Access NT-proBNP

K232164 · Beckman Coulter, Inc. · NBC · Apr 12, 2024 · Clinical Chemistry

Device Facts

• Record ID: K232164
• Device Name: Access NT-proBNP
• Applicant: Beckman Coulter, Inc.
• Product Code: NBC · Clinical Chemistry
• Decision Date: Apr 12, 2024
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Intended Use

The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl Access Immunoassay Analyzers to aid in the following: 1. diagnosis of patients suspected of having acute heart failure in the Emergency Department 2. assessment of heart failure severity 3. risk stratification of patients with heart failure 4. risk stratification of patients with acute coronary syndrome

Device Story

Access NT-proBNP is a two-site sandwich chemiluminescent immunoassay for quantitative measurement of NT-proBNP in human serum/plasma. It uses paramagnetic particles coated with monoclonal anti-NT-proBNP antibodies and an alkaline phosphatase-conjugated monoclonal anti-NT-proBNP antibody. The device operates on automated Dxl Access Immunoassay Analyzers in clinical laboratory settings. During analysis, the analyte binds to the solid-phase antibody and the conjugate; after magnetic separation and washing, a chemiluminescent substrate is added. Light output, measured by a luminometer, is directly proportional to analyte concentration. Results are used by clinicians to aid in diagnosing acute heart failure, assessing disease severity, and performing risk stratification for heart failure and acute coronary syndrome. The device provides objective data to support clinical decision-making, potentially improving patient management and outcomes.

Clinical Evidence

Prospective multicenter study of 2,384 patients presenting to the ED with suspected acute heart failure. Adjudicated diagnosis by independent committee. AUC for rule-out was 0.8692 (95% CI: 0.8549-0.8835). Rule-in AUCs: <50 years (0.8919), 50-75 years (0.8802), >75 years (0.8122). Comparison to predicate showed comparable diagnostic accuracy (Access AUC 0.8536 vs. Elecsys AUC 0.8562). Significant trend relationship (p<0.0001) between NT-proBNP values and NYHA functional classification.

Technological Characteristics

Paramagnetic particle, chemiluminescent sandwich immunoassay. Materials: monoclonal anti-NT-proBNP antibodies, alkaline phosphatase conjugate, chemiluminescent substrate. Form factor: reagent packs for automated Dxl Access Immunoassay Analyzers. Connectivity: standalone analyzer system. Standards: CLSI EP05-A3 (precision), EP06-ED2 (linearity), EP17-A2 (detection capability), EP07-A3 (interference).

Indications for Use

Indicated for patients 22 years and older presenting with signs and symptoms of acute heart failure in the Emergency Department. Excludes patients with stage 4 or 5 chronic kidney disease, chronic dialysis, or dyspnea not secondary to heart failure.

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

• Elecsys®proBNP II Immunoassay (K072437)

Submission Summary (Full Text)

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

April 12, 2024

Beckman Coulter Inc. Kate Oelberg Senior Staff Quality and Regulatory Affairs 1000 Lake Hazeltine Drive Chaska, Minnesota 55331

Re: K232164

Trade/Device Name: Access NT-proBNP Regulation Number: 21 CFR 862.1117 Regulation Name: B-Type Natriuretic Peptide Test System Regulatory Class: Class II Product Code: NBC Dated: March 15, 2024 Received: March 15, 2024

Dear Kate Oelberg:

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 (the 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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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.

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

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2

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

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 Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

Paula V. Caposino -S

Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

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## Indications for Use

510(k) Number (if known) K232164

Device Name Access NT-proBNP

| <b>Indications for Use (<i>Describe</i>)</b> |
|----------------------------------------------|
|----------------------------------------------|

The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated DxI Access Immunoassay Analyzers to aid in the following:

- 1. diagnosis of patients suspected of having acute heart failure in the Emergency Department
- 2. assessment of heart failure severity
- 3. risk stratification of patients with heart failure
- 4. risk stratification of patients with acute coronary syndrome

| Type of Use (Select one or both, as applicable) | |
|-------------------------------------------------|--|
|-------------------------------------------------|--|

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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Image /page/3/Picture/0 description: The image shows the logo for Beckman Coulter. On the left is a red oval with two white curved lines inside. To the right of the oval is the company name, "BECKMAN COULTER", in black, with "BECKMAN" on the top line and "COULTER" on the bottom line.

### 510(k) Summary

# This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

510(k) Number: K232164

Date Prepared: April 12, 2024

Staff Regulatory Affairs Specialist

Email: [e-mail]

Alternate Contact:

Phone: [phone]

Rachel Clark

### Submitter Name and Address:

Beckman Coulter, Inc 1000 Lake Hazeltine Drive Chaska, MN 55318

### Primary Contact:

Kate Oelberg Senior Staff Quality and Regulatory Affairs Phone: [phone] Email: [e-mail]

Trade Device Name: Access NT-proBNP Common Name: Access NT-proBNP Classification name: B-Type natriuretic peptide test system Classification Regulation: 21 CFR 862.1117 Classification Product Code: NBC

Predicate Device: Elecsys® proBNP II - k072437

Reference Device: VITROS® NT-proBNP II – k201312

#### Device Description

The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl 9000 Access Immunoassay Analyzers to aid in the following: 1) diagnosis of patients suspected of acute heart failure in the Emergency Department, 2) assessment of heart failure severity, 3) risk stratification of patients with heart failure, 4) risk stratification of patients with acute coronary syndrome.

