ARCHITECT BNP ASSAY, MODEL 8K28

K060964 · Fujirebio Diagnostics,Inc. · NBC · May 25, 2006 · Clinical Chemistry

Device Facts

• Record ID: K060964
• Device Name: ARCHITECT BNP ASSAY, MODEL 8K28
• Applicant: Fujirebio Diagnostics,Inc.
• Product Code: NBC · Clinical Chemistry
• Decision Date: May 25, 2006
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Indications for Use

The ARCHITECT BNP assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma on the ARCHITECT i System. BNP values are used as an aid in the diagnosis and assessment of severity of heart failure. The ARCHITECT BNP Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma. Refer to the ARCHITECT BNP reagent package insert and ARCHITECT i System for additional information. The ARCHITECT BNP Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT i System (reagents, calibrators, and instrument), when used for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma. Refer to the ARCHITECT BNP reagent package insert and ARCHITECT i System for additional information.

Device Story

ARCHITECT BNP assay is a two-step chemiluminescent microparticle immunoassay (CMIA) for quantitative BNP measurement in human EDTA plasma. Input: patient EDTA plasma sample. Process: sample incubated with anti-BNP coated paramagnetic microparticles; BNP binds to particles; anti-BNP acridinium-labeled conjugate added; pre-trigger and trigger solutions added to induce chemiluminescence. Output: relative light units (RLUs) measured by ARCHITECT i System optics; RLU intensity directly proportional to BNP concentration. Used in clinical and hospital laboratories by trained personnel. Healthcare providers use quantitative BNP results to assist in diagnosing and assessing heart failure severity. Benefits include standardized, automated laboratory assessment of cardiac biomarkers.

Clinical Evidence

Method comparison study per NCCLS EP9-A2. N=171 EDTA plasma samples (128 heart failure, 43 non-heart failure). Comparison between ARCHITECT BNP and AxSYM BNP. Passing-Bablok regression: correlation coefficient 0.96; intercept -38.32 (95% CI: -48.26 to -28.50); slope 1.03 (95% CI: 0.98 to 1.09). Sample range 0-3702 pg/mL.

Technological Characteristics

CMIA technology; paramagnetic microparticles; anti-BNP (106.3) mouse monoclonal capture antibody; anti-BNP (BC203) mouse monoclonal conjugate antibody; chemiluminescent detection; automated on ARCHITECT i System; EDTA plasma specimen; 6-level calibration; 3-level controls.

Indications for Use

Indicated for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma to aid in the diagnosis and assessment of heart failure severity in patients.

Regulatory Classification

Identification

The B-type natriuretic peptide (BNP) test system is an in vitro diagnostic device intended to measure BNP in whole blood and plasma. Measurements of BNP are used as an aid in the diagnosis of patients with congestive heart failure.

Special Controls

*Classification.* Class II (special controls). The special control is “Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers.”

Predicate Devices

• Abbott AxSYM® B-Type Natriuretic Peptide (BNP) Microparticle Enzyme Immunoassay (MEIA) (k033606)

Submission Summary (Full Text)

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

A. 510(k) Number:
k060964

B. Purpose for Submission:
New device

C. Measurand:
B-type natriuretic peptide test system (BNP)

D. Type of Test:
Quantitative

E. Applicant:
Fujirebio Diagnostics, Inc.

F. Proprietary and Established Names:
ARCHITECT BNP Reagent Kit
ARCHITECT BNP Calibrator Kit
ARCHITECT BNP Control Kit

G. Regulatory Information:
1. Regulation section:
862.1117, B-type natriuretic peptide test system
862.1150, Calibrator, Secondary
862.1660, Quality Control Material (assayed and unassayed)

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2. Classification:
Class II, Class I

3. Product code:
NBC; JIT; JJX

4. Panel:
75, Chemistry

H. Intended Use:

1. Intended use(s):
See Indications for Use

2. Indication(s) for use:

ARCHITECT BNP Reagent Kit

The ARCHITECT BNP Assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma on the ARCHITECT I System. BNP values are used as an aid in the diagnosis and assessment of severity of heart failure.

ARCHITECT BNP Calibrator Kit

The ARCHITECT BNP Calibrators are for the calibration of the ARCHITECT I System when used for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma. Refer to the ARCHITECT BNP reagent package insert and ARCHITECT I System for additional information.

