ADVIA CENTAUR B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAY

K031038 · Bayer Healthcare, LLC · NBC · Jun 23, 2003 · Clinical Chemistry

Device Facts

• Record ID: K031038
• Device Name: ADVIA CENTAUR B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAY
• Applicant: Bayer Healthcare, LLC
• Product Code: NBC · Clinical Chemistry
• Decision Date: Jun 23, 2003
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Intended Use

The Bayer ADVIA® Centaur® BNP assay is an in vitro immunoassay for the quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma using the ADVIA® Centaur® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis of heart failure.

Device Story

ADVIA Centaur BNP assay is a fully automated two-site sandwich immunoassay; utilizes direct chemiluminescent technology. Input: human plasma sample (EDTA anticoagulant). Process: sample incubated with acridinium ester-labeled monoclonal mouse anti-human BNP antibody (Lite Reagent); biotinylated monoclonal mouse anti-human antibody (Solid Phase) added; immuno-complex formed; unbound conjugates washed away. Output: chemiluminescence signal measured in luminometer; relative light units (RLUs) proportional to BNP concentration. Used in clinical laboratory settings; operated by trained laboratory personnel. Output used by physicians to aid in heart failure diagnosis; results interpreted alongside medical history and clinical evaluation. Benefits: provides quantitative BNP measurement to assist clinical decision-making.

Clinical Evidence

Clinical study at 2 sites with 187 subjects (167 heart failure, 20 non-heart failure). Compared ADVIA Centaur BNP to predicate device at 100 pg/mL threshold. Analytical agreement: 94.7% (95% CI: 90.4-97.4%). Clinical sensitivity: 87.4% (95% CI: 81.4-92.0%); specificity: 85.0% (95% CI: 62.1-96.8%).

Technological Characteristics

Two-site sandwich immunoassay; chemiluminescence detection. Reagents: acridinium ester-labeled monoclonal mouse anti-human BNP F(ab')2 fragment; biotinylated monoclonal mouse anti-human antibody coupled to streptavidin magnetic particles. Automated, random-access analyzer (ADVIA Centaur System). Measuring range: <2.0 - 5000 pg/mL. Sample type: EDTA plasma. Connectivity: standalone analyzer.

Indications for Use

Indicated for quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma as an aid in the diagnosis of heart failure. For prescription use only.

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

• Triage BNP Test (K003475/K010266)

Submission Summary (Full Text)

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# Bayer Diagnostics ADVIA Centaur BNP Assay

# Summary of Safety and Effectiveness

This Summary of Safety and Effectiveness has been prepared in accordance with the requirements of 21 CFR 807.92, to provide sufficient information to understand the basis for a determination of substantial equivalence.

| 1. Submitter Information | |
|--------------------------|------------------------------------------------------------------------------|
| Contact Person: | Kenneth T. Edds, Ph.D. |
| Address: | Bayer Diagnostics Corporation<br>511 Benedict Ave.<br>Tarrytown, N.Y. 10591 |
| | Phone: [phone]<br>Fax: [phone]<br>e-mail: [e-mail] |
| Date Summary Prepared: | March 28, 2003 |

## 2. Device Information

| Propriety Name: | ADVIA Centaur® B-Type Natriuretic Peptide (BNP) Assay |
|----------------------|-------------------------------------------------------|
| Common Name: | BNP assay |
| Classification Name: | B-type natriuretic peptide test system |
| Class: | II |
| CFR: | 21 CFR 862.1117 |
| Product Code: | NBC, JIT, JJX |

## 3. Predicate Device Information

| Name: | Triage BNP Test |
|------------------|----------------------------------|
| Manufacturer: | |
| Manufactured by: | Biosite Diagnostics Incorporated |
| | 11030 Roselle Street |
| | San Diego, California 92121, USA |
| 510(k) Number: | K003475/K010266 |

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## 4. Device Description

The ADVIA® Centaur® BNP assay is a fully automated two-site sandwich immunoassay using direct chemiluminescent technology, which uses constant amounts of two monoclonal antibodies. The first antibody, in the Lite Reagent, is an acridinium ester labeled monoclonal mouse anti-human BNP F(ab')> fragment specific to the ring structure of BNP. The second antibody, in the Solid Phase, is a biotinylated monoclonal mouse anti-human antibody specific to the C-terminal portion of BNP, which is coupled to streptavidin magnetic particles. Patient sample (calibrator or control materials) is incubated for 5 minutes at 37°C with the Lite Reagent that contains the tracer antibody conjugate. Subsequently, Solid Phase reagent is added and incubated for 2.5 minutes at 37°C. An immuno-complex is formed between the BNP in the sample and the two antibody conjugates. Following incubation, the unbound antibody conjugates are washed away. The chemiluminescence of the immuno-complex signal is measured in a luminometer. Samples with low BNP levels will have a minimum amount of bound AE label, while samples with high levels of BNP will have maximum label complex bound. Thus, a direct relationship exists between the amount of BNP present in the patient sample and the amount of relative light units (RLUs) detected by the system.