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The Access NT-proBNP is a two-site immunoenzymatic (sandwich) assay. Paramagnetic particles coated with monoclonal anti-NT-proBNP antibody and monoclonal anti-NTproBNP antibody conjugated to alkaline phosphatase are added to a reaction vessel along with a surfactant-containing buffer and serum or plasma sample. The human NTproBNP binds to the anti-NT-proBNP antibody on the solid phase, while the anti-NTproBNP antibody-alkaline phosphatase conjugate reacts with a different antigenic site on the NT-proBNP molecule. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.

Other items required to use the assay include calibrators, Lumi-Phos PRO, and wash buffer. The Access NT-proBNP reagent packs. Access NT-proBNP calibrators, along with the Access wash buffer, and Lumi-Phos PRO are designed for use on the Dxl 9000 Access Immunoassay Analyzers in a clinical laboratory setting.

#### Intended use

The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl Access Immunoassay Analyzers to aid in the following:

- 1. diagnosis of patients suspected of having acute heart failure in the Emergency Department
- 2. assessment of heart failure severity
- 3. risk stratification of patients with heart failure
- 4. risk stratification of patients with acute coronary syndrome

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Image /page/5/Picture/0 description: The image shows the logo for Beckman Coulter. The logo consists of a red circle with two white curved lines inside, resembling a stylized wave or flow. To the right of the circle, the words "BECKMAN" and "COULTER" are stacked on top of each other in a bold, sans-serif font. The overall design is clean and modern.

### Table 1: Device Comparison

| Device<br>Characteristics | New Device<br>Access NT-proBNP | Predicate Device<br>Elecsys® NT-pro BNP II<br>k072437 | Reference Device<br>VITROS® NT-proBNP II<br>k201312 | Comment |
|------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use /<br>Indications for<br>Use | Rx ONLY<br>For in vitro diagnostic use only.<br>The Access NT-proBNP assay is<br>a paramagnetic particle,<br>chemiluminescent immunoassay<br>for the quantitative determination<br>of N-terminal pro B-type<br>natriuretic peptide levels in<br>human serum and plasma using<br>the automated Dxl Access<br>Immunoassay Analyzers to aid in<br>the following:<br>1. diagnosis of patients<br>suspected of having acute heart<br>failure in the Emergency<br>Department<br>2. assessment of heart failure<br>severity<br>3. risk stratification of patients<br>with heart failure<br>4. risk stratification of patients<br>with acute coronary syndrome | Rx ONLY<br>For in vitro diagnostic use only.<br>For the quantitative determination<br>of N terminal pro-Brain natriuretic<br>peptide in human serum and<br>plasma. Elecsys® proBNP II<br>assay is used as an aid in the<br>diagnosis of individuals<br>suspected of having congestive<br>heart failure. The test is further<br>indicated for the risk stratification<br>of patients with acute coronary<br>syndrome and congestive heart<br>failure. The test may also serve<br>as an aid in the assessment of<br>increased risk of cardiovascular<br>events and mortality in patients at<br>risk for heart failure who have<br>stable coronary artery disease.<br>The electrochemiluminescence<br>immunoassay "ECLIA" is<br>intended for use on Elecsys and<br>cobas e immunoassay analyzers. | Rx ONLY<br>For in vitro diagnostic use<br>only.<br>For the quantitative<br>measurement of N-terminal<br>pro Brain Natriuretic Peptide<br>(NT-proBNP) in human<br>serum and plasma (K₂<br>EDTA or Lithium Heparin)<br>using VITROS 3600<br>Immunodiagnostic System to<br>aid in the diagnosis of heart<br>failure. The test can also be<br>used in the assessment of<br>heart failure severity in<br>patients diagnosed with<br>heart failure. | Similar |
| Analyte<br>Measured | NT-proBNP | NT-proBNP | NT-proBNP | Same |
| Antibody | Monoclonal anti-NT-proBNP | Monoclonal anti-NT-proBNP | Monoclonal anti-NT-proBNP | Same |
| Device<br>Characteristics | New Device<br>Access NT-proBNP | Predicate Device<br>Elecsys® NT-pro BNP II<br>k072437 | Reference Device<br>VITROS® NT-proBNP II<br>k201312 | Comment |
| Sample Type | Human Serum and Plasma<br>(Lithium Heparin and EDTA) | Human Serum and Plasma | Human Serum and Plasma | Same |
| Method | The Access NT-proBNP assay is<br>used in association with the<br>automated Dxl Access<br>Immunoassay Analyzer | Elecsys and cobas e<br>immunoassay analyzers | VITROS 3600<br>Immunodiagnostic System | Different |
| Format | Chemiluminescent | Electrochemiluminescent | Immunometric | Different |
| Assay Principle | Sandwich | Sandwich | Sandwich | Same |
| Measuring Range | 10.0 ng/L - 35,000 ng/L (pg/mL) | 5 - 35,000 pg/mL | 20.0 -30,000 pg/mL | Similar |
| Traceability | The Access NT-proBNP<br>Calibrator is traceable to<br>manufacturer's working<br>calibrators. Traceability process<br>is based on EN ISO 17511 | Standardized against the Elecsys<br>NT-proBNP assay | Standardized against the<br>Elecsys NT-proBNP II assay | There is no<br>internationally<br>recognized<br>standard for NT-<br>proBNP specific<br>antibody. The<br>Elecsys proBNP<br>assay reference<br>materials are<br>proprietary to<br>Roche<br>Diagnostics. |
| High Dose Hook<br>Effect | No high dose hook effect<br>observed up to 400,000 ng/L<br>(pg/mL) | Hook effect studies demonstrated<br>no effect up to 300,000 pg/mL | no high dose hook effect up<br>to a concentration of<br>300,000 pg/mL | Similar |