ARCHITECT BNP Control Kit

The ARCHITECT BNP Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT I System (reagents, calibrators, and instrument), when used for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma. Refer to the ARCHITECT BNP reagent package and ARCHITECT I System for additional information.

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3. Special conditions for use statement(s):

Prescription use only

4. Special instrument requirements:

ARCHITECT i System

I. Device Description:

ARCHITECT BNP Reagent Kit (100/ 500 tests) consists of: 1 or 4 bottles (6.6 mL for the 100 test bottle/27.0 mL for the 500 test bottle) Anti-BNP (Mouse, Monoclonal) Coated Microparticles in TRIS Buffer with protein (bovine, mouse) stabilizers; 1 or 4 bottles (5.9 mL for the 100 test bottle/26.3 mL for the 500 test bottle) Anti-BNP (Mouse, Monoclonal) Acridium labeled conjugate in MES buffer with protein (bovine) stabilizers; and 1 or 4 bottles (6.6 mL for the 100 test bottle/27.0 mL for the 500 test bottle) Specimen Diluent containing TRIS buffer with protein (bovine) stabilizers.

ARCHITECT BNP Calibrator Kit consists of 6 Bottles (4 mL each) of ARCHITECT BNP Calibrators. Calibrator A (0 pg/mL) is Acetate buffer with protein (bovine) stabilizers. Calibrators B-F contain BNP in Acetate buffer with protein (bovine) stabilizers.

ARCHITECT BNP Control Kit consists of 3 Bottles (8 mL each) of ARCHITECT BNP Controls containing BNP in Acetate buffer with protein (bovine) stabilizers.

J. Substantial Equivalence Information:

1. Predicate device name(s):

Abbott AxSYM® B-Type Natriuretic Peptide (BNP) Microparticle Enzyme Immunoassay (MEIA)

2. Predicate 510(k) number(s):

k033606

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3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Indications for Use | for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma. BNP values are used as an aid in the diagnosis and assessment of severity of heart failure. | for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma. BNP values are used as an aid in the diagnosis and assessment of severity of heart failure. |
| Capture antibody | Anti-BNP (106.3) mouse monoclonal | Anti-BNP (106.3) mouse monoclonal |
| Conjugate antibody | Anti-BNP (BC203) mouse monoclonal | Anti-BNP (BC203) mouse monoclonal |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Principle of operation | Chemiluminescent Microparticle Immunoassay (CMIA) | Microparticle Enzyme Immunoassay (MEIA) |

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

Clinical and Laboratory Standards Institute (CLSI) guideline EP5-A2; CLSI guideline EP9-A2; CLSI EP7-A; European Committee for Standardization (CEN) Standard 13640 "Stability Testing of In-Vitro Diagnostic Reagents."

# L. Test Principle:

ARCHITECT BNP Assay is a two-step immunoassay for the quantitative determination of human B-type natriuretic peptide (BNP) in human EDTA plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex®. In the first step, sample and anti-BNP coated paramagnetic microparticles are combined. BNP present in the sample binds to the anti-BNP coated microparticles. After washing, anti-BNP acridium-labeled conjugate is added to create a reaction mixture in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLU's). A direct relationship exists between the amount of BNO in the sample and the RLU's detected by the ARCHITECT I System optics.

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M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:
The study was conducted according to the Clinical and Laboratory Standards Institute (CLSI) Protocol EP5-A2. A three member panel was assayed in replicates of two at two separate times of the day for 20 days (n = 80 for each panel member). Testing was performed on two ARCHITECT Systems using a single calibration on each instrument. Within run CV(%) ranged from 0.9 to 5.6 %. Total CV(%) ranged from 1.7 to 6.7 %.

b. Linearity/assay reportable range:
Aliquots of 5 EDTA plasma pools were augmented by the addition of BNP antigen to concentrations within the assay dynamic range. These plasma samples were diluted with normal plasma (BNP concentration < 10 pg/mL) containing protease inhibitors. The undiluted and diluted samples were tested in replicates of two using the ARCHITECT BNP assay. The range of average recoveries for the samples assayed using the routine protocol for the ARCHITECT BNP assay was 91.1% to 112.2% for dilutions to 1:30. The range of average recoveries for the samples assayed using the STAT protocol for the ARCHITECT BNP assay was 91.2% to 96.9% for dilutions to 1:30.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):
The ARCHITECT BNP Calibrators are traceable to an internal reference standard that has been prepared gravimetrically with synthetic BNP. The internal reference standard underwent a one-time value assignment to align with the AxSYM BNP assay with a decision threshold of 100 pg/mL.