## 5. Statement of Intended Use

The Bayer ADVIA® Centaur® BNP assay is an in vitro immunoassay for the quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma using the ADVIA® Centaur® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis of heart failure.

## 6. Substantial Equivalence

The Bayer ADVIA Centaur BNP assay is substantially equivalent to other devices legally marketed in the United States. The ADVIA Centaur BNP assay is similar to the Biosite Triage BNP predicate device cleared under K010266. Both products are two-site immunoassays, which are intended for use in the quantitative determination of the B-type Natriuretic Peptide.

## (a) Technological Characteristics

The following table compares the technology features of the Bayer ADVIA Centaur BNP assay with the Biosite Triage BNP predicate device:

| Feature | Bayer ADVIA Centaur® BNP<br>Immunoassay | Biosite Triage® BNP Test<br>(Predicate Device) |
|------------------------------|-------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| Intended Use | Quantitative determination of B-<br>type Natriuretic Peptide | Measurement of B-type<br>Natriuretic Peptide |
| Indication for Use | An aid in the diagnosis of heart<br>failure. | An aid in the diagnosis of<br>congestive heart failure. |
| Assay Principle | Chemiluminescence<br>immunoassay | Fluorescence immunoassay |
| Traceability/Standardization | • Reference standard - synthetic<br>human BNP (amino acid 77 to<br>108) in buffer based matrix. | Purified protein preparation of<br>BNP based on the mass<br>(concentration) of analyte<br>present in EDTA plasma. |

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| Feature | Bayer ADVIA Centaur® BNP<br>Immunoassay | Biosite Triage® BNP Test<br>(Predicate Device) |
|----------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| Calibration Interval | • After 28 days when using the<br>same reagent lot<br>• With every new primary<br>reagent lot | Each kit |
| Sample Type | Human plasma using EDTA as<br>anticoagulant | Human whole blood and plasma<br>using EDTA as anticoagulant |
| Sample Volume | 100 µL | ~200 µL |
| Calibrator | BNP Calibrator set (2 levels) | Electronic code chip |
| Controls | BNP 1,2,3 Quality Control set | Triage® BNP Controls |
| Reagent Stability | Unopened<br>• Until the expiration date when<br>stored at 2-8°C<br>Onboard<br>• 41.6 days (or 60 days with the<br>use of version 3.0 software or<br>higher) | • Until the expiration date when<br>stored at 2-8°C<br>• 14 days at room temperature |
| Instrument | ADVIA Centaur System, a fully<br>automated, random-access<br>immunoassay analyzer | Triage® Meter |
| Measuring Range | <2.0 - 5000 pg/mL | 5 - 5000 pg/mL |

# (b) Performance Characteristics

The following table compares the performance characteristics of the Bayer ADVIA Centaur BNP assay with the Biosite Triage BNP predicate device:

| Feature | Bayer ADVIA Centaur® BNP<br>Immunoassay | Biosite Triage® BNP Test<br>(Predicate Device) |
|---------------------------------|----------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Expected Values | Age and gender-matched descriptive statistics provided Decision threshold of 100 pg/mL recommended | Age and gender-matched descriptive statistics provided Decision threshold of 100 pg/mL recommended |
| Precision | Within-run 1.8 - 4.3 %CV from 29.4 - 1736.0 pg/mL Total 2.3 - 4.7 %CV from 29.4 - 1736.0 pg/mL | Average within-day 9.4 - 15.2 %CV from 28.8 - 1080.4 pg/mL Average total 10.1 - 16.2 % CV from 28.8 - 1080.4 pg/mL |
| Hook Effect | No high dose effect up to 100,000 pg/mL | N/A |
| Analytical Sensitivity | <2 pg/mL | 5 pg/mL |
| Dilution Recovery | On-board dilution 1:2, 1:5 and 1:10 with average recovery of 97%. | No sample dilution. For patient samples with BNP levels higher than the measurable range of the Triage BNP Test (>5000 pg/mL), the test should be interpreted as having a positive result because the BNP concentration is significantly elevated. |
| Limitations/Warning/Precautions | This test has been evaluated with plasma using EDTA as the anticoagulant. Serum, | This test has been evaluated with whole blood and plasma using EDTA as the |