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| Device<br>Characteristics | New Device<br>Access NT-proBNP | Predicate Device<br>Elecsys® NT-pro BNP II<br>k072437 | Reference Device<br>VITROS® NT-proBNP II<br>k201312 | Comment | | | | | | | | | | | | | | | | | | |
|----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|-----------------------------------------------------|------------------------------------------------------------------------------------------------------------|--|--|--|------------------------------------------------------------------------------------------------------------------------------------------------------------|--|--|--|--|--|--|-------------------------------------------------------------------------------------------------------------------------------------|--|--|--|--|--|--|---------|
| Reagent Storage<br>and Stability | Access NT-proBNP<br>Reagent Stability Unopened at<br>2 -10°C Up to stated Expiration Date After Opening<br>at 2-10°C 61 days On analyzer 61 days | | | | | | | Elecsys NT-proBNP II<br>Reagent Stability Unopened at 2<br>-8°C Up to stated Expiration Date After Opening<br>at 2-8°C 12 weeks On analyzers 8 weeks | | | | | | | VITROS NT-proBNP II<br>Reagent Stability Unopened 2-<br>8°C Expiration Date Open on<br>system ≤ 8 weeks Opened 2-8°C ≤8 weeks | | | | | | | Similar |
| | See Table A. below | 125 pg/mL for patients, 75 years;<br>450 pg/mL for patients ≥ 75 years | See Table B. below | Same for Access<br>NT-proBNP and<br>VITROS® NT-<br>proBNP II<br>Different from<br>Elecsys NT-<br>proBNP II | | | | | | | | | | | | | | | | | | |

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| Table A. Access NT-proBNP |
|---------------------------|
|---------------------------|

| Expected Values | All Subjects ng/L (pg/mL) | | | |
|-----------------------------|---------------------------|----------|----------|----------|
| Age (years) | <50 | 50 - 75 | >75 | All ages |
| N | 267 | 256 | 152 | 675 |
| Mean | 48 | 94 | 158 | 90 |
| SD | 43 | 79 | 103 | 85 |
| Median | 37 | 69 | 129 | 64 |
| IQR: 25th - 75th percentile | 19 - 65 | 36 - 125 | 85 - 190 | 30 - 121 |
| 95th percentile ULN | 118 | 273 | 413 | 252 |
| 97.5th percentile ULN | 162 | 311 | 457 | 358 |
| % <125 ng/L (pg/mL) | 95.1% | 75.0% | 44.1% | 76.0% |

## Table B. VITROS® NT-proBNP II

| VITROS Expected Values | | | | | |
|------------------------|--------|-----|---------------------------|---------------------------|--|
| Age | Gender | N | RI Lower Limit<br>(pg/mL) | RI Upper Limit<br>(pg/mL) | |
| 22-<50 | Female | 129 | <20.0 | 95.3 | |
| 50-<75 | Female | 127 | <20.0 | 221 | |
| ≥75 | Female | 129 | <20.0 | 296 | |
| 22-<50 | Male | 131 | <20.0 | 125 | |
| 50-<75 | Male | 120 | <20.0 | 299 | |
| ≥75 | Male | 123 | <20.0 | 326 | |
| Overall | | 756 | <20.0 | 217 | |

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### Standard /Guidance Document Referenced

CLSI EP05-A3: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline – Third Edition CLSI EP06-201 Edition : Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approved Guideline

CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – 2ª Edition CLSI EP07 3rd Edition - Interference Testing in Clinical Chemistry Approved Guideline

### Summary of Non-Clinical Studies

### Imprecision

The assay was designed to have within-laboratory imprecision as listed below:

- ≤ 4.0 ng/L (pg/mL) SD at concentrations ≤ 50 ng/L (pg/mL) .
- ≤ 8.0% CV at concentrations > 50 ng/L (pg/mL) .

A study based on CLSI EP05-A3 performed on the Dxl 9000 Access Immunoassay Analyzer tested multiple samples in duplicate in 2 runs per day for a minimum of 20 days.