Stability studies were performed to evaluate the intended storage (open and closed vial) for the ARCHITECT BNP Calibrators and Controls. The data support a closed vial shelf life of 9 months for the calibrators and controls. A study was conducted to evaluate the open vial stability of the ARCHITECT BNP Calibrator Kits and ARCHITECT BNP Control Kits when all bottled components are manually opened and closed. The study was performed to support the package insert claim instructing the end user to tightly close the caps on the bottles after each use and return to 2-8°C storage. Three lots each of the ARCHITECT BNP Calibrator Kits and ARCHITECT BNP Control Kits were evaluated during this study. At time zero, all of the bottles set aside for this study were opened and closed and stored at 2-8°C continuously. One of the kit lots for each product (one lot of the ARCHITECT BNP Calibrator Kit and one lot of the ARCHITECT BNP Control Kit) was stored inverted. Each of the three lots of ARCHITECT BNP Calibrators and Controls were tested monthly following the Time Zero test point. This study supports a shelf life of 9 months and verifies the package insert instructions for the ARCHITECT BNP Calibrator Kits and ARCHITECT BNP Control Kits

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d. Detection limit:

A study was conducted to determine the lowest measurable BNP concentration that can be distinguished from zero for the ARCHITECT BNP assay. The acceptance criterion for the analytical sensitivity (Limit of Detection or LOD) for the ARCHITECT BNP assay is $< 10~\mathrm{pg / mL}$ . The Minimal Detectable Dose (MDD) of the ARCHITECT BNP assay was determined by testing ARCHITECT BNP Calibrator A $(0~\mathrm{pg / mL})$ in replicates of 10 followed by two replicates of ARCHITECT BNP Calibrator B (75 pg/mL), on each of three instruments (two instruments were run using the STAT assay protocol and one instrument was run using the Routine assay protocol), using two lots of reagents and two lots of calibrators $(n = 18$ runs). The mean values and the standard deviations of the 18 sets of A Calibrators and the mean values of the 18 sets of B Calibrators were used to determine the MDD for each run. Analytical sensitivity (Limit of Detection or LOD) is defined as the concentration at two standard deviations (SD) above the mean MDD, and represents the lowest measurable concentration of analyte that can be distinguished from zero. The Analytical Sensitivity (LOD) of the ARCHITECT BNP assay was calculated to be $3.8~\mathrm{pg / mL}$ , which meets the acceptance criteria, and supports the package insert claim for sensitivity of $10.0~\mathrm{pg / mL}$ .

e. Analytical specificity:

The ARCHITECT BNP assay was evaluated for analytical specificity in a study where cross-reactivity with human ANP, Angiotensin I, II, and III, CNP, and NT-proBNP was measured by the assay. Each potential cross reactant was added to protease-inhibitor treated plasma and then assayed.

| Cross-reactant | Cross-reactant Concentration % (pg/mL) | % Cross-reactivity |
| --- | --- | --- |
| ANP | 1000 | <10 |
| Angiotensin I | 600 | <10 |
| Angiotensin II | 600 | <10 |
| Angiotensin III | 1000 | <10 |
| CNP | 1000 | <10 |
| NT-proBNP (47-76) | 1000 | <10 |

The ARCHITECT BNP assay demonstrated an average interference $\leq 10\%$ (for each compound) in a study based upon guidance from CLSI Protocol EP7-A.

Specimens were supplemented with various drugs and potentially interfering compounds (bilirubin, hemoglobin, total protein, and triglycerides) at the levels indicated in the following table.