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| Feature | Bayer ADVIA Centaur® BNP<br>Immunoassay | Biosite Triage® BNP Test<br>(Predicate Device) |
|---------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | sodium citrate, lithium heparin<br>and sodium fluoride sample<br>tubes have also been tested<br>and are not recommended.<br>• No interference from<br>hemoglobin up to 1000 mg/dL<br>• No interference from<br>triglycerides up to 800 mg/dL<br>• No interference from<br>cholesterol up to 1000 mg/dL<br>• No interference from urea up<br>to 200 mg/dL<br>• No interference from<br>creatinine up to 2.5 mg/dL<br>• No interference from<br>unconjugated bilirubin up to<br>25 mg/dL<br>• No interference from<br>conjugated bilirubin up to<br>25 mg/dL<br>• No interference from human<br>IgG up to 5.3 g/dL<br>• No interference from 55<br>commonly used<br>pharmaceutical drugs.<br>• Results should always be<br>assessed in conjunction with<br>the patient's medical history,<br>clinical evaluation and other<br>diagnostic procedures. | anticoagulant. Serum and<br>blood or plasma specimens<br>obtained using other<br>anticoagulants (e.g. heparin<br>or citrate) have not been<br>evaluated and should not be<br>used.<br>• No interference from<br>hemoglobin up to<br>10000 mg/dL<br>• Severely hemolyzed<br>specimens should be avoided<br>• No interference from<br>triglycerides up to 1000 mg/dL<br>• No interference from<br>cholesterol up to 1000 mg/dL<br>• No interference from bilirubin<br>up to 20 mg/dL<br>• No interference from 55<br>commonly used<br>pharmaceutical drugs.<br>• Results should be evaluated<br>in the context of all the clinical<br>and laboratory data available. |

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# (c) Analytical Comparison and Clinical Agreement

A paired comparison was performed at 2 clinical trial sites to assess the relationship of the ADVIA Centaur BNP assay to the predicate device. A total of 167 patients with heart failure (HF; clinical diagnoses of Class I – IV) and 20 individuals without heart failure (non-HF) were compared for both analytical and clinical agreement at a decision threshold of 100 pg/mL.

#### Analytical Comparison - ADVIA Centaur vs. Predicate Device

| | Predicate Device | | | |
|---------|------------------|-------------|-------|-----|
| | ≥ 100 pg/mL | < 100 pg/mL | Total | |
| Centaur | ≥ 100 pg/mL | 145 | 4 | 149 |
| | < 100 pg/mL | 6 | 32 | 38 |
| | Total | 151 | 36 | 187 |

| | Estimate | 95% Confidence Interval |
|------------------------|------------------|-------------------------|
| % Analytical Agreement | 94.7 % (177/187) | 90.4% to 97.4% |

#### Clinical Agreement - ADVIA Centaur BNP

| | Clinical Status | | | |
|---------|-----------------|-----|--------|-------|
| | | HF | Non-HF | Total |
| Centaur | ≥ 100 pg/mL | 146 | 3 | 149 |
| | < 100 pg/mL | 21 | 17 | 38 |
| | Total | 167 | 20 | 187 |

| | Estimate | 95% Confidence Interval |
|----------------------|-----------------|-------------------------|
| % Clinical Agreement | 87.2% (163/187) | 81.5% to 91.6% |
| % Sensitivity | 87.4% (146/167) | 81.4% to 92.0% |
| % Specificity | 85.0% (17/20) | 62.1% to 96.8% |

#### Clinical Agreement - Predicate Device

| | Clinical Status | | | |
|---------------------|-----------------|-----|--------|-------|
| | | HF | Non-HF | Total |
| Predicate<br>Device | ≥ 100 pg/mL | 146 | 5 | 151 |
| | < 100 pg/mL | 21 | 15 | 36 |
| | Total | 167 | 20 | 187 |

| | Estimate | 95% Confidence Interval |
|----------------------|-----------------|-------------------------|
| % Clinical Agreement | 86.1% (161/187) | 80.3% to 90.7% |
| % Sensitivity | 87.4% (146/167) | 81.4% to 92.0% |
| % Specificity | 75.0% (15/20) | 50.9% to 91.3% |

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Image /page/5/Picture/1 description: The image is a black and white logo for the U.S. Department of Health & Human Services. The logo features a stylized image of an eagle with three lines forming its wings and head. The words "DEPARTMENT FOR HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

JUN 2 3 2003

Kenneth T. Edds, Ph.D. Manager, Regulatory Affairs Bayer HealthCare LLC Diagnostics Division 511 Benedict Avenue Tarrytown, NY 10591-5097

Re: k031038

Trade/Device Name: Bayer Diagnostics ADVIA® Centaur® BNP Assay Regulation Number: 21 CFR 862.1117 Regulation Name: B-type natriuretic peptide test systems Regulatory Class: Class II Product Code: NBC; JIT; JJX Dated: March 31, 2003 Received: April 4, 2003

Dear Dr. Edds:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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#### Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at [phone]. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number [phone] or [phone] or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.

Sincerely yours,

Steven Sutman

Steven I. Gutman, M.D., M.B.A. Director Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Page

Ko31038 510(k) Number (if known):

Device Name: Bayer Diagnostics ADVIA® Centaur® BNP Assay

Indications for Use:

For in vitro diagnostic use in the quantitative determination of Btype Natriuretic Peptide (BNP) in human plasma using the ADVIA Centaur® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis of heart failure. This assay is not intended for use on any other system.

Dean Cooper

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K031038

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Image /page/7/Figure/9 description: The image shows a form titled "Concurrence of CDRH, Office of Device Evaluation (ODE)". The form has two options: "Prescription Use (Per 21 CFR 801.109)" and "Over-The-Counter Use (Optional Format 1-2-96)". An arrow points to the "Prescription Use" option, indicating that it has been selected.