| | | Mean | Repeatability<br>(Within Run) | | Between Run | | Between Day | | Within Laboratory<br>precision | |
|----------|----|--------|-------------------------------|-----|--------------|-----|--------------|-----|--------------------------------|-----|
| Sample | N | (ng/L) | SD<br>(ng/L) | %CV | SD<br>(ng/L) | %CV | SD<br>(ng/L) | %CV | SD<br>(ng/L) | %CV |
| Sample 1 | 86 | 31 | 0.7 | 2.3 | 0.5 | 1.5 | 0.7 | 2.2 | 1.1 | 3.5 |
| Sample 2 | 84 | 129 | 2.9 | 2.2 | 7.2 | 5.6 | 0.0 | 0.0 | 7.8 | 6.0 |
| Sample 3 | 83 | 266 | 5.3 | 2.0 | 15.8 | 5.9 | 0.0 | 0.0 | 16.7 | 6.3 |
| Sample 4 | 84 | 377 | 7.7 | 2.0 | 25.3 | 6.7 | 0.0 | 0.0 | 26.4 | 7.0 |
| Sample 5 | 85 | 1,777 | 45.1 | 2.5 | 63.2 | 3.6 | 44.5 | 2.5 | 89.5 | 5.0 |
| Sample 6 | 86 | 12,076 | 225.5 | 1.9 | 638.0 | 5.3 | 0.0 | 0.0 | 676.7 | 5.6 |
| Sample 7 | 86 | 26,126 | 534.1 | 2.0 | 1,418.9 | 5.4 | 1.5 | 0.0 | 1516.1 | 5.8 |

### Table 2: Access NT-proBNP Imprecision, Dxl 9000

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### High Dose Hook Effect

The study was performed using samples containing increasing concentrations of NT-pro antigen in a range greater than > 400,000 ng/L exceeding the dose of the S6 Calibrator. Access NT-proBNP assay has no high dose hook effect observed up to 400,000 ng/L.

### Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ)

Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) studies were conducted on the Dxl 9000 Access Immunoassay Analyzer following CLSI EP17-A2,Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition. The LoB study included multiple reagent lots and 3 instruments for 3 days. The LoD and LoQ studies included multiple reagent lots and 3 instruments up to 5 days.

### Table 4: Access NT-proBNP LoB, LoD and LoQ

| | Maximum Observed Result | Design Criteria |
|----------------------------------------------------|-------------------------|-----------------|
| | ng/L (pg/mL) | ng/L (pg/mL) |
| Limit of Blank (LoB) | 1.1 | <10.0 |
| Limit of Detection (LoD) | 4.8 | ≤10.0 |
| Limit of Quantitation (LoQ)<br>≤ 20% within-lab CV | 4.8 | ≤10.0 |

### Linearity

A full range and a low range study was performed following a protocol based on CLSI quideline EP06-ED2. Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approved Guideline. All native patient samples from each sample type were run on Dxl 9000 Access Immunoassay analyzer. The results demonstrate the Access NT-

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proBNP assay is within ± 10% for values > 50 ng/L and is within ± 5.0 ng/L for values ≤ 50 ng/L. The assay demonstrates acceptable non-linearity across the analytical measuring range (10.0 -35,000 ng/L).

#### Matrix Comparison

Lithium heparin plasma and serum are preferred sample types. EDTA plasma is also an acceptable sample type. A sample type comparison study was performed on the Access NT-proBNP assay. The study included sixty-eight (68) matched serum, lithium heparin and EDTA plasma samples spanning range that were analyzed in replicates of three (3). The results of the study demonstrate all sample types are suitable for use on the Access NTproBNP assay.

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### Interfering Substances

Lithium heparin plasma samples that contained NT-proBNP concentrations of approximately 125 and 1,800 ng/L (pg/mL) were spiked with the substances listed in Table 5. The spiked samples were run on the Dxl 9000 Access Immunoassay Analyzer. The values were calculated based upon CLSI EP07-A3 guidelines. The interference was determined by testing controls (with no interfering substance added) and matched test samples (with interfering substance added). None of the compounds tested were found to cause significant interference (as defined by a shift in dose > 10%) using the test concentrations provided in the following table.

| Substance | Concentration | Substance | Concentration |
|---------------------------------|---------------|-----------------------------|---------------|
| (+)-cis-Diltiazem hydrochloride | 120 ug/mL | Hydralazine | 20 µg/mL |
| Acetaminophen | 1456 umol/L | Hydrochlorothiazide | 20 µg/mL |
| Alkaline Phosphatase | 2000 U/L | Ibuprofen | 2425 umol/L |
| Allopurinol | 240 ug/mL | Indomethacin | 36 µg/mL |
| Amiodarone | 4.2 mg/dL | Intralipid | 1600 mg/dL |
| Amlodipine besylate | 4 ug/mL | Isosorbide dinitrate | 0.593 mg/dL |
| Ampicillin | 200 ug/mL | L-Ascorbic Acid | 376 umol/L |
| Ascorbic acid | 20 mg/dL | Levothyroxine | 0.042 mg/dL |
| Atenolol | 40 ug/mL | Lidocaine | 1.5 mg/dL |
| Atorvastatin calcium trihydrate | 32 ug/mL | Lisinopril x 2H2O | 16 µg/mL |
| Bilirubin, conjugated | 19 mg/dL | Losartan potassium | 130 µmol/L |
| Bilirubin, unconjugated | 15 mg/dL | Lovastatin | 0.021 mg/dL |
| Biotin | 30,000 ng/mL | Methyldopa<br>sesquihydrate | 100 ug/mL |
| Caffeine | 10.8 mg/dL | Metoprolol hemitartrate | 18.7 umol/L |
| Captopril | 40 ug/mL | Naproxen sodium | 2170 umol/L |
| Carvedilol | 74 umol/L | Nicotine | 1.6 µg/mL |
| Chloramphenicol | 7.8 mg/dL | Nicotinic acid | 40 µg/mL |
| Cholesterol | 400 mg/dL | Nifedipine | 36 ug/mL |
| Clopidogrel hydrogen sulfate | 30 ug/mL | Nitrofurantoin | 40 µg/mL |
| Creatinine | 15 mg/dL | Oxazepam | 12 µg/mL |