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| Drug | Drug Concentration | Drug | Drug Concentration |
| --- | --- | --- | --- |
| Acetaminophen | 30 μg/mL | Indomethacin | 36 μg/mL |
| Acetylsalicylic Acid | 600 μg/mL | Isosorbide Dinitrate | 150 ng/mL |
| Amiodarone | 6 μg/mL | Lisinopril | 4 μg/mL |
| Amlodipine besylate | 100 ng/mL | Lovastatin | 20 μg/mL |
| Ampicillin | 53 μg/mL | Methyldopa | 15 μg/mL |
| Ascorbic Acid | 40 μg/mL | Nicotine | 1 μg/mL |
| Atenolol | 10 μg/mL | Nifedipine | 400 ng/mL |
| Caffeine | 60 μg/mL | Nitrofurantoin | 4 μg/mL |
| Captopril | 5 μg/mL | Nitroglycerine | 500 ng/mL |
| Chloramphenicol | 50 μg/mL | Oxazepam | 5 μg/mL |
| Clopidogrel | 2.5 μg/mL | Oxytetracycline | 15 μg/mL |
| Bisulphate | | | |
| Cyclosporine | 2.5 μg/mL | Phenobarbitol | 100 μg/mL |
| Diclofenac | 50 μg/mL | Phenytoin | 50 μg/mL |
| Digoxin | 2 ng/mL | Probenecid | 600 μg/mL |
| Diltiazem | 40 μg/mL | Procainamide | 24 μg/mL |
| Dipyridamole | 80 μg/mL | Propranolol | 2 μg/mL |
| Dobutamine | 100 μg/mL | Quinidine | 12 μg/mL |
| Dopamine | 900 ng/mL | Simvastatin | 16 μg/mL |
| Enalapril Maleate | 300 ng/mL | Spironolactone | 600 ng/mL |
| Erythromycin | 60 μg/mL | Sulfamethoxazole | 400 μg/mL |
| Fenofibrate | 45 μg/mL | Trandolapril | 40 μg/mL |
| Furosemide | 60 μg/mL | Trimethoprim | 40 μg/mL |
| Heparin | 8 U/mL | Verapamil | 2 μg/mL |
| Hydralazine | 6.4 μg/mL | Warfarin | 20 μg/mL |
| Hydrochlorothiazide | 6 μg/mL | | |
| Interfering Substance | Interfering Substance Concentration |
| --- | --- |
| Triglycerides | 3000 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Bilirubin | 20 mg/dL |
| Total Protein | 3 g/L |
| Total Protein | 12 g/dL |

f. Assay cut-off:

BNP results less than or equal to 100 pg/mL are representative of normal values in patients without CHF. See Clinical Cut-off in 4. below.

2. Comparison studies:

a. Method comparison with predicate device:

A Passing Bablok regression analysis between the AxSYM BNP and the ARCHITECT BNP using 171 specimens with BNP values ranging from 0 to 3702 pg/mL, yielded a correlation coefficient of 0.96, a slope of 1.03 (95%

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Confidence Interval of 0.98 to 1.09) and a y-axis intercept of -38.32 (95% Confidence Interval of -48.26 to -28.50).

# b. Matrix comparison:

EDTA plasma is the only sample type indicated.

# 3. Clinical studies:

# a. Clinical Sensitivity:

The information from the clinical study performed with the AxSYM BNP Assay is provided in the labeling for the ARCHITECT I BNP Assay. A new clinical study was not performed since the capture and conjugate antibodies are the same. In studies performed with the AxSYM BNP Assay, age-matched analysis of the heart failure and non-heart failure populations was performed based on the data published by the American Heart Association in the 2000 Heart and Stroke Statistical Update and according to the age structure of the United States population. The age distributions in the intended use population are approximately as follows: individuals less than 45 years old comprise $9\%$ , individuals 45-54 years old comprise $11\%$ , individuals 55-64 years old comprise $22\%$ , individuals 65-74 years old comprise $26\%$ , and individuals 75 years and older comprise $32\%$ . The resulting combined AUC is 0.87 (0.85 to 0.90, $95\%$ CI). The clinical sensitivity and specificity using a decision threshold of $100~\mathrm{pg / mL}$ is presented in the table below.

| | Males (Age Group) | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | All | <45 Years | 45-54 Years | 55-64 Years | 65-74 Years | 75+ Years |
| Sensitivity | 71.0% | 47.1% | 57.1% | 57.3% | 70.6% | 86.1% |
| | (328/462) | (8/17) | (24/42) | (51/89) | (115/163) | (130/151) |
| 95% Confidence | 66.6 to | 23.0 to | 41.0 to | 46.4 to | 62.9 to | 79.5 to |
| Interval | 75.1% | 72.2% | 72.3% | 67.7% | 77.4% | 91.2% |
| Specificity | 94.8% | 97.2% | 100.0% | 97.9% | 88.7% | 89.5% |
| | (403/425) | (104/107) | (71/71) | (92/94) | (102/115) | (34/38) |
| 95% Confidence | 92.3 to | 92.0 to | 94.9 to | 92.5 to | 81.5 to | 75.2 to |
| Interval | 96.7% | 99.4% | 100.0% | 99.7% | 93.8% | 97.1% |

