0.124 (-0.101 to 0.350) | 0.024 (-0.118 to 0.166) |
| Correlation Coefficient | 0.997 | 0.998 | 0.998 | 0.999 |
| Range (mg/dL) | 0.49 to 36.23 | 0.49 to 36.23 | 0.49 to 36.23 | 0.49 to 36.23 |
| N | 71 | 71 | 71 | 71 |

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3. Clinical studies:

a. Clinical Sensitivity:
Not applicable.

b. Clinical specificity:
Not applicable.

c. Other clinical supportive data (when a. and b. are not applicable):
Not applicable.

4. Clinical cut-off:
Not applicable.

5. Expected values/Reference range:

The sponsor references literature for the expected values as follows:

Serum/Plasma¹

| | Range (mg/dL) | Range (umol/L) |
| --- | --- | --- |
| Male | 0.73 to 1.18 | 64 to 104 |
| Female | 0.55 to 1.02 | 49 to 90 |

Urine¹

| | Adult Male | Adult Female |
| --- | --- | --- |
| 24- Hour Excretion | 11.1 to 27.9 mg/kg/day (98 to 247 umol/kg/day) | 9.8 to 24.7 mg/kg/day (87 to 218 umol/kg/day) |
| | 870 to 2410 mg/day (7.7 to 21.3 mmol/day) | 670 to 1590 mg/day (5.9 to 14.1 mmol/day) |
| Average Concentration * | 58 to 161 mg/dL (5.1 to 14.2 mmol/L) | 45 to 106 mg/dL (3.9 to 9.4 mmol/L) |
| Creatinine Clearance | 61 to 147 mL/min/1.73 m² BSA (1.02 to 2.45 mL/sec/1.73 m² BSA) | 59 to 151 mL/min/1.73 m² BSA (0.98 to 2.52 mL/sec/1.73 m² BSA) |

* Concentration is based on a daily urine output of 1.5L.

Junge W, Wilke B, Halabi A., et al. Determination of reference intervals for serum creatinine, creatinine excretion and creatinine clearance with an enzymatic and a modified Jaffe method. Clin Chim Acta 2004; 344; 137-148.

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N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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