#### Table 5: Interfering Substances

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### Table 5: Interfering Substances

| Substance | Concentration | Substance | Concentration |
|---------------------------------------|---------------|----------------------------|---------------|
| Cyclosporine | 40 ug/mL | Oxytetracycline | 100 µg/mL |
| Diclofenac sodium salt | 60 ug/mL | Phenobarbital | 69 mg/dL |
| Digitoxin | 60 ug/mL | Phenytoin | 6.00 mg/dL |
| Digoxin | 0.0039 mg/dL | Probenecid | 600 µg/mL |
| Disopyramide | 1.68 mg/dL | Procainamide | 4.80 mg/dL |
| Dobutamine | 100 µg/mL | Propranolol | 64 µg/mL |
| Dopamine hydrochloride | 116 µg/mL | Quinidine | 20 µg/mL |
| Dipyridamole | 30 ug/mL | Ramipril | 14.4 µmol/L |
| Enalaprilat dihydrate | 16 ug/mL | Rheumatoid Factor | 500 IU/mL |
| Erythromycin | 13.8 mg/dL | Salicylic acid | 200 ug/mL |
| Fenofibrate | 45 µg/mL | Simvastatin | 32 µg/mL |
| Fibrinogen | 1000 mg/dL | Spironolactone | 600 mg/dL |
| Furosemide | 199 µmol/L | Sulfamethoxazole | 1.7 µmol/L |
| Hemoglobin | 1000 mg/dL | Theophylline | 6 mg/dL |
| Heparin | 330 units/dL | Trasylol/Aprotinin | 100 KIE/mL |
| Human anti-Mouse Antibodies<br>(HAMA) | 800 µg/L | Trimethoprim | 64 µg/mL |
| Human gamma-globulin | 30 g/L | Verapamil<br>hydrochloride | 96 ug/mL |
| Human Serum Albumin | 60 g/L | Warfarin | 7.5 mg/dL |

{14}------------------------------------------------

#### Cross Reactivity

A study evaluated the potential for cross-reactivity of substances that are similar in structure to NT-proBNP. Lithium heparin samples that contain NT-proBNP concentrations of 125 ng/L (pg/mL) and 1,800 ng/L (pg/mL) were spiked with concentrations of the substances listed in Table 6. The spiked samples were run on the Dxl 9000 Access Immunoassay Analyzer. The values were calculated based upon CLSI EP07-A3 guidelines. No significant cross-reactivity (>10%) was observed when the listed substances were tested at the indicated concentrations.

| Substance | High<br>Concentration | Substance | High<br>Concentration |
|-----------------|-----------------------|--------------------------------------|-----------------------|
| Adrenomedullin | 1.0 ng/mL | CNP22 | 2.2 ug/mL |
| Aldosterone | 0.6 ng/mL | Endothelin I | 2000 pg/mL |
| Angiotensin I | 0.6 ng/mL | NT-proANP1-30<br>(preproANP26-55) | 3.5 ug/mL |
| Angiotensin II | 0.6 ng/mL | NT-proANP31-67<br>(preproANP56-92) | 1.0 ng/mL |
| Angiotensin III | 1.0 ng/mL | NT-proANP79-98<br>(preproANP104-123) | 1.0 ng/mL |
| ANP28 | 3.1 ug/mL | Renin | 50 ng/mL |
| Arg-Vasopressin | 1.0 ng/mL | Urodilatin | 3.5 ug/mL |
| BNP32 | 3.5 ug/mL | | |

#### Table 6: Access NT-proBNP Cross Reactivity

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### Expected Values

Each laboratory should validate or establish its own reference intervals to assure proper representation of specific populations.

A multicenter prospective reference interval study was conducted to establish the upper limit of normal (ULN) for Access NT-proBNP in a population of apparently healthy adults. A total of 306 males were included with 39.6% < 50, 37.9% from 50 to 75, and 22.5% > 75 years of age.

Subjects were surveyed and were excluded if they met any of the following criteria:

- · Disease(s) of/or affecting the cardiovascular system
- Poorly controlled hypertension (defined as current blood pressure ≥ 140 mm Hg systolic, or ≥ 85 mm Hg diastolic)
- · Currently taking medication for cardiovascular disease (except medications to control hypertension)
- Body-mass index (BMI) ≥ 30 kg/m2
- Diabetes
- Chronic kidney disease.
- · Other serious chronic disease(s) (e.g. cancer, COPD, HIV, lupus erythematosus, etc.)
- Acute bacterial or viral infection

Additional surrogate biomarkers were screened, and subjects were also excluded based on abnormal estimated glomerular filtration rate (eGFR) and high-sensitivity cardiac troponin (hsTnl). Descriptive statistics for NT-proBNP concentrations are shown in Table 9.