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| | Females (Age Group) | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | All | <45 Years | 45-54 Years | 55-64 Years | 65-74 Years | 75+ Years |
| Sensitivity | 80.5% | 44.4% | 73.3% | 50.0% | 80.6% | 91.7% |
| | (186/231) | (4/9) | (11/15) | (13/26) | (58/72) | (100/109) |
| 95% | 74.8 to | 13.7 to | 44.9 to | 29.9 to | 69.5 to | 84.9 to |
| Confidence Interval | 85.4% | 78.8% | 92.2% | 70.1% | 88.9% | 96.2% |
| Specificity | 88.4% | 95.9% | 90.7% | 89.6% | 85.7% | 80.5% |
| | (411/465) | (94/98) | (68/75) | (69/77) | (114/133) | (66/82) |
| 95% | 85.1 to | 89.9 to | 81.7 to | 80.6 to | 78.6 to | 70.3 to |
| Confidence Interval | 91.2% | 98.9% | 96.2% | 95.4% | 91.2% | 88.4% |

b. Clinical specificity:
See Clinical Sensitivity section in 3. a. above.

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

4. Clinical cut-off:
Data from the clinical studies performed with the AxSYM BNP assay were used to generate The Receiver Operating Characteristic (ROC) curve of BNP decision thresholds versus clinical sensitivity and clinical specificity. At a decision threshold of 100 pg/mL, the BNP assay demonstrated a clinical sensitivity and specificity of 74.2% and 91.5% respectively. The area under the curve is 0.90 (0.86 to 0.92, 95% CI).

5. Expected values/Reference range:
Plasma samples from 890 individuals (465 females, 425 males) who had not been diagnosed with heart failure were tested with the AxSYM BNP assay. This population included non-hospitalized patients with renal disease (not on dialysis), diabetes, hypertension and chronic obstructive pulmonary disease. BNP levels for these patients were not statistically different from the population of apparently healthy individuals. The data are summarized below.

Non-Heart Failure Population - All (Age Group)

| | All | <45 Years | 45-54 Years | 55-64 Years | 65-74 Years | 75+ Years |
| --- | --- | --- | --- | --- | --- | --- |
| Sample Size (N=) | 890 | 205 | 146 | 171 | 248 | 120 |
| Median (pg/mL) | 21 | 17 | 9 | 24 | 23 | 31 |
| Mean (pg/mL) | 39 | 28 | 21 | 37 | 47 | 63 |
| SD (pg/mL) | 66 | 36 | 30 | 48 | 80 | 109 |
| 95th Percentile | 135 | 85 | 87 | 119 | 160 | 254 |
| Percentage < 100 pg/mL | 91.5% | 96.6% | 95.2% | 94.2% | 87.1% | 83.3% |
| Minimum (pg/mL) | 0 | 0 | 0 | 0 | 0 | 0 |
| Maximum (pg/mL) | 907 | 263 | 142 | 380 | 907 | 837 |

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Non-Heart Failure Population - Males (Age Group)

| | All | <45 Years | 45-54 Years | 55-64 Years | 65-74 Years | 75+ Years |
| --- | --- | --- | --- | --- | --- | --- |
| Sample Size (N=) | 425 | 107 | 71 | 94 | 115 | 38 |
| Median (pg/mL) | 14 | 12 | 1 | 17 | 21 | 37 |
| Mean (pg/mL) | 30 | 23 | 9 | 26 | 47 | 49 |
| SD (pg/mL) | 61 | 34 | 14 | 45 | 96 | 51 |
| 95th Percentile | 104 | 73 | 40 | 80 | 150 | 121 |
| Percentage < 100 pg/mL | 94.8% | 97.2% | 100.0% | 97.9% | 88.7% | 89.5% |
| Minimum (pg/mL) | 0 | 0 | 0 | 0 | 0 | 0 |
| Maximum (pg/mL) | 907 | 200 | 57 | 380 | 907 | 254 |