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| | All Subjects ng/L (pg/mL) | | | |
|-----------------------------|---------------------------|----------------------|----------|----------|
| Age (years) | <50 | 50 - 75 | >75 | All ages |
| N | 267 | 256 | 152 | 675 |
| Mean | 48 | 94 | 158 | 90 |
| SD | 43 | 79 | 103 | 85 |
| Median | 37 | 69 | 129 | 64 |
| IQR: 25th - 75th percentile | 19 - 65 | 36 - 125 | 85 - 190 | 30 - 121 |
| 95th percentile ULN | 118 | 273 | 413 | 252 |
| 97.5th percentile ULN | 162 | 311 | 457 | 358 |
| % <125 ng/L (pg/mL) | 95.1% | 75.0% | 44.1% | 76.0% |
| | | Males ng/L (pg/mL) | | |
| Age (years) | <50 | 50 - 75 | >75 | All ages |
| N | 132 | 111 | 63 | 306 |
| Mean | 33 | 68 | 130 | 66 |
| SD | 38 | 71 | 82 | 72 |
| Median | 23 | 48 | 115 | 41 |
| IQR: 25th - 75th percentile | 13 - 39 | 28 - 77 | 77 - 148 | 20 - 84 |
| 95th percentile ULN | 84 | 188 | 243 | 188 |
| 97.5th percentile ULN | 103 | 284 | 434 | 267 |
| % <125 ng/L (pg/mL) | 99.2% | 87.4% | 58.7% | 86.6% |
| | | Females ng/L (pg/mL) | | |
| Age (years) | <50 | 50 - 75 | >75 | All ages |
| N | 135 | 145 | 89 | 369 |
| Mean | 63 | 114 | 178 | 111 |
| SD | 42 | 80 | 111 | 89 |
| Median | 54 | 91 | 154 | 82 |
| IQR: 25th - 75th percentile | 32 - 80 | 54 - 155 | 93 - 216 | 49 - 149 |
| 95th percentile ULN | 152 | 282 | 443 | 294 |
| 97.5th percentile ULN | 178 | 317 | 457 | 370 |
| % <125 ng/L (pg/mL) | 91.1% | 65.5% | 33.7% | 67.2% |

## Table 7: Access NT-proBNP Healthy population ULN and descriptive statistics

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### Clinical Performance Evaluation

### Clinical Sensitivity

The Access NT-proBNP assay is not intended to be used in isolation; results should be interpreted in conjunction with other diagnostic tests and clinical information.

A multicenter prospective study was conducted to validate clinical performance of the established diagnostic cutoffs and evaluate the clinical utility of the Access NT-proBNP assay on the Dxl 9000 Immunoassay Analyzer as an aid in the diagnosis of adults aged 21 and older presenting to the Emergency Department with a clinical suspicion of acute heart failure. NT-proBNP concentrations were determined in samples from 2,384 patients presenting to the Emergency Department with clinical suspicion of acute heart failure (AHF). Final diagnoses were adjudicated by an independent committee of medical doctors who decided on presence of acute heart failure. Adjudicators were blinded to the Access NT-proBNP assay results. The AHF incidence was 44.4% (1059/2384) consisting of 48.2% Females (1149/2384) and 51.8% (1235/2384) Males, 57.8% White or Caucasian (1377/2384), 35.7% Black or African American (850/2384), and 6.5% Asian (155/2384). Two subjects did not have their races reported.

Descriptive statistics were determined by age group for the enrolled population and are presented below.

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| | Adjudicated Acute Heart Failure (positive) | Adjudicated Acute Heart Failure (negative) | | | | | | |
|-----------------------------|--------------------------------------------|--------------------------------------------|-----------|-----------|----------|--------|---------|----------|
| Age (years) | All ages | <50 | 50 - 75 | >75 | All ages | <50 | 50 - 75 | >75 |
| N | 1044 | 308 | 440 | 296 | 1324 | 569 | 469 | 286 |
| Mean | 5377 | 4119 | 5659 | 6266 | 1077 | 716 | 1009 | 1905 |
| SD | 5511 | 4868 | 5442 | 6008 | 2358 | 2226 | 2282 | 2537 |
| Median | 3,776 | 2,466 | 4,111 | 4,291 | 218 | 106 | 204 | 926 |
| IQR: 25th - 75th percentile | 1406-7483 | 959-5745 | 1539-8222 | 2077-8394 | 63-904 | 39-347 | 72-670 | 335-2325 |
| Min | <10 | < 10 | 33 | 188 | < 10 | < 10 | < 10 | 16 |
| Max | 34,973 | 34,973 | 33,611 | 33,866 | 23,996 | 23,996 | 23,968 | 16,253 |

Table 8: Descriptive statistics for Access NT-proBNP concentrations (nglL [pg/mL]) in patients Adjudicated as (AHF-)

Note: A lesser N is observed in this table compared to the clinical performance data tables since only results based on measured responses within the assay analytical measuring range are used to generate descriptive statistics tables.

Table 9: Access NT-proBNP Test positive counts in relation to the adjudicated diagnosis of acute heart failure within each age group and by age group.

| Age (Years) | Access NT-proBNP<br>Test Result | Adjudicated Diagnosis | | Total |
|-------------|---------------------------------|-----------------------|--------|-------|
| | | HF | Non-HF | |
| < 50 | Positive | 279 | 127 | 406 |
| | Grey Zone | 12 | 25 | 37 |
| | Negative | 19 | 417 | 436 |
| | Total | 310 | 569 | 879 |

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| Age (Years) | Access NT-proBNP<br>Test Result | Adjudicated Diagnosis | | Total | ALL Subjects<br>Age, Prevalence, Test Result | | Posttest Probability<br>of HF | | Posttest Probability of Non-HF | | Likelihood Ratio and Cl | | |
|-------------|---------------------------------|-----------------------|--------|-------|----------------------------------------------|-------------------------------------------------------------------|-------------------------------------------------------|---------------------|--------------------------------|--------------------|-------------------------|--------------------------------------|--------------|
| | | HF | Non-HF | | Age Group<br>(Years) | Pretest Probability of<br>HF (Prevalence of HF<br>in Study) (n/N) | Access NT-<br>proBNP Test<br>Result<br>Interpretation | Estimate<br>(%) | 95% CI *<br>(%) | Estimate<br>(%) | 95% CI*<br>(%) | Likelihood<br>Ratio Positive<br>(HF) | 95% CI** |
| 50 -75 | Positive | 380 | 105 | 485 | < 50 years | 35.3%<br>(310/879) | Positive | 68.7%<br>(279/406) | (64.1-73.0%) | - | - | 4.03 | (3.44, 4.72) |
| | Grey Zone | 47 | 96 | 143 | | | Grey Zone | 32.4% (12/37) | (19.6-48.5%) | 67.6% (25/37) | (51.5-80.4%) | 0.88 | (0.45, 1.73) |
| | Negative | 19 | 268 | 287 | | | Negative | - | - | 95.6%<br>(417/436) | (93.3-97.2%) | 0.08 | (0.05, 0.13) |
| | Total | 446 | 469 | 915 | 50-75<br>years | 48.7%<br>(446/915) | Positive | 78.4%<br>(380/485) | (74.5-81.8%) | - | - | 3.81 | (3.20, 4.52) |
| > 75 | Positive | 240 | 94 | 334 | | | Grey Zone | 32.9%<br>(47/143) | (25.7-40.9%) | 67.1%<br>(96/143) | (59.1-74.3%) | 0.51 | (0.37, 0.71) |
| | Grey Zone | 59 | 132 | 191 | | | Negative | - | - | 93.4%<br>(268/287) | (89.9-95.7%) | 0.07 | (0.05, 0.11) |
| | Negative | 4 | 61 | 65 | >75 years | 51.4%<br>(303/590) | Positive | 71.9%<br>(240/334) | (66.8-76.4%) | - | - | 2.42 | (2.03, 2.88) |
| | Total | 303 | 287 | 590 | | | Grey Zone | 30.9%<br>(59/191) | (24.8-37.8%) | 69.1%<br>(132/191) | (62.2-75.2%) | 0.42 | (0.33, 0.55) |
| All | Positive | 899 | 326 | 1225 | | | Negative | - | - | 93.8% (61/65) | (85.2-97.6%) | 0.06 | (0.02, 0.16) |
| | Grey Zone | 118 | 253 | 371 | All<br>Subjects | 44.4% (1059/2384) | Positive | 73.4%<br>(899/1225) | (70.8-75.8%) | - | - | 3.45 | (3.13, 3.80) |
| | Negative | 42 | 746 | 788 | | | Grey Zone | 31.8%<br>(118/371) | (27.3-36.7%) | 68.2%<br>(253/371) | (63.3-72.7%) | 0.58 | (0.48, 0.71) |
| | Total | 1059 | 1325 | 2384 | | | Negative | - | - | 94.7%<br>(746/788) | (92.9-96.0%) | 0.07 | (0.05, 0.09) |

The pretest probability of acute heart failure (prevalence of heart failure in the subject adjudicated diagnosis), posttest probabilities, likelihood ratios and the two-tailed 95% confidence interval of the Access NT-proBNP test result were determined across the age groups using the age-independent rule-out (300 ng/L) cutoffs and agedependent rule-in (450 ng/L for subjects <50 years old; 900 ng/L for subjects 50-75 years old; 1800 ng/L for subjects >75 years old). Table 10 displays data for all subjects by age group.

{20}------------------------------------------------

Table 10: Access NT-proBNP of all subjects (LiHep samples)

*Wilson Score confidence intervals **log method confidence intervals

{21}------------------------------------------------

Sensitivity and specificity are also calculated and plotted in separate receiver operation curves (ROC) for both an overall age-independent analysis and individual age-dependent groups separately. Area under the curve (AUC) is also reported with 95% 2-sided confidence intervals. The ROC results for the Rule-Out sensitivity and 1-specificity data are provided in Table 12.

| Age Group | Area Under the Curve | Standard Error | Lower 95% CI | Upper 95% CI |
|-------------------------|----------------------|----------------|--------------|--------------|
| All Subjects (Rule-Out) | 0.8692 | 0.00729 | 0.8549 | 0.8835 |
| < 50 years (Rule-In) | 0.8919 | 0.0115 | 0.8694 | 0.9143 |
| 50-75 years (Rule-In) | 0.8802 | 0.0113 | 0.8581 | 0.9024 |
| > 75 years (Rule-In) | 0.8122 | 0.0175 | 0.7779 | 0.8465 |

Table 11: The Area Under the Curve (AUC) for Rule-Out and Rule-In cutoffs with Upper / Lower Cls

{22}------------------------------------------------

Image /page/22/Picture/0 description: The image shows the logo for Beckman Coulter. The logo consists of a red oval shape with two white curved lines inside, placed to the left of the company name. The text "BECKMAN" is written in bold, sans-serif font above the text "COULTER", which is also in bold, sans-serif font.