Non-Heart Failure Population - Males (Age Group)

| | All | <45 Years | 45-54 Years | 55-64 Years | 65-74 Years | 75+ Years |
| --- | --- | --- | --- | --- | --- | --- |
| Sample Size (N=) | 465 | 98 | 75 | 77 | 133 | 82 |
| Median (pg/mL) | 26 | 23 | 23 | 37 | 23 | 25 |
| Mean (pg/mL) | 46 | 34 | 34 | 51 | 46 | 69 |
| SD (pg/mL) | 70 | 37 | 36 | 48 | 63 | 126 |
| 95th Percentile | 150 | 89 | 111 | 155 | 159 | 266 |
| Percentage < 100 pg/mL | 88.4% | 95.9% | 90.7% | 89.6% | 85.7% | 80.5% |
| Minimum (pg/mL) | 0 | 0 | 0 | 0 | 0 | 0 |
| Maximum (pg/mL) | 837 | 263 | 142 | 230 | 374 | 837 |

Plasma samples from 693 patients with diagnosed heart failure (231 females, 462 males) were tested with the AxSYM BNP assay. All patients in this population were categorized according to the functional classification system published by the New York Heart Association (NYHA). This system divides heart failure patients into one of four categories of increasing disease progression (classes I to IV) based upon a subjective assessment of the patient's clinical signs and symptoms. The data from this study are summarized below.

Heart Failure Population - All

| | NYHA Functional Class | | | | |
| --- | --- | --- | --- | --- | --- |
| | All | I | II | III | IV |
| Sample Size (N=) | 693 | 124 | 319 | 190 | 60 |
| Median (pg/mL) | 298 | 133 | 266 | 335 | 1531 |
| Mean (pg/mL) | 578 | 320 | 432 | 656 | 1635 |
| SD (pg/mL) | 771 | 388 | 574 | 841 | 1097 |
| 5thPercentile | 14 | 9 | 15 | 12 | 188 |
| 95th Percentile | 2154 | 1257 | 1534 | 2516 | >4000 |
| Percentage ≥ 100 pg/mL | 74.2% | 58.1% | 73.0% | 79.0% | 98.3% |
| Minimum (pg/mL) | 0 | 3 | 0 | 0 | 14 |
| Maximum (pg/mL) | >4000 | 1651 | >4000 | >4000 | >4000 |

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Heart Failure Population - Males

| | NYHA Functional Class | | | | |
| --- | --- | --- | --- | --- | --- |
| | All | I | II | III | IV |
| Sample Size (N=) | 462 | 94 | 215 | 121 | 32 |
| Median (pg/mL) | 268 | 122 | 258 | 293 | 1645 |
| Mean (pg/mL) | 524 | 314 | 409 | 597 | 1646 |
| SD (pg/mL) | 719 | 390 | 539 | 821 | 1032 |
| 5^{th} Percentile | 12 | 9 | 14 | 22 | 265 |
| 95th Percentile | 1976 | 1281 | 1356 | 2288 | 3654 |
| Percentage ≥ 100 pg/mL | 71.0% | 56.4% | 70.7% | 76.0% | 96.9% |
| Minimum (pg/mL) | 0 | 3 | 0 | 0 | 14 |
| Maximum (pg/mL) | >4000 | 1408 | 3782 | >4000 | >4000 |

Heart Failure Population - Females

| | NYHA Functional Class | | | | |
| --- | --- | --- | --- | --- | --- |
| | All | I | II | III | IV |
| Sample Size (N=) | 231 | 30 | 104 | 69 | 28 |
| Median (pg/mL) | 385 | 174 | 298 | 466 | 1408 |
| Mean (pg/mL) | 685 | 341 | 481 | 760 | 1623 |
| SD (pg/mL) | 858 | 388 | 641 | 870 | 1186 |
| 5th Percentile | 16 | 14 | 21 | 12 | 244 |
| 95^{th} Percentile | 2593 | 1022 | 2031 | 2718 | >4000 |
| Percentage ≥ 100 pg/mL | 80.5% | 63.3% | 77.9% | 84.1% | 100.0% |
| Minimum (pg/mL) | 0 | 10 | 0 | 0 | 173 |
| Maximum (pg/mL) | >4000 | 1651 | >4000 | >4000 | >4000 |

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.