### Access NT-proBNP Correlation to New York Heart Association (NYHA) functional classification in patients diagnosed with acute HF

There was an even distribution of classifications across the 1043 subject group adjudicated to acute HF with a clinical ED site NYHA evaluation and represents the accurate performance estimates for this claim. The population consisted of 450/1043 (43.14%) females and 593/1043 (56.86%) males. The descriptive statistics for the Access NT-proBNP results (ng/L) were determined across gender and are summarized in Table 12.

The JT test of trending was conducted on the 1043 all-subject group, resulting in a Z statistic of 4.1991 and a one-sided p-value <0.0001 indicating a significant trend relationship between NT-proBNP values and NYHA classification.

The JT test of trending was conducted on the 450 Female sub-group, resulting in a Z statistic of 3.2729 and a one-sided p-value 0.0005, indicating significant trend relationship between NT-proBNP values and NYHA classification.

The JT test of trending was conducted on the 593 Male sub-group, resulting in a Z statistic of 2.7120 and one-sided p-value 0.0033 indicating significant trend relationship between NT-proBNP value and NT-proBNP values and NYHA classification.

| Clinical ED Site NYHA Evaluation | | | | | | | | | |
|----------------------------------|------------------------|--------|---------|----------|---------|--------|--|--|--|
| Group | Statistics | NYHA I | NYHA II | NYHA III | NYHA IV | All HF | | | |
| All Subjects | N | 91 | 271 | 485 | 196 | 1043 | | | |
| | Mean (ng/L) | 3485 | 4718 | 5656 | 6460 | 5374 | | | |
| | SD (ng/L) | 3499 | 4539 | 5939 | 6087 | 5513 | | | |
| | Median (ng/L) | 2350 | 3547 | 3717 | 5073 | 3773 | | | |
| | 5th Percentile (ng/L) | 425 | 345 | 382 | 185 | 360 | | | |
| | 95th Percentile (ng/L) | 11643 | 13291 | 18446 | 18290 | 16302 | | | |
| Female | N | 37 | 112 | 213 | 88 | 450 | | | |

Table 12: Descriptive statistics of the clinical enrollment ED site NYHA classification in the subjects adjudicated as acute Heart Failure

{23}------------------------------------------------

| Clinical ED Site NYHA Evaluation | | | | | | |
|----------------------------------|------------------------|--------|---------|----------|---------|--------|
| Group | Statistics | NYHA I | NYHA II | NYHA III | NYHA IV | All HF |
| | Mean (ng/L) | 2282 | 4659 | 5297 | 7206 | 5264 |
| | SD (ng/L) | 1857 | 4465 | 5987 | 7144 | 5795 |
| | Median (ng/L) | 1546 | 3698 | 3173 | 4533 | 3342 |
| | 5th Percentile (ng/L) | 343 | 294 | 291 | 150 | 272 |
| | 95th Percentile (ng/L) | 7384 | 12706 | 17152 | 26226 | 16481 |
| Male | N | 54 | 159 | 272 | 108 | 593 |
| | Mean (ng/L) | 4309 | 4761 | 5938 | 5852 | 5458 |
| | SD (ng/L) | 4093 | 4604 | 5896 | 5020 | 5293 |
| | Median (ng/L) | 2948 | 3422 | 4173 | 5149 | 4044 |
| | 5th Percentile (ng/L) | 425 | 432 | 606 | 379 | 443 |
| | 95th Percentile (ng/L) | 12527 | 13402 | 20869 | 14584 | 16047 |

Note: A lesser N is observed in this table compared to the clinical performance data tables since only results based on measured responses within the assay analytical measuring range are used to generate descriptive statistics tables.

### Comparison to Other Commercially Available NT-proBNP Assays

Samples from the prospective multicenter study were also run on the Elecsys proBNP II assay (Roche Diagnostics) and Receiver Operating Characteristic (ROC) curves were generated for each assay, which are presented in the figure below. Area under the curve (AUC) for Access NT-proBNP was 0.8536 (95% Cl: 0.8362 - 0.8710), demonstrating comparable diagnostic accuracy to the Roche Elecsys proBNP II assay [0.8562 (95% C1: 0.8361 - 0.8762)].

{24}------------------------------------------------

Image /page/24/Figure/0 description: This image is a plot of sensitivity vs 1-specificity. The plot shows three curves: Access NT-proBNP, Elecsys proBNP II, and Baseline. The AUC for Access NT-proBNP is 0.8536 (0.8362 - 0.8710), and the AUC for Elecsys proBNP II is 0.8562 (0.8361 - 0.8762).

Figure 1: ROC Curves for Beckman Coulter Access NT-proBNP and Roche Elecsys proBNP II

{25}------------------------------------------------

### Risk Stratification of Patients with Heart Failure and Acute Coronary Syndrome

An objective and systematic analysis of recent peer-reviewed literature and clinical practice quidelines was conducted to verify clinical performance supporting use of NTproBNP for risk stratification. Prognostic utility was assessed in the following patient groups:

- Patients with heart failure
- · Patients with Acute Coronary Syndrome

Based on peer-reviewed scientific papers, guidelines for an assay measuring